(S)-N-Phenyl-1-(pyridin-2-yl)pyrrolidine-2-carboxamide derivatives

Abstract

The present invention relates to a (S)-N-phenyl-1-(pyridin-2-yl)pyrrolidine-2-carboxamide derivative and its use in the treatment and / or prevention of cancer, as well as a composition containing the derivative and a preparation method.

Description

Technical Field

[0001] The present invention relates to an (S)-N-phenyl-1-(pyridin-2-yl)pyrrolidine-2-carboxamide derivative and its use in the treatment and prevention of cancer, as well as a composition containing the derivative and a preparation method thereof. Background Art

[0002] Cancer remains the number one killer of human health. According to statistics from the US NIH, in 2012, the number of new cases globally was 14.1 million, and the number of cancer-related deaths was 8.2 million. In 2018 alone, the number of new cancer cases exceeded 1.7 million person-times. By 2030, it is expected that the number of newly diagnosed cancer cases per year will increase to 23.6 million. In recent years, the benefits of anti-tumor drugs have been increasing. In 2017, the global cancer treatment cost exceeded $133 billion, an increase of nearly $96 billion compared to 2013. Some studies claim that in the next five years, the R & D funds in this field can reach $180 - $200 billion, with a 5-year compound growth rate of 10% - 13%. In the past 5 years, 63 anti-tumor drugs have been approved, covering 24 different tumor types. In 2017, 14 drugs were approved for marketing, among which 11 drugs were granted breakthrough therapy status by the US FDA, and the overall response rate of this group of drugs exceeded 50%, significantly improving the survival rate of patients and their quality of life. The development of cancer cells is driven by genomic instability and depends on the misregulation or inhibition of the tumor with DNA damage response (DDR). However, excessive DNA damage is incompatible with life. Therefore, reducing the DNA repair ability of cancer cells will also lead to an increased dependence on the remaining survival process. Thus, cancer cells with DDR defects are vulnerable to targeted DNA repair inhibitors. We can utilize this feature to develop novel specific DNA repair enzyme inhibitors, which can be used as a single therapy or in combination with other drugs in a predictable, identifiable population of tumors with DDR defects.

[0003] DNA repair defects have emerged as an effective anti-cancer strategy. Over the past few decades, it has become increasingly evident that selective deficiencies in DNA repair pathways occur in 40% to 50% of a variety of tumors. Deficiencies in DNA repair promote tumor cell proliferation, leading to genetic instability and / or increased mutation rates, driving tumor evolution. Cancers with DNA repair defects often rely on backup DNA repair pathways, which have been targeted and successfully developed poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BRCA-deficient breast and ovarian cancers. However, the need for new treatment methods that exploit other DNA repair defects remains urgent to overcome acquired and congenital resistance to PARP inhibitors (PARPi). DNA polymerase theta (POLQ) is involved in DNA repair and not only synergizes with PARP inhibitors but also has broader uses in cancer treatment. An important reason for POLQ to become a major focus of drug development is that it is essentially not expressed in normal cells but is upregulated in many cancers, whether or not accompanied by homologous recombination deficiency (HRD).

[0004] POLQ is a key component of the POLQalt-EJ pathway, also known as microhomology-mediated end joining (MMEJ) pathway, which is involved in DNA double-strand break repair. MMEJ can operate in parallel to the HR and NHEJ pathways (Truong et al., PNAS 2003, 110(19), 7720-7725). POLQ is expressed at low levels in normal tissues but is upregulated in many tumor types. POLQ inhibitors have the potential to be used in a wide range of clinical settings, especially in HR-deficient tumors such as breast cancer. Mechanistically, they can also be combined with PARP1 inhibitors to expand the indications.

[0005] POLQ overexpression has been observed in a large number of cancers, and the upregulated levels are associated with poor prognosis. For example, approximately 70% of breast cancers show 5-fold or more POLQ overexpression, and this overexpression is observed in both HR-proficient and HR-deficient breast cancers. In addition, POLQ is highly expressed in cancer cells and confers resistance to ionizing radiation and chemotherapeutic drugs. The abnormal expression of POLQ also promotes the survival of homologous recombination-deficient cells, a feature commonly observed in cells with BRCA1 or BRCA2 gene mutations. Therefore, POLQ is considered a promising new cancer target, and novel POLQ inhibitors will become part of new anti-cancer therapies. Summary of the Invention

[0006] The object of the present invention is to provide a compound represented by formula (I-A), its preparation method, and its use in the prevention and / or treatment of diseases mediated by POLQ.

[0007] In one aspect, the present invention relates to a compound represented by formula (I-A), and its stereoisomers, geometric isomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts:

[0008]

[0009] n1 is 0, 1 or 2; for example, n1 is 0 or 1;

[0010] Each occurrence of R1 is independently deuterium, tritium, -OH or -CH2-R 11 , where R 11 is C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or hydroxy C 1-6 alkyl; when n1 = 2, each R1 can be the same or different; for example, R1 is independently -OH;

[0011] n2 is 1 or 2; for example, n2 is 1;

[0012] Each occurrence of R2 is independently deuterium, tritium, -(C 0-5 alkyl)C(-NH2)(=N-OH), R h -SO2-, R h -SO2NH-, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-8 membered heteroaryl, -C(O)-NR b -SO2-R a , -C(O)-OR a , -C(O)-O(CH2) w -O-C(O)-R a , -C(O)-R a , -C(O)-NR b R c , -C(O)-NR b -(CH2) w -C(O)R a , -C(O)-NR b -(CH2) w -C(O)NR b R c , -NR b -C(O)-R a1 , -NR b -C(O)-NR b R c , -(CR d R e ) w -C(O)-NR b R c , -(CRd R e ) w -NR b -SO2R a 、-NHR f 、OH (provided that n2 is 2 and one of R2 is -C(O)-NR b -SO2-R a 、-C(O)-OR a 、-C(O)-R a 、-C(O)-NR b R c 、-C(O)-NR b -(CH2) w -C(O)R a 、or -C(O)-NR b -(CH2) w -C(O)NR b R c )、halogen (provided that n2 is 2 and one of R2 is -C(O)-NR b -SO2-R a 、-C(O)-OR a 、-C(O)-R a 、-C(O)-NR b R c 、-C(O)-NR b -(CH2) w -C(O)R a 、-C(O)-NR b -(CH2) w -C(O)NR b R c )、-CH3 (provided that n2 is 2 and one of R2 is -C(O)-NR b -SO2-R a 、-C(O)-OR a 、-C(O)-R a 、-C(O)-NR b R c 、-C(O)-NR b -(CH2) w -C(O)R a 、or -C(O)-NR b -(CH2) w -C(O)NR b R c )、-(C 1-6 alkyl)-C(O)-NR b R c 、-(C 1-6 alkyl)-NRb R c 、 -(C 1-6 alkyl)-OR a 、 -C(O)-(CH2) w -O-C(O)-R a or -C(O)-NR b -(CH2) w -O-(CH2) w -O-(CH2) w -NR b R c wherein the alkenyl, alkynyl, and heteroaryl may be substituted by cyano, R a 、 or -(CH2) w R a ;

[0013] Preferably, each occurrence of R2 is independently deuterium, tritium, (HO-N=)(NH2-)(C 1-5 alkyl)-, R h -SO2-, R h -SO2NH-, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-8 membered heteroaryl, -C(O)-NR b -SO2-R a 、 -C(O)-OR a 、 -C(O)-R a 、 -C(O)-NR b R c 、 -C(O)-NR b -(CH2) w -C(O)R a 、 -C(O)-NR b -(CH2) w -C(O)NR b R c 、 -NR b -C(O)-R a1 、 -NR b -C(O)-NR b R c 、 -(CR d R e ) w -C(O)-NR b R c 、 -(CR d R e ) w -NR b -SO2R a 、 -NHR f, OH (provided that n2 is 2 and one of R2 is -C(O)-NR b -SO2-R a , -C(O)-OR a , -C(O)-R a , -C(O)-NR b R c , -C(O)-NR b -(CH2) w -C(O)R a , or -C(O)-NR b -(CH2) w -C(O)NR b R c ), or halogen (provided that n2 is 2 and one of R2 is -C(O)-NR b -SO2-R a , -C(O)-OR a , -C(O)-R a , -C(O)-NR b R c , -C(O)-NR b -(CH2) w -C(O)R a , or -C(O)-NR b -(CH2) w -C(O)NR b R c ), wherein the alkenyl, alkynyl, and heteroaryl may be substituted by cyano, R a , or -(CH2) w R a ;

[0014] When n2 = 2, each R2 may be the same or different;

[0015] R a is independently of each other, at each occurrence, hydrogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered heteroaryl or 6-12 membered aryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl may be substituted by one or more substituents selected from halogen, hydroxy, mercapto, oxo, sulfone, -NR b R c , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, hydroxyC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkylthio, -C(O)C 1-3 alkyl, -C(O)C1-3 substituted by substituents of an alkoxy group and a 3- to 8-membered heterocyclic group; for example, R a is independently, each time it appears, hydrogen, C 1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, or 5- to 8-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, and heteroaryl may be substituted by one or more selected from halogen, hydroxy, mercapto, oxo, sulfone, -NR b R c 、C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, hydroxy C 1-3 alkyl, halo C 1-3 alkyl, halo C 1-3 alkylthio, -C(O)C 1-3 alkyl, -C(O)C 1-3 alkoxy, and substituents of a 3- to 8-membered heterocyclic group; for example, R a is independently, each time it appears, hydrogen, C 1-3 alkyl, 3- to 8-membered heterocyclic group, or 5- to 6-membered heteroaryl, wherein the alkyl, heterocyclic group, and heteroaryl may be substituted by one or more selected from halogen, hydroxy, -NR b R c 、C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, halo C 1-3 alkyl, halo C 1-3 alkylthio, -C(O)C 1-3 alkyl, and -C(O)C 1-3 alkoxy; further, for example, R a is independently, each time it appears, hydrogen, methyl, ethyl, propyl, 4- to 8-membered heterocyclic group, or 5- to 6-membered heteroaryl, and the methyl, ethyl, propyl, heterocyclic group, and heteroaryl may be substituted by one or more selected from halogen, hydroxy, -NR b R c 、C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, halo C 1-3 alkyl, halo C 1-3 alkylthio, -C(O)C 1-3 alkyl, and -C(O)C 1-3 alkoxy;

[0016] R a1Each occurrence is independently hydrogen, a 3- to 8-membered cycloalkyl, a 3- to 8-membered heterocyclic group, or a 5- to 8-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, and heteroaryl may be substituted by one or more substituents selected from halogen, hydroxy, mercapto, oxo, sulfone, -NR b R c 、C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, hydroxyC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkylthio, -C(O)C 1-3 alkyl, -C(O)C 1-3 alkoxy, and substituents of 3- to 8-membered heterocyclic groups; for example, R a1 Each occurrence is independently hydrogen, a 3- to 8-membered heterocyclic group, or a 5- to 6-membered heteroaryl, wherein the heterocyclic group and heteroaryl may be substituted by one or more substituents selected from halogen, hydroxy, -NR b R c 、C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, haloC 1-3 alkyl, haloC 1-3 alkylthio, -C(O)C 1-3 alkyl, and -C(O)C 1-3 alkoxy; further, for example, R a1 Each occurrence is independently hydrogen, a 4- to 8-membered heterocyclic group, or a 5- to 6-membered heteroaryl, and the heterocyclic group and heteroaryl may be substituted by one or more substituents selected from halogen, hydroxy, -NR b R c 、C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, haloC 1-3 alkyl, haloC 1-3 alkylthio, -C(O)C 1-3 alkyl, and -C(O)C 1-3 alkoxy;

[0017] R b and R c Each occurrence is independently hydrogen, C 1-6 alkyl, a 3- to 8-membered cycloalkyl, a 3- to 8-membered heterocyclic group, or a 5- to 8-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, and heteroaryl may be substituted by one or more substituents selected from R a2 、halogen, hydroxy, mercapto, oxo, sulfone, bis(C 1-3 alkyl)amino, mono(C 1-3(alkyl)amino, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, hydroxy C 1-3 alkyl, halo C 1-3 alkyl, halo C 1-3 alkylthio, -C(O)C 1-3 alkyl, -C(O)C 1-3 alkoxy, and a substituent of a 3-8 membered heterocyclic group, cyano; for example, R b and R c are each independently, at each occurrence, hydrogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, or 5-8 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic group, and heteroaryl may be substituted with one or more substituents selected from R a2 , halogen, hydroxy, mercapto, oxo, sulfone, di(C 1-3 alkyl)amino, mono(C 1-3 alkyl)amino, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, hydroxy C 1-3 alkyl, halo C 1-3 alkyl, halo C 1-3 alkylthio, -C(O)C 1-3 alkyl, -C(O)C 1-3 alkoxy, and a substituent of a 3-8 membered heterocyclic group; for example, R b and R c are each independently, at each occurrence, hydrogen, C 1-3 alkyl, 3-6 membered cycloalkyl, or 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, and heteroaryl may be substituted with one or more substituents selected from R a2 , halogen, hydroxy, di(C 1-3 alkyl)amino, mono(C 1-3 alkyl)amino, amino, C 1-3 alkyl, C 1-3 alkoxy, hydroxy C 1-3 alkyl, halo C 1-3 alkyl, and a substituent of a 3-6 membered heterocyclic group; further, for example, R b and R c are each independently, at each occurrence, hydrogen, methyl, 3-6 membered cycloalkyl, or 5-6 membered heteroaryl, wherein said methyl, cycloalkyl, and heteroaryl may be substituted with one or more substituents selected from R a2 , halogen, hydroxy, di(C 1-3 alkyl)amino, mono(C 1-3 alkyl)amino, amino, C 1-3substituted by substituents of alkyl group and 3- to 6-membered heterocyclic group;

[0018] R a2 each independently, when occurring each time, is C 1-6 alkyl group, C 2-6 alkenyl group, or C 2-6 alkynyl group, which is optionally substituted by one or more substituents selected from halogen, hydroxy group, mercapto group, oxo group, sulfone group, di(C 1-3 alkyl)amino group, mono(C 1-3 alkyl)amino group, amino group, C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylthio group, hydroxy C 1-3 alkyl group, halo C 1-3 alkyl group, halo C 1-3 alkylthio group, -C(O)C 1-3 alkyl group, -C(O)C 1-3 alkoxy group, and substituents of 3- to 8-membered heterocyclic group; for example, R a2 each independently, when occurring each time, is C 1-6 alkyl group; further, for example, R a2 each independently, when occurring each time, is ethyl group or propyl group;

[0019] R d and R e each independently, when occurring each time, is hydrogen, hydroxy group, halogen, C 1-6 alkyl group, or halo C 1-6 alkyl group; for example, R d and R e each independently, when occurring each time, is hydrogen, hydroxy group, halogen, C 1-3 alkyl group, or halo C 1-3 alkyl group; further, for example, R d and R e each independently, when occurring each time, is hydrogen;

[0020] R f each independently, when occurring each time, is 5- to 12-membered heteroaryl group, and the heteroaryl group can be substituted by one or more substituents selected from halogen, hydroxy group, di(C 1-3 alkyl)amino group, mono(C 1-3 alkyl)amino group, amino group, mercapto group, sulfone group, R h -CONH-, R h -SO2-, C 1-3 alkyl group, C 1-3 alkoxy group, hydroxy C 1-3 alkyl group, halo C 1-3 alkyl group, and substituents of 3- to 8-membered heterocyclic group; for example, R fEach occurrence is independently a 5- to 8-membered heteroaryl, which heteroaryl may be substituted by one or more halogens, hydroxyl groups, amino groups, mercapto groups, amides, sulfonyl groups, sulfone groups, C 1-3 alkyl, C 1-3 alkoxy, hydroxy C 1-3 alkyl, halo C 1-3 alkyl, 3- to 8-membered heterocyclic groups; further, for example, R f Each occurrence is independently a 5- to 8-membered heteroaryl, which heteroaryl may be substituted by one or more halogens, hydroxyl groups, amino groups, mercapto groups, amides, sulfonyl groups, sulfone groups, C 1-3 alkyl, C 1-3 alkoxy, hydroxy C 1-3 alkyl, halo C 1-3 alkyl, 3- to 6-membered heterocyclic groups;

[0021] R h Each occurrence is independently a halogen, hydroxyl group, di(C 1-3 alkyl)amino, mono(C 1-3 alkyl)amino, amino group, mercapto group, C 1-3 alkyl, C 1-3 alkoxy, hydroxy C 1-3 alkyl, halo C 1-3 alkyl, 3- to 8-membered heterocyclic groups;

[0022] For example, (R2) n2 is

[0023]

[0024]

[0025] For example, (R2) n2 is

[0026]

[0027]

[0028] For example, (R2) n2 is

[0029] n3 is independently 0, 1, or 2 at each occurrence; for example, n3 is 0 or 1;

[0030] R3 is independently deuterium, tritium, halogen, oxo group, C 1-6 alkyl, C1-6 an alkoxy group or -CH2-R 13 , wherein R 13 is C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or hydroxy C 1-6 alkyl; or two R3s together with the same connected C atom form a cycloalkyl or heterocycloalkyl group; for example, R3 is, each time it appears, independently of the others, deuterium, tritium, halogen, oxo group, C 1-6 alkyl, or two R3s together with the same connected C atom form a cycloalkyl or heterocycloalkyl group; further, for example, R3 is, each time it appears, independently of the others, deuterium, tritium, halogen, oxo group, C 1-3 alkyl, or two R3s together with the same connected C atom form a cycloalkyl or heterocycloalkyl group;

[0031] When n3 = 2, each R3 can be the same or different;

[0032] or R2 and R3 are connected to form a 2-fused heterocycle with the pyrrolidine ring, for example

[0033] R4 is absent, or is, each time it appears, independently of the others, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halogen, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, cyano, or -NR b R c ; for example, R4 is absent, or is, each time it appears, independently of the others, halogen, methyl or cyano; further, for example, R4 is absent, or is, each time it appears, independently of the others, halogen, or cyano; still further, for example, R4 is absent, or is, each time it appears, independently of the others, cyano; still further, for example, R4 is absent;

[0034] R5 is absent, or is, each time it appears, independently of the others, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halogen, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, cyano, or -NR b R c ; for example, R5 is absent, or is, each time it appears, independently of the others, halogen, or C 1-6 alkyl; further, for example, R5 is absent, or is, each time it appears, independently of the others, halogen, methyl, ethyl or propyl; still further, for example, R5 is methyl;

[0035] m is, each time it appears, independently of one another, 0, 1, 2, 3, 4 or 5; for example, m is 1, 2 or 3; further, for example, m is 2 or 3; still further, for example, m is 2;

[0036] When m > 1, each R6 can be the same or different;

[0037] R6 is, each time it appears, independently of one another, halogen, hydroxy, amino, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, or halo C 1-3 alkoxy; for example, R6 is, each time it appears, independently of one another, halogen, C 1-3 alkyl, or halo C 1-3 alkyl; further, for example, R6 is, each time it appears, independently of one another, halogen, or methyl; for example, R6 is, each time it appears, independently of one another, fluorine, chlorine or methyl;

[0038] For example, is

[0039] w is, independently of one another, 1, 2 or 3; for example, w is 1 or 2; further, for example, w is 1;

[0040] R7 is absent, or is, each time it appears, independently of one another, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halogen, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, cyano, or -NR b R c ; for example, R7 is, each time it appears, independently of one another, halo C 1-6 alkyl; further, for example, R7 is, each time it appears, independently of one another, perhalogenated methyl; still further, for example, R7 is CF3;

[0041] R8 is absent, or is, each time it appears, independently of one another, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halogen, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, cyano, or -NR b R c ; for example, R8 is absent, or is, each time it appears, independently of one another, halogen, or C 1-6Alkyl; further, for example, R8 is absent, or is independently of each other at each occurrence halogen, or C 1-3 alkyl; still further, for example, R8 is absent;

[0042] R9 is absent, or is independently of each other at each occurrence C 1-6 alkyl, halo C 1-6 alkyl, or C 3-8 cycloalkyl; for example, R9 is methyl.

[0043] In a preferred embodiment of the present invention, the compound represented by formula (I-A), or its stereoisomers, geometric isomers, tautomers or mixtures thereof, medicinal salts, wherein the compound represented by formula (I-A) is selected from the following compounds:

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] The present invention also provides a pharmaceutical composition comprising the compound represented by formula (I-A) as shown in the present invention, or its stereoisomers, geometric isomers, tautomers or mixtures thereof, and pharmaceutically acceptable salts.

[0064] The present invention also provides a pharmaceutical composition comprising the compound represented by formula (I-A) as shown in the present invention, or its stereoisomers, geometric isomers, tautomers or mixtures thereof, and pharmaceutically acceptable salts, as well as pharmaceutically acceptable excipients and / or adjuvants.

[0065] The present invention also aims to provide the use of the compound represented by formula (I-A) as shown in the present invention, or its stereoisomers, geometric isomers, tautomers or mixtures thereof, and pharmaceutically acceptable salts in the preparation of a medicament for treating POLQ-mediated diseases.

[0066] In some embodiments, the POLQ-mediated diseases are cancer or cancer-related diseases, such as solid tumors, for example breast cancer.

[0067] The present invention also aims to provide a method for preventing and / or treating POLQ-mediated diseases, which comprises administering to a patient a therapeutically effective dose of the compound represented by general formula (I-A), or its stereoisomers, geometric isomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts, or the pharmaceutical composition of the present invention.

[0068] The compound represented by general formula (I-A) as shown in the present invention, or its stereoisomers, geometric isomers, tautomers or mixtures thereof, and pharmaceutically acceptable salts can be administered in combination with other anti-cancer agents or immune checkpoint inhibitors for treating cancer or tumors.

[0069] When the compound represented by general formula (I-A) as shown in the present invention, or its stereoisomers, geometric isomers, tautomers or mixtures thereof, and pharmaceutically acceptable salts are administered in combination with other anti-cancer agents or immune checkpoint inhibitors for treating cancer or tumors, enhanced anti-cancer effects can be provided.

[0070] The present invention has achieved one or more of the following beneficial effects:

[0071] (1) The present invention has designed a class of compounds with novel structures, providing a new direction for the development of drugs of the POLQ inhibitor type.

[0072] (2) In vitro enzyme activity inhibition studies have shown that these compounds have strong inhibitory effects on the POLQ enzyme and can be used as promising compounds for treating POLQ-mediated diseases.

[0073] (3) The present invention has studied a specific synthesis method, which has a simple process, convenient operation, and is conducive to large-scale industrial production and application. Specific implementation examples

[0074] Definition

[0075] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, including straight-chain or branched-chain groups containing 1 to 20 carbon atoms, such as those containing 1 to 10 carbon atoms (i.e., C 1-10 alkyl), those containing 1 to 8 carbon atoms (C 1-8 alkyl), or those containing 1 to 6 carbon atoms (i.e., C 1-6 alkyl). For example, "C 1-6 alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5, or 6). Examples of "alkyl" include but are not limited to methyl, ethyl, propyl, isopropyl, n-propyl, butyl, tert-butyl, isobutyl, n-butyl, sec-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 1-ethylpropyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, pentyl, neopentyl, n-pentyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2,2-trimethylpropyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1-methylpentyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1-ethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 2-ethylbutyl, 3,3-dimethylbutyl, 3-methylpentyl, 4-methylpentyl, hexyl, n-hexyl, n-heptyl, n-octyl, etc.

[0076] Unless otherwise specified, the term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl can contain 2 to 20 carbon atoms, such as those containing 2 to 10 carbon atoms (i.e., C 2-10 alkenyl), those containing 2 to 8 carbon atoms (C 2-8 alkenyl), those containing 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), 2 to 5 carbon atoms (i.e., C 2-5 alkenyl), 2 to 4 carbon atoms (i.e., C 2-4 alkenyl), 2 to 3 carbon atoms (i.e., C 2-3 alkenyl), 2 carbon atoms (i.e., C2 alkenyl). For example, "C 2-6 alkenyl" means that the group is an alkenyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl, etc.

[0077] Unless otherwise specified, the term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, for example, it may contain 2 to 10 carbon atoms (i.e., C 2-10 alkynyl), contain 2 to 8 carbon atoms (C 2-8 alkynyl), contain 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), 2 to 5 carbon atoms (i.e., C 2-5 alkynyl), 2 to 4 carbon atoms (i.e., C 2-4 alkynyl), 2 to 3 carbon atoms (i.e., C 2-3 alkynyl), 2 carbon atoms (i.e., C2 alkynyl). For example, "C 2-6 alkynyl" means that the group is an alkynyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl, etc.

[0078] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, for example, it may contain 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), contain 3 to 10 carbon atoms (C 3-10 cycloalkyl), 3 to 6 carbon atoms (C 3-6 cycloalkyl), 4 to 6 carbon atoms (C 4-6 cycloalkyl), 5 to 6 carbon atoms (C 5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0079] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, and the alkyl group is defined as above, that is, it contains 1 to 20 carbon atoms. For example, it may contain 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0080] Unless otherwise specified, the term "alkylthio" means replacing the oxygen in the above "alkoxy" with sulfur.

[0081] Unless otherwise specified, the term "halogen" or "halo" means F, Cl, Br, or I. The term "haloalkyl" means that one, two, or more hydrogen atoms or all hydrogen atoms in the alkyl group as defined above are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc.

[0082] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure, containing 3 to 20 ring atoms, wherein 1, 2, 3, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. The bicyclic or polycyclic "heterocyclic group" includes the case where one ring is an aromatic ring and the other rings are non-aromatic rings.

[0083] Unless otherwise specified, the term "aryl" means a monocyclic, bicyclic, and tricyclic aromatic carbocyclic system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. One or more of the rings may be a cycloalkyl group or a heterocycloalkyl group, provided that the point of attachment to the rest of the molecule is an aromatic ring atom. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, or pyrenyl, etc.

[0084] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic or polycyclic ring system having a structure of 5 to 16 members, preferably 5 to 14 members, 5 to 12 members, 5 to 10 members, 5 to 8 members, more preferably 5 to 6 members, in which one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon, and the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Bicyclic or polycyclic heterocyclic groups include fused ring heteroaryls. Examples of heteroaryls include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0085] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "(pharmaceutically) acceptable salt" refers to a salt that is suitable for contact with mammalian tissues, particularly human tissues, within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio. For example, pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0086] Unless otherwise specified, the compounds of the present invention also include their "isotope derivatives" (such as deuterated compounds). The term "isotope derivative" means that the compounds of the present invention can exist in an isotopically labeled or enriched form, containing one or more atoms whose atomic weight or mass number is different from that of the atoms found in the largest amount in nature. The isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used for isotope labeling are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotope: 18 F; iodine isotopes: 123 I and 125I; Nitrogen Isotopes: 13 N and 15 N; Oxygen Isotopes: 15 O, 17 O and 18 O and Sulfur Isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. The substitution of certain heavy isotopes, such as deuterium ( 2 H), can enhance metabolic stability, extend the half-life, and thus achieve the purpose of reducing the dose and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques in the same way as non-isotope-labeled compounds.

[0087] Unless otherwise specified, the compounds of the present invention also include their "solvates (or solvated compounds)". The terms "solvate" and "solvated compound" mean the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate can exist in an ordered or disordered arrangement. Solvates can contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both the solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0088] Unless otherwise specified, the compounds of the present invention also include their "hydrates". The term "hydrate" refers to a substance formed when water molecules are bound to cations or anions in a compound by coordination bonds or covalent bonds, or when water molecules do not directly bind to cations or anions but are present in a definite position in the solid lattice in a certain proportion.

[0089] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc. Any mixture of the resulting stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers based on the differences in the physical and chemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0090] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons.

[0091] Unless otherwise specified, the term "geometric isomer" means that when a double bond is present in a compound, the compound can exist as cis isomers, trans isomers, E isomers, and Z isomers. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.

[0092] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric (or conformational) isomers): for example, the R and S configurations containing an asymmetric center, the (Z) and (E) isomers of a double bond, and the (Z) and (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention, or mixtures of their enantiomers, diastereomers, or geometric (or conformational) isomers are within the scope of the present invention.

[0093] Unless otherwise specified, the compounds of the present invention also include their "prodrugs", the term "prodrug" referring to a drug that is converted in vivo to the parent drug. Prodrugs are often useful as they can improve certain undesirable physical or biological properties. Physical properties are typically related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological characteristics include too rapid metabolism or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable by oral administration, while the parent cannot. The solubility of prodrugs in pharmaceutical compositions is also increased compared to the parent drug. One example of a prodrug, but not limited to, can be any compound of the present invention administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility but beneficial once inside the cell, and which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0094] Unless otherwise specified, the compounds of the present invention also include their "cocrystals", and the term "cocrystal" is used to describe the situation where neutral molecular components are present in a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical cocrystals enables the modification of the crystal form of the active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters and L. Quere, RSCPublishing, 2012).

[0095] Unless otherwise specified, the compounds of the present invention also include their "polymorphs", and the term "polymorph" refers to different arrangements of chemical drug molecules, generally manifested as the existence forms of drug raw materials in the solid state. A drug can exist in multiple crystalline forms, and the dissolution and absorption of different polymorphs of the same drug in the body may be different, which will in turn affect the dissolution and release of the preparation.

[0096] Unless otherwise specified, the compounds of the present invention also include their "metabolites", and the term "metabolite" refers to the products obtained by the metabolic action of a specific compound or its salt in the body. The metabolites of a compound can be identified by techniques well-known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes the metabolites of the compound, including the metabolites produced by contacting the compound of the present invention with a mammal for a sufficient period of time.

[0097] Unless otherwise specified, the term "absent" means that the said substituent is absent, that is, the hydrogen atom at the corresponding connection site is not substituted.

[0098] Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable site of the said group is not substituted or is substituted by one or more substituents, and the said substituents are preferably selected from the following groups of substituents: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3- to 10-membered heterocycloalkyl, C 6-14 aryl or 5- to 10-membered heteroaryl, wherein the C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3 - 10 membered heterocycloalkyl, C 6-14 Aryl or 5 - 10 membered heteroaryl may be optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, and the oxo group means that two H at the same substitution position are replaced by the same O to form a double bond. The present invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0099] Synthesis scheme

[0100] Unless otherwise indicated, in the synthesis scheme, R b , R c , R1, R2, R3, n1, n2, n3, R4, R5, R6, m, R7, R8, and R9 have the same meanings as described herein.

[0101] Scheme I

[0102]

[0103] Wherein, Halo means halogen, preferably, Cl or Br; L means a leaving group, for example, when R2 = COOH, L can be C 1-6 Alkyl, such as methyl, and at this time (R2) n2 -L = COOC 1-6 Alkyl.

[0104] Conditions for step i:

[0105] Temperature: 70 °C - 130 °C

[0106] Reaction reagents: base (such as cesium carbonate), metal catalyst (such as tris(dibenzylideneacetone)dipalladium) and ligand (such as 4,5 - bis(diphenylphosphino)-9,9 - dimethyloxanthrene), polar organic solvent (such as dioxane)

[0107] Time: 2 hours - 10 hours

[0108] Conditions for step ii:

[0109] Temperature: 15 °C - 50 °C

[0110] Reaction reagents: base (such as LiOH), polar solvent (such as water, THF)

[0111] Time: 2 hours - 10 hours

[0112] Scheme II

[0113]

[0114] Conditions:

[0115] Temperature: 20°C - 100°C

[0116] Reaction reagents: condensing agents (such as HATU, T3P), bases (DIEA / DIPEA), polar organic solvents (such as DMF, CH3CN)

[0117] Time: 1 hour - 18 hours

[0118] Examples

[0119] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following examples are generally carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to the described content can be applied to the methods of the present invention. The preferred methods and materials shown in the text are for illustrative purposes only.

[0120] The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography - mass spectrometry (LC - MS) or / and high - performance liquid chromatography (HPLC). The instrument used for NMR measurement is Wuhan Zhongke Niujin Magnetic Resonance Tecnology Co., Ltd Quantum - I, 400 MHz; the instrument used for LC - MS is Agilent, 1290 Infinity Ⅱ; the instrument used for HPLC is Thermo, ultimate 3000.

[0121] The sources of all raw materials in each starting step are prior arts and are purchased from various raw material consumable companies.

[0122] The following abbreviations refer to the following definitions respectively:

[0123] ACN Acetonitrile

[0124] AcOH Acetic acid

[0125] aq Aqueous

[0126] Boc tert - butoxycarbonyl

[0127] CD3OD Deuterated methanol

[0128] CDCl3 Deuterated chloroform

[0129] CDI N,N'-carbonyldiimidazole

[0130] CH3CN Acetonitrile

[0131] c-hex Cyclohexane

[0132] DAST Diethylaminosulfur trifluoride

[0133] DCC Dicyclohexylcarbodiimide

[0134] DCM Dichloromethane

[0135]

[0136] mL Milliliter

[0137] mm Millimeter

[0138] mmol Millimole

[0139] MS Mass spectrometry

[0140] MTBE Methyl tert-butyl ether

[0141] NaBH4 Sodium borohydride

[0142] NaHCO3 Sodium bicarbonate

[0143] NMM N-Methylmorpholine

[0144] NMI N-Methylimidazole

[0145] NMR Nuclear magnetic resonance

[0146] Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)

[0147] PyBOP Benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate

[0148] rt Room temperature

[0149] SPE Solid-phase extraction

[0150] T3P 1-Propylphosphonic anhydride

[0151] TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

[0152] TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate

[0153] TEA Triethylamine

[0154] TFA Trifluoroacetic acid

[0155] THF Tetrahydrofuran

[0156] TLC thin layer chromatography

[0157] UV ultraviolet

[0158] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0159] Preparation of intermediate:

[0160] Intermediate A: Preparation of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile

[0161]

[0162] First step: Take a 250 mL single-necked flask, dissolve 2-cyanoacetamide (5 g, 59.47 mmol, 1 eq) in anhydrous ethanol (30 mL), then add 1,1,1-trifluoropropane-2,4-dione (1 eq), slowly drop diethylamine (2 eq) with stirring, and then reflux at 70 °C for 8 hours. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Cool to room temperature, a large amount of solid precipitates. After filtering the reaction solution, the filter cake is washed batchwise with ice ethanol. Finally, the filter cake is transferred to a single-necked flask and the solvent is dried under vacuum to obtain 2-hydroxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (yield 45.75%).

[0163] MS(ESI): m / z 202.8(M+H) + .

[0164] 1 H NMR(400 MHz, DMSO-d6) δ 6.31(s, 1H), 2.25(s, 3H).

[0165] Second step: Take a 500 mL single-necked flask, add 2-hydroxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (13 g, 64.32 mmol, 1 eq), then carefully add phosphorus oxychloride (195 mL) at room temperature. After purging with nitrogen, reflux and stir at 110 °C for 3 hours. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Slowly pour the reaction solution into warm water (500 mL) at 45 °C, stir for half an hour, then add ethyl acetate for extraction (500 mL * 3). Combine the organic phases, and wash with saturated brine three times (500 mL * 3). Then concentrate the organic phase, mix with silica gel and separate and purify by column chromatography (PE:EA = 10:1) to obtain 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (yield 61.32%).

[0166] MS(ESI): m / z 220.8(M+H) + . 1HNMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 2.73 (s, 3H).

[0167] Intermediate B: Preparation of 3-chloro-4-fluoro-N-methylaniline hydrochloride

[0168]

[0169] First step: Dissolve 3-chloro-4-fluoroaniline (10 g, 68.7 mmol, 1 eq) and di-tert-butyl malonate (2 eq) in 100 mL of water. Add triethylamine (3 eq) under nitrogen protection at 25 °C and stir for 3 hours. TLC (PE:EA = 5:1) was used to detect the completion of the reaction. Filter the reaction solution, concentrate the filtrate, mix with silica gel, and separate and purify by column chromatography (PE:EA = 92:8) to obtain tert-butyl N-(3-chloro-4-fluorophenyl)carbamate (yield 91.83%).

[0170] 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.32 (t, J = 9.2 Hz, 1H), 1.49 (s, 9H).

[0171] Second step: Dissolve tert-butyl N-(3-chloro-4-fluorophenyl)carbamate (15.5 g, 63.09 mmol, 1 eq) in 100 mL of DMF. Add 60% sodium hydride (2 eq) at 0 °C, then displace nitrogen, stir at 0 °C for 1 hour, and then dropwise add iodomethane (3 eq). After stirring at 25 °C for 2 hours, LC-MS monitoring showed that the raw materials disappeared and the target compound was found. Quench with water, extract with ethyl acetate (20 mL * 3), wash the organic phase with saturated sodium chloride, and then distill off the solvent under reduced pressure to obtain the crude product of tert-butyl N-(3-chloro-4-fluorophenyl)-N-methylcarbamate, which was used directly in the next step without purification.

[0172] MS (ESI): m / z 204.2 (M - 55) + .

[0173] Third step: Dissolve tert-butyl N-(3-chloro-4-fluorophenyl)-N-methylcarbamate (18.4 g, crude product, obtained from the previous step) in hydrochloric acid ethyl acetate (4 M, 80 mL, 320 mmol) at 0 °C. Stir under nitrogen protection for 1 hour, and then naturally rise to room temperature (30 °C) and react for 2 hours. LC-MS monitoring showed that the raw materials disappeared and the target compound was found. Filter the reaction solution under reduced pressure, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 3-chloro-4-fluoro-N-methylaniline hydrochloride (yield of two steps 97.28%).

[0174] MS(ESI): m / z 160.0 (M+H) + .

[0175] 1 H NMR(400 MHz, DMSO-d6) δ 7.24 (t, J=9.2 Hz, 1H), 6.93 (d, J=3.2 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 2.71 (s, 3H).

[0176] Example 1

[0177] (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (Compound 1) synthesis:

[0178]

[0179] First step: To the methanol (10 mL) of (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 5.24 mmol, 1.0 eq), add hydrochloric acid / dioxane solution (4 M, 10 mL). Stir at 25 °C for 6 hours. LC-MS monitoring of the reaction shows the disappearance of the starting material and the discovery of the target compound. The reaction solution is adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL * 2), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is separated and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]pyrrolidine-3-carboxylate (yield 54.59%).

[0180] MS(ESI): m / z 315.1 (M+H) + .

[0181] Step 2: To a solution of methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]pyrrolidine-3-carboxylate (350 mg, 1.11 mmol, 1.0 eq) in dioxane (10 mL), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.2 eq), cesium carbonate (2.0 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq) were added. Under nitrogen protection, tris(dibenzylideneacetone)dipalladium (0.1 eq) was added, and the mixture was stirred at 100 °C for 5 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction mixture was cooled to room temperature and concentrated, and the residue was separated and purified by column chromatography (PE / EA = 3 / 1) to obtain methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 72.12%).

[0182] MS(ESI): m / z 474.2 (M+H) + .

[0183] 1 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.36 (s, 1H), 7.24 - 7.22 (m, 1H), 6.63 (s, 1H), 6.41 (s, 1H), 4.60 - 4.54 (m 1H), 3.96 - 3.87 (m, 1H), 3.81 - 3.76 (m, 1H), 3.74 (s, 3H), 3.26 (s, 3H), 3.14 - 3.08 (m, 1H), 2.49 (s, 3H), 2.39 - 2.34 (m, 1H), 2.31 - 2.22 (m, 1H).

[0184] Step 3: To a solution of methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (50 mg, 0.11 mmol, 1.0 eq) in tetrahydrofuran (3 mL), a solution of lithium hydroxide (2.0 eq) in water (3 mL) was slowly added, and the mixture was stirred at 25 °C for 5 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction mixture was concentrated, and the residue was separated and purified by preparative HPLC to obtain (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (yield 17.8%).

[0185] MS(ESI): m / z 460.0 (M+H) + .

[0186] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 5.2 Hz, 1H), 7.59 - 7.58 (m, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 4.40 - 4.37 (m, 1H), 3.79 - 3.76 (m, 1H), 3.59 (t, J = 9.2 Hz, 1H), 3.14 (s, 3H), 3.10 - 3.09 (m, 1H), 2.46 (s, 3H), 2.30 - 2.24 (m, 1H), 2.14 - 2.08 (m, 1H).

[0187] Example 2

[0188] Synthesis of (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (Compound 2):

[0189]

[0190] First step: To a solution of methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]pyrrolidine-3-carboxylate (350 mg, 1.11 mmol, 1.0 eq) in dioxane (20 mL), add 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (1.2 eq), cesium carbonate (2.0 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq). Then add tris(dibenzylideneacetone)dipalladium (0.1 eq). Stir the reaction at 100 °C for 5 hours under nitrogen protection. LC-MS monitoring shows the disappearance of the starting material and the discovery of the target compound. Cool to room temperature, concentrate the reaction solution, and purify the residue by column chromatography (PE / EA = 3 / 1) to obtain methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 55.88%).

[0191] MS (ESI): m / z 499.2 (M + H) + .

[0192] 11H NMR (400 MHz, CDCl3) δ 7.60 - 7.59 (m, 1H), 7.39 - 7.37 (m, 1H), 7.20 - 7.17 (m, 1H), 6.81 (s, 1H), 4.74 (t, J = 7.6 Hz, 1H), 4.39 - 4.30 (m, 2H), 3.73 (s, 3H), 3.25 (s, 3H), 3.08 - 3.00 (m, 1H), 2.53 (s, 3H), 2.38 - 2.30 (m, 1H), 2.22 - 2.13 (m, 1H).

[0193] Step 2: To a solution of methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (50 mg, 0.1 mmol, 1.0 eq) in tetrahydrofuran (3 mL), a solution of lithium hydroxide (2.0 eq) in water (3 mL) was slowly added. The mixture was stirred at 25 °C for 5 h. LC-MS monitoring of the reaction showed disappearance of the starting material and the formation of the target compound. The reaction mixture was concentrated and the residue was separated and purified by preparative HPLC to give (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (yield 20.63%).

[0194] MS (ESI): m / z 485.2 (M + H) + .

[0195] 1 1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 7.82 (d, J = 4.8 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.11 (s, 1H), 4.60 (t, J = 8.0 Hz, 1H), 4.10 (t, J = 9.2 Hz, 1H), 3.98 (t, J = 9.6 Hz, 1H), 3.14 (s, 3H), 3.10 - 3.08 (m, 1H), 2.51 (s, 3H), 2.25 - 2.20 (m, 1H), 2.04 - 1.96 (m, 1H).

[0196] Example 3

[0197] Synthesis of (3R,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (Compound 3):

[0198]

[0199] To a solution of methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (550 mg, 1.16 mmol, 1.0 equiv.) in tetrahydrofuran (15 mL) was slowly added a solution of lithium hydroxide (2.0 equiv.) in water (5 mL). The mixture was stirred at 25 °C for 5 h. LC-MS monitoring of the reaction showed disappearance of the starting material and formation of the target compound. The reaction mixture was concentrated and the residue was separated and purified by preparative HPLC to give (3R,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 8.43%).

[0200] MS(ESI): m / z 460.0 [M+H] + ;

[0201] 1 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 7.90 (d, J = 6.4 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 6.75 (s, 1H), 6.52 (s, 1H), 4.48 (d, J = 6.0 Hz, 1H), 3.76 (t, J = 9.6 Hz, 1H), 3.60 - 3.56 (m, 1H), 3.38 - 3.34 (m, 1H), 3.15 (s, 3H), 2.46 (s, 3H), 2.28 - 2.23 (m, 1H), 2.16 - 2.09 (m, 1H).

[0202] Example 4

[0203] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(2-(dimethylamino)-2-oxoethyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 9) synthesis:

[0204]

[0205] Step 1: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1.0 eq.) in N,N-dimethylformamide (2 mL) was added compound HATU (1.2 eq.). The reaction mixture was first stirred at 25 °C for 30 min, then compound 2-amino-N,N-dimethylacetamide (1.2 eq.) and DIEA (3.0 eq.) were successively added to the reaction system. After the addition was completed, the reaction mixture was continuously stirred at 25 °C for 1.5 h. LC-MS monitoring of the reaction showed that the raw materials disappeared and the target compound was found. The reaction solution was separated and purified by a C18 column (0.1% HCOOH / water, MeOH) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(2-(dimethylamino)-2-oxoethyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 59.1%).

[0206] MS(ESI): m / z 544.31 / 546.28 [M+H] + ;

[0207] 1 H NMR (400 MHz, DMSO-d6): δ 8.09 - 8.04 (m, 1H), 7.85 (d, J = 6.1 Hz, 1H), 7.61 - 7.56 (m, 2H), 6.74 (s, 1H), 6.50 (s, 1H), 4.33 (t, J = 8.2 Hz, 1H), 4.02 - 3.86 (m, 2H), 3.81 - 3.70 (s, 1H), 3.52 - 3.44 (m, 1H), 3.15 (s, 3H), 3.09 - 2.99 (m, 1H), 2.95 (s, 3H), 2.84 (s, 3H), 2.45 (s, 3H), 2.22 - 2.14 (m, 1H), 2.13 - 1.97 (m, 1H).

[0208] Example 5

[0209] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 4 -(2-morpholin-2-oxoethyl)pyrrolidine-2,4-dicarboxamide (Compound 10) synthesis:

[0210]

[0211] Step 1: At 25 °C, to a solution of compound Boc-glycine (1.00 g, 5.71 mmol, 1.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq.), 1-hydroxybenzotriazole (1.1 eq.) and 4-dimethylaminopyridine (1.2 eq.) in dichloromethane (50 mL) was added compound morpholine (1.2 eq.). The reaction mixture was continuously stirred at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. The reaction solution was poured into saturated sodium bicarbonate solution (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by column chromatography (DCM:MeOH = 10:1) to obtain tert-butyl (2-morpholin-2-oxoethyl)carbamate (yield 45.89%).

[0212] MS(ESI): m / z 245.25 [M+H] + ;

[0213] 1 H NMR: EN1149-146-P1 (400 MHz, DMSO-d6): δ 6.76 (t, J = 5.7 Hz, 1H), 3.77 (d, J = 5.8 Hz, 2H), 3.58 - 3.51 (m, 4H), 3.41 - 3.36 (m, 4H), 1.38 (s, 9H).

[0214] Step 2: At 25 °C, compound tert-butyl (2-morpholin-2-oxoethyl)carbamate (300 mg, 1.23 mmol, 1.0 eq.) was dissolved in hydrochloric acid ethyl acetate (5 mL, 4 M) solution. The reaction mixture was continuously stirred at 25 °C for 2 h. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. The reaction solution was concentrated to obtain the crude product of 2-amino-1-morpholinoethan-1-one hydrochloride, which was used directly in the next step without purification.

[0215] MS(ESI): m / z 145.25 [M+H] + .

[0216] Step 3: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1.0 eq.) in N,N-dimethylformamide (2 mL) was added HATU (1.2 eq.). The reaction mixture was first stirred at 25 °C for 30 min, and then compound 2-amino-1-morpholinoethan-1-one hydrochloride (24 mg, crude product, obtained from the previous step) and DIEA (4.0 eq.) were successively added to the reaction system. After the addition was completed, the reaction mixture was continuously stirred at 25 °C for 1.5 h. LC-MS monitoring of the reaction showed that the starting material disappeared and the target compound was found. The reaction solution was separated and purified by a C18 column (0.1% HCOOH / water, MeOH) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 4 -(2-morpholino-2-oxoethyl)pyrrolidine-2,4-dicarboxamide (two-step yield 59.0%).

[0217] MS(ESI): m / z 586.29 / 588.28 [M+H] + ;

[0218] 1 1H NMR (400 MHz, DMSO-d6): δ 8.12 (t, J = 4.8 Hz, 1H), 7.85 (d, J = 5.9 Hz, 1H), 7.64 - 7.53 (m, 2H), 6.74 (s, 1H), 6.50 (s, 1H), 4.33 (t, J = 8.2 Hz, 1H), 4.04 - 3.90 (m, 2H), 3.81 - 3.72 (m, 1H), 3.62 - 3.53 (m, 4H), 3.52 - 3.46 (m, 5H), 3.15 (s, 3H), 3.10 - 2.98 (m, 1H), 2.46 (s, 3H), 2.25 - 2.16 (m, 1H), 2.10 - 2.01 (m, 1H).

[0219] Example 6

[0220] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 4 -(2,2,2-trifluoroethyl)pyrrolidine-2,4-dicarboxamide (Compound 11) Synthesis:

[0221]

[0222] Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq.) in acetonitrile (1.5 mL, 100.0%). Add 2,2,2-trifluoroethan-1-amine (1.2 eq.) and T3P (1.5 eq.) at room temperature, and heat at 80 °C for 1 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Pour the reaction solution into saturated NaHCO3 solution (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify the residue to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 4 -(2,2,2-trifluoroethyl)pyrrolidine-2,4-dicarboxamide (yield 29.87%).

[0223] MS(ESI): m / z 541.27 (M + H) + ;

[0224] 1 1H NMR (400 MHz, MeOD) δ 7.90 - 7.77 (m, 1H), 7.62 - 7.49 (m, 1H), 7.41 (t, J = 8.8 Hz, 1H), 6.69 (s, 1H), 6.48 (s, 1H), 4.55 - 4.45 (m, 1H), 4.02 - 3.83 (m, 2H), 3.81 - 3.73 (m, 1H), 3.72 - 3.65 (m, 1H), 3.25 (s, 3H), 3.11 - 2.98 (m, 1H), 2.50 (s, 3H), 2.38 - 2.17 (m, 2H).

[0225] Example 7

[0226] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(2-(dimethylamino)ethyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 12) synthesis:

[0227]

[0228] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq.), (2-aminoethyl)dimethylamine (1.1 eq.) and T3P (3 eq.) were dissolved in acetonitrile (1.5 mL, 100.0%), and stirred at 80 °C for two hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was poured into saturated NaHCO3 solution (100 mL), extracted with ethyl acetate (30 mL * 3), the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and purified to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(2-(dimethylamino)ethyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 38%).

[0229] MS(ESI): m / z 530.32 (M + H) + ;

[0230] 1 1H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.54 (s, 1H), 7.41 (t, J = 8.8 Hz, 1H), 6.69 (s, 1H), 6.46 (s, 1H), 4.47 (t, J = 8.1 Hz, 1H), 3.80 - 3.65 (m, 2H), 3.47 - 3.34 (m, 2H), 3.25 (s, 3H), 3.08 - 2.94 (m, 1H), 2.70 - 2.55 (m, 2H), 2.50 (s, 3H), 2.42 (s, 6H), 2.31 - 2.22 (m, 2H).

[0231] Example 8

[0232] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-4-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 13) Synthesis:

[0233]

[0234] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 equiv.), 1-methylpyrazol-4-amine (1.2 equiv.), and HATU (1.5 equiv.) were successively added to a solution of N,N-dimethylformamide (1 mL). DIPEA (3 equiv.) was added, and the reaction was stirred under nitrogen protection at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting material, and the target compound was found. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-4-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 10.49%).

[0235] MS (ESI): m / z 539.1;

[0236] 1 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.87 (s, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 7.26 - 7.23 (m, 1H), 6.73 (s, 1H), 6.47 (s, 1H), 4.57 - 4.56 (m, 1H), 4.02 - 3.98 (m, 1H), 3.87 (s, 3H), 3.82 - 3.77 (m, 1H), 3.33 (s, 3H), 3.29 - 3.28 (m, 1H), 2.58 (s, 3H), 2.50 - 2.42 (m, 1H), 2.35 - 2.31 (m, 1H).

[0237] Example 9

[0238] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 14) synthesis:

[0239]

[0240] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 equiv.) was successively added to a solution of N,N-dimethylformamide (1 mL), followed by the addition of pyridin-2-amine (1.2 equiv.), HATU (1.5 equiv.), and DIPEA (3 equiv.). Under nitrogen protection, the mixture was stirred at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 4.26%).

[0241] MS (ESI): m / z 536.2;

[0242] 1 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.37 (s, 1H), 7.22 - 7.17 (m, 1H), 7.16 (t, J = 6.4 Hz, 1H), 6.69 (s, 1H), 6.44 (s, 1H), 4.58 (t, J = 8.8 Hz, 1H), 4.02 - 3.98 (m, 1H), 3.83 (t, J = 8.8 Hz, 1H), 3.31 (s, 3H), 3.27 - 3.36 (m, 1H), 2.52 (s, 3H), 2.50 - 2.49 (m, 1H), 2.46 - 2.41 (m, 1H).

[0243] Example 10

[0244] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 45) synthesis:

[0245]

[0246] Step 1: To a solution of (2S,4S)-4-cyano-1,2-pyrrolidinedicarboxylic acid 1-(tert-butyl) 2-methyl ester (10 g, 39.33 mmol, 1.0 eq) in tetrahydrofuran (50 mL) was slowly added a solution of lithium hydroxide (3.0 eq) in water (20 mL). The mixture was stirred at 25 °C for 5 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was adjusted to pH 5 with 2 M dilute HCl (15 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified to obtain (2S,4S)-1-(tert-butoxycarbonyl)-4-cyanopyrrolidine-2-carboxylic acid (yield 97.36%).

[0247] MS(ESI): m / z 241.2 (M + H) + .

[0248] 1 1H NMR (400 MHz, CDCl3) δ 8.09 (brs, 1H), 4.43 - 4.31 (m, 1H), 4.02 - 3.91 (m, 1H), 3.72 - 3.62 (m, 1H), 3.13 - 3.11 (m, 1H), 2.77 - 2.67 (m, 1H), 2.48 - 2.36 (m, 1H), 1.48 - 1.43 (m, 9H).

[0249] Step 2: To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-cyanopyrrolidine-2-carboxylic acid (800 mg, 3.33 mmol, 1.0 eq) in pyridine (20 mL) were added 3-chloro-4-fluoro-N-methylaniline hydrochloride (1.0 eq) and propylphosphonic anhydride (50% in DMF, 5 mL). The mixture was stirred at 25 °C under nitrogen for 15 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was concentrated, and the residue was separated and purified by column chromatography (PE / EA = 2 / 1) to obtain (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylic acid tert-butyl ester (yield 58.9%).

[0250] MS(ESI): m / z 382.2 (M + H) + .

[0251] Step 3: Trifluoroacetic acid (3.0 eq) was added to a solution of tert-butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (900 mg, 2.36 mmol, 1.0 eq) in dichloromethane (10 mL). The mixture was stirred at 25 °C for 3 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. Saturated aqueous sodium bicarbonate was slowly added to the reaction mixture to adjust the pH to 8. The mixture was extracted with dichloromethane (30 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified to give (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (yield 75.3%).

[0252] MS(ESI): m / z 282.2(M + H) + .

[0253] Step 4: 2-Chloro-6-methyl-4-(trifluoromethyl)pyridine (1.2 eq), cesium carbonate (2.0 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq) were added to a solution of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (500 mg, 1.77 mmol, 1.0 eq) in dioxane (15 mL). Tris(dibenzylideneacetone)dipalladium (0.1 eq) was added, and the reaction mixture was purged with nitrogen three times and stirred at 100 °C for 3 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was concentrated, and the residue was separated and purified by column chromatography (PE / EA = 2 / 1) to give (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 38.34%).

[0254] MS(ESI): m / z 441.3(M + H) + .

[0255] Step 5: To a solution of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (280 mg, 0.64 mmol, 1.0 eq) in dimethyl sulfoxide (5 mL), potassium carbonate (2.0 eq) and 30% H2O2 (1.2 mL) were added. The reaction was stirred at 60 °C for 5 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction was cooled to room temperature, quenched by adding water, extracted with ethyl acetate (20 mL * 2), and the organic layers were combined. The combined organic layer was washed with saturated brine (10 mL * 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 68.62%).

[0256] MS(ESI): m / z 459.0 (M + H) + .

[0257] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 - 7.84 (m, 1H), 7.59 - 7.84 (m, 2H), 7.41 (s, 1H), 7.02 (s, 1H), 6.73 (s, 1H), 6.50 (s, 1H), 4.33 (t, J = 9.6 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.47 (t, J = 10.0 Hz, 1H), 3.14 (s, 3H), 2.94 - 2.89 (m, 1H), 2.45 (s, 3H), 2.22 - 2.16 (m, 1H), 2.04 - 1.98 (m, 1H).

[0258] Example 11

[0259] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,N 4 -dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 46) Synthesis:

[0260]

[0261] To a solution of (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-carboxylic acid (150 mg, 0.33 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL) were added methylamine hydrochloride (2.0 eq), HATU (1.5 eq) and DIEA (3.0 eq). The reaction mixture was stirred at 25 °C for 3 h under nitrogen atmosphere. LC-MS monitoring showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,N 4 -dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 32.41%).

[0262] MS(ESI): m / z 473.0 (M+H) + .

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.83 (m, 2H), 7.58 - 7.57 (m, 2H), 6.73 (s, 1H), 6.50 (s, 1H), 4.32 (t, J = 8.0 Hz, 1H), 3.75 - 3.71 (m, 1H), 3.46 (t, J = 10.0 Hz, 1H), 3.14 (s, 3H), 2.91 - 2.87 (m, 1H), 2.59 (d, J = 4.4 Hz, 3H), 2.45 (s, 3H), 2.20 - 2.13 (m, 1H), 2.09 - 2.03 (m, 1H).

[0264] Example 12

[0265] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,N 4 ,N 4 -trimethyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 47) Synthesis:

[0266]

[0267] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (45 mg, 0.1 mmol, 1 equiv.) was added successively to a solution of N,N-dimethylformamide (1 mL), followed by dimethylamine hydrochloride (2 equiv.) and HATU (1.5 equiv.). DIPEA (3 equiv.) was added and the reaction was stirred under nitrogen protection at 25 °C for 16 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction solution was concentrated and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,N 4 ,N 4 -trimethyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 30.95%).

[0268] MS (ESI): m / z 487.2 (M+H) + ;

[0269] 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 6.0 Hz, 2H), 6.73 (s, 1H), 6.54 (s, 1H), 4.37 (t, J = 8.4 Hz, 1H), 3.82 - 3.78 (m, 1H), 3.44 - 3.40 (m, 2H), 3.15 (s, 3H), 3.00 (s, 3H), 2.84 (s, 3H), 2.45 (s, 3H), 2.14 - 2.07 (m, 2H).

[0270] Example 13

[0271] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 2 ,N 4 -dimethylpyrrolidine-2,4-dicarboxamide (Compound 48) synthesis:

[0272]

[0273] In N,N-dimethylformamide (10 mL) of (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (200 mg, 0.41 mmol, 1.0 eq), methylamine hydrochloride (2.0 eq), HATU (1.5 eq) and DIEA (3.0 eq) were added, and the mixture was stirred at 25 °C for 3 hours under nitrogen protection. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 2 ,N 4 -dimethylpyrrolidine-2,4-dicarboxamide (yield 17.04%).

[0274] MS(ESI): m / z 498.0 (M+H) + .

[0275] 1 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 4.4 Hz, 1H), 7.82 (d, J = 4.8 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.11 (s, 1H), 4.53 (t, J = 8.0 Hz, 1H), 4.00 (t, J = 8.8 Hz, 1H), 3.90 (t, J = 10.0 Hz, 1H), 3.15 (s, 3H), 2.89 - 2.85 (m, 1H), 2.59 (d, J = 4.4 Hz, 3H), 2.55 (s, 3H), 2.14 - 2.07 (m, 1H), 2.01 - 1.93 (m, 1H).

[0276] Example 14

[0277] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(2-hydroxyethyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 49) Synthesis:

[0278]

[0279] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (45 mg, 0.1 mmol, 1 equiv.), 2-aminoethanol (2 equiv.), HATU (1.5 equiv.) were successively added to a solution of N,N-dimethylformamide (1 mL), and DIPEA (3 equiv.) was added. Under nitrogen protection, the mixture was stirred at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(2-hydroxyethyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (20.42%).

[0280] MS (ESI): m / z 503.2 (M+H) + ;

[0281] 1 1H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.93 (m, 1H), 7.83 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 6.8 Hz, 2H), 6.71 (s, 1H), 6.48 (s, 1H), 4.65 (s, 1H), 4.30 (t, J = 8.0 Hz, 1H), 3.75 - 3.69 (m, 1H), 3.47 - 3.44 (m, 1H), 3.42 - 3.38 (m, 3H), 3.12 (s, 3H), 3.10 - 3.09 (m, 1H), 2.95 - 2.89 (m, 1H), 2.43 (s, 3H), 2.20 - 2.14 (m, 1H), 2.07 - 1.99 (m, 1H).

[0282] Example 15

[0283] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(2-morpholinoethyl)pyrrolidine-2,4-dicarboxamide (Compound 55) synthesis:

[0284]

[0285] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (45 mg, 0.1 mmol, 1 equiv.), 2-morpholinoethan-1-amine (2 equiv.), HATU (1.5 equiv.) were added successively to a solution of N,N-dimethylformamide (1 mL). DIPEA (3 equiv.) was added and the reaction was stirred under nitrogen protection at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the target compound was found. The reaction solution was concentrated and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(2-morpholinoethyl)pyrrolidine-2,4-dicarboxamide (yield 10.72%).

[0286] MS (ESI): m / z 572.2 [M+H] + ;

[0287] 1 1H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.89 (m, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.58 - 7.57 (m, 2H), 6.73 (s, 1H), 6.50 (s, 1H), 4.32 (t, J = 8.0 Hz, 1H), 3.77 - 3.71 (m, 1H), 3.57 - 3.55 (m, 4H), 3.46 (t, J = 10.0 Hz, 1H), 3.21 - 3.18 (m, 2H), 3.14 (s, 3H), 2.95 - 2.89 (m, 1H), 2.45 (s, 3H), 2.36 - 2.32 (m, 6H), 2.20 - 2.13 (m, 1H), 2.09 - 2.00 (m, 1H).

[0288] Example 16

[0289] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 56) synthesis:

[0290]

[0291] In N,N-dimethylformamide (2 mL) of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50.0 mg, 0.11 mmol, 1.0 equiv.), 1-methylpyrazol-3-amine (1.5 equiv.), HATU (1.5 equiv.) and DIPEA (3.0 equiv.) were added and stirred at 25 °C for 3 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the target compound was found. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 18.4%).

[0292] MS (ESI): m / z 539.2 [M+H] + ;

[0293] 1 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.59 (d, J = 6.4 Hz, 2H), 7.54 (d, J = 2.0 Hz, 1H), 6.74 (s, 1H), 6.54 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 4.35 (t, J = 8.0 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.73 (s, 3H), 3.53 (t, J = 10.0 Hz, 1H), 3.15 (s, 3H), 3.12 - 3.07 (m, 1H), 2.46 (s, 3H), 2.33 - 2.25 (m, 1H), 2.15 - 2.07 (m, 1H).

[0294] Example 17

[0295] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[(1s,3r)-3-hydroxycyclobutyl]pyrrolidine-2,4-dicarboxamide (Compound 57) Synthesis:

[0296]

[0297] In N,N-dimethylformamide (2 mL) of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50.0 mg, 0.11 mmol, 1.0 equiv.), (1s,3s)-3-aminocyclobutan-1-ol hydrochloride (1.5 equiv.), HATU (1.5 equiv.) and DIPEA (3.0 equiv.) were added and stirred at 25 °C for 3 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the target compound was found. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[(1s,3r)-3-hydroxycyclobutyl]pyrrolidine-2,4-dicarboxamide (yield 57.5%).

[0298] MS (ESI): m / z 529.2 [M+H] + ;

[0299] 1 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 2H), 6.73 (s, 1H), 6.51 (s, 1H), 4.31 (t, J = 6.4 Hz, 1H), 3.80 - 3.64 (m, 4H), 3.46 - 3.41 (m, 2H), 3.14 (s, 3H), 2.88 - 2.82 (m, 1H), 2.48 - 2.46 (m, 1H), 2.45 (s, 3H), 2.22 - 2.15 (m, 1H), 2.05 - 1.99 (m, 1H), 1.73 - 1.70 (m, 2H).

[0300] Example 18

[0301] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[(1r,3s)-3-hydroxycyclobutyl]pyrrolidine-2,4-dicarboxamide (Compound 58) synthesis:

[0302]

[0303] In N,N-dimethylformamide (2 mL) of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50.0 mg, 0.11 mmol, 1.0 equiv.), (1r,3r)-3-aminocyclobutanol hydrochloride (1.5 equiv.), HATU (1.5 equiv.) and DIPEA (3.0 equiv.) were added and stirred at 25 °C for 3 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[(1r,3s)-3-hydroxycyclobutyl]pyrrolidine-2,4-dicarboxamide (yield 17.4%).

[0304] MS (ESI): m / z 529.2 [M+H] + ;

[0305] 1 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 6.8 Hz, 1H), 7.85 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 6.8 Hz, 2H), 6.73 (s, 1H), 6.52 (s, 1H), 4.33 - 4.29 (m, 1H), 4.26 - 4.22 (m, 1H), 4.20 - 4.15 (m, 1H), 3.75 - 3.71 (m, 1H), 3.45 (t, J = 10.0 Hz, 2H), 3.14 (s, 3H), 2.89 - 2.84 (m, 1H), 2.45 (s, 3H), 2.20 - 2.15 (m, 1H), 2.10 - 2.07 (m, 4H), 2.05 - 1.99 (m, 1H).

[0306] Example 19

[0307] Synthesis of (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-4-(4H-1,2,4-triazol-3-yl)pyrrolidine-2-carboxamide (Compound 71):

[0308]

[0309] Step 1: Add (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (400 mg, 0.91 mmol, 1 eq), hydrogen peroxide (60%, 19 eq), potassium carbonate (2 eq) and DMSO (7 mL) into a 10 mL sealed tube, and react at 60 °C for 16 h. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction solution with water, extract with ethyl acetate, combine the organic phases, wash the organic phases with water and saturated brine, then dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide, without purification, and directly used for the next step.

[0310] MS(ESI): m / z 459.2 (M+H) + ;

[0311] 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 5.3 Hz, 1H), 7.58 (d, J = 6.9 Hz, 2H), 7.42 (s, 1H), 7.03 (s, 1H), 6.73 (s, 1H), 6.51 (s, 1H), 4.33 (t, J = 8.1 Hz, 1H), 3.81 - 3.66 (m, 1H), 3.47 (t, J = 9.9 Hz, 1H), 3.15 (s, 3H), 2.97 - 2.83 (m, 1H), 2.45 (s, 3H), 2.25 - 2.13 (m, 1H), 2.11 - 2.00 (m, 1H).

[0312] Step 2: Add (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2-Methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (200 mg, crude, obtained from the previous step reaction) and N,N-dimethylformamide dimethyl acetal (2 mL) were reacted at 80 °C for 2 h. The solvent was rotary evaporated, hydrazine hydrate (100 mg) and acetic acid (1 mL) were added, and the reaction was carried out at 115 °C for 1 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the target compound was found. The reaction solution was concentrated under reduced pressure, and the product was separated and purified by preparative HPLC to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-4-(4H-1,2,4-triazol-3-yl)pyrrolidine-2-carboxamide (the yield of two steps was 34.21%).

[0313] MS(ESI):m / z 483.3(M+H) + ;

[0314] 1 1H NMR(500MHz,DMSO-d6)δ13.84(s,1H),8.50(s,1H),7.87(s,1H),7.58(s,2H),6.75(d,J=14.3Hz,1H),6.56(s,1H),4.46(s,1H),4.06 - 3.87(m,1H),3.71 - 3.53(m,2H),3.15(s,3H),2.47(s,3H),2.40(m,1H),2.23 - 2.11(m,1H).

[0315] Example 20

[0316] Synthesis of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(1H-imidazol-2-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 72) and synthesis of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(1H-imidazol-2-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 80):

[0317]

[0318] Step 1: Add (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (150 mg, 0.33 mmol, 1.0 equiv.) to the solvent of tetrahydrofuran (10 mL) in a 100 mL three-necked flask. After replacing nitrogen, add 1 M borane tetrahydrofuran solution (2.0 eq) dropwise at 0 °C and stir at 0 - 25 °C for 3 hours. LC-MS monitoring of the reaction shows the disappearance of the raw material and the discovery of the target compound. Quench the reaction solution with water, then extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain the crude product of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide. Without purification, it is directly used for the next step.

[0319] MS(ESI): m / z 446.2[M+H] + 。

[0320] Step 2: Add the crude product of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (150 mg crude product, obtained from the previous step) to the solvent of dichloromethane (10 mL) in a 100 mL three-necked flask. Add Dess-Martin (140 mg) at 0 °C. After replacing nitrogen, stir at 25 °C for 2 hours. LC-MS monitoring of the reaction shows the disappearance of the raw material and the discovery of the target compound. Quench the reaction solution with water, then extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure. Purify the residue to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-formyl-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (the yield of two steps is 68.36%).

[0321] MS(ESI): m / z 443.8[M+H] + 。

[0322] Step 3: In a 20 mL sealed tube, (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-formyl-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (100 mg, 0.23 mmol, 1.0 equiv.) was added to a solvent mixture of 7M ammonia in methanol (4 mL) and aqueous glyoxal solution (4 mL). After displacing nitrogen, the mixture was stirred at 50 °C for 16 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction mixture was quenched with water, then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and purified by preparative HPLC to obtain P2: (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(1H-imidazol-2-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 72) (yield 4.99%); P1: (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(1H-imidazol-2-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 80) (yield 9.73%).

[0323] P2: MS(ESI): m / z 482.0 [M+H] + , t R = 1.567 min; 1 H NMR: (400 MHz, DMSO d6) δ 11.88 (s,

[0324] 1H), 7.86 (d, J = 5.6 Hz, 1H), 7.59 (d, J = 6.4 Hz, 2H), 7.05 - 6.74 (m, 3H), 6.53 (s, 1H), 4.43 (t, J = 8.0 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.59 (t, J = 10.0 Hz, 1H), 3.51 – 3.45 (m, 1H), 3.16 (s, 3H), 2.47 (s, 3H), 2.42 - 2.36 (m, 1H), 2.20 - 2.11 (m, 1H).

[0325] P1: MS(ESI): m / z 482.0 [M+H] + , t R = 1.539 min; 1 H NMR: (400 MHz, DMSO d6) δ 11.87 (s,

[0326] 1H), 7.88 (d, J = 6.4 Hz, 1H), 7.59 (d, J = 6.8 Hz, 2H), 7.01 - 6.70 (m, 3H), 6.49 (s, 1H), 4.56 (d, J = 7.6 Hz, 1H), 4.01–3.78 (m, 2H), 3.55 (t, J = 8.0 Hz, 1H), 3.17 (s, 3H), 2.46 (s, 3H), 2.40 - 2.34 (m, 1H), 2.28 - 2.203 (m, 1H).

[0327] Example 21

[0328] (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-[(Z)-N'-hydroxycarbamimidoyl]-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (Compound 86) Synthesis:

[0329]

[0330] First step: Add (2S,4S)-tert-butyl 2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (1.2 g, 3.26 mmol, 1 eq), TFA (4 mL) and DCM (8 mL) into a 50 mL single-necked flask, react at room temperature for 30 min. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. The reaction solution is adjusted to pH 8 - 9 with an aqueous NaHCO3 solution, extracted with DCM, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the crude product of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide, which is used directly in the next step without purification.

[0331] MS(ESI): m / z 282.2 (M + H) + .

[0332] Step 2: Add (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (875 mg, crude product, obtained from the previous step reaction), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (729 mg), tris(dibenzylideneacetone)dipalladium (284 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (72 mg), cesium carbonate (2.023 g) and dioxane (30 mL) into a 50 mL single-necked flask. Replace the nitrogen three times, and react at 120 °C for 16 hours. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Dilute the reaction solution with water, extract with ethyl acetate, combine the organic phases, wash the organic phases with saturated brine, then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (two-step yield 63.98%).

[0333] MS(ESI): m / z 466.4(M+H) + ;

[0334] 1 1H NMR(400 MHz, CDCl3) δ 7.77 - 7.60(m, 1H), 7.36(dt, J = 16.3, 8.2 Hz, 1H), 7.26(t, J = 8.7 Hz, 1H), 6.70(s, 1H), 6.40(s, 1H), 4.59(t, J = 7.8 Hz, 1H), 3.96(t, J = 8.6 Hz, 1H), 3.88(t, J = 9.4 Hz, 1H), 3.27(s, 3H), 3.18 - 3.01(m, 1H), 2.51(s, 3H), 2.50 - 2.42(m, 1H), 2.33(m, 1H).

[0335] Step 3: Add (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (100 mg, 0.23 mmol, 1 eq), hydroxylamine hydrochloride (3 eq), DIEA (5 eq) and EtOH (2 mL) into a 10 mL sealed tube, and react at 85 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the raw materials and the discovery of the target compound. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, then dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-[(Z)-N'-hydroxycarbamimidoyl]-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 66.12%).

[0336] MS(ESI): m / z 474.2(M+H) + ;

[0337] 1 1H NMR(400 MHz, DMSO-d6) δ 9.01(s, 1H), 7.85(s, 1H), 7.58(s, 2H), 6.74(s, 1H), 6.49(s, 1H), 5.52(s, 2H), 4.34(t, J = 8.3 Hz, 1H), 3.77(s, 1H), 3.46(t, J = 9.7 Hz, 1H), 3.15(s, 3H), 2.91 - 2.77(m, 1H), 2.45(s, 3H), 2.31 - 2.21(m, 1H), 2.05 - 1.91(m, 1H).

[0338] Example 22

[0339] (2S)-N 2 -(3-chloro-2,4-difluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-4-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 29) synthesis:

[0340]

[0341] Step 1: Dissolve (2S,4S)-1-[(tert-butoxy)carbonyl]-4-cyanopyrrolidine-2-carboxylic acid (1.50 g, 6.24 mmol, 1 eq.) in dichloromethane (20 mL). Add DIEA (3 eq.), 3-chloro-2,4-difluoroaniline (1.5 eq.) and HATU (2 eq.) at room temperature. Stir at room temperature for 6 hours. LC-MS monitoring shows that the raw materials disappear and the target compound is found. Pour the reaction solution into water (100 mL), extract with dichloromethane (30 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by silica gel column (dichloromethane / methanol = 10 / 1) to obtain tert-butyl (2S,4S)-2-[(3-chloro-2,4-difluorophenyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (yield 65%).

[0342] MS(ESI): m / z 330.1(M+H) + .

[0343] 1 H NMR(400MHz,MeOD)δ7.92 - 7.65(m,1H),7.12(t,J = 8.1Hz,1H),4.56 - 4.44(m,1H),3.94(dd,J = 10.6,7.7Hz,1H),3.65(dd,J = 10.6,7.4Hz,1H),3.46 - 3.35(m,1H),2.85 - 2.62(m,1H),2.42 - 2.10(m,1H),1.41(s,9H).

[0344] Step 2: Dissolve tert-butyl (2S,4S)-2-[(3-chloro-2,4-difluorophenyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (800 mg, 2.07 mmol, 1 eq.) in N,N-dimethylformamide (10 mL). Add sodium hydride (2 eq.) at 0 °C and stir for 20 minutes. Then add iodomethane (1.5 eq.) at 0 °C and warm up to room temperature. Stir for 2 hours. LC-MS monitoring shows that the raw materials disappear and the target compound is found. Quench the reaction solution by pouring it into ice water (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by flash silica gel column (petroleum ether / ethyl acetate = 3 / 1 - 1 / 1) to obtain tert-butyl (2S,4S)-2-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (yield 90%).

[0345] MS(ESI): m / z 422.3(M+H) + .

[0346] 1 1H NMR (400 MHz, MeOD) δ 7.53 - 7.39 (m, 1H), 7.34–7.25 (m, 1H), 4.37–4.19 (m, 1H), 3.95 - 3.82 (m, 1H), 3.55–3.48 (m, 1H), 3.46 - 3.40 (m, 1H), 3.23 (s, 3H), 3.18 - 3.10 (m, 1H), 2.45 - 2.30 (m, 1H), 2.27–2.08 (m, 1H), 1.47–1.42 (m, 9H).

[0347] Step 3: Add tert-butyl (2S,4S)-2-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (800 mg, 1.5 mmol, 1 eq.) to trifluoroacetic acid (5 mL) and dichloromethane (10 mL), stir at room temperature for 1 hour. LC-MS monitoring of the reaction shows the disappearance of the starting material and the discovery of the target compound. Pour the reaction solution into saturated sodium bicarbonate solution, extract with dichloromethane (30 mL * 3), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure to dryness to obtain (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (yield 93%).

[0348] MS (ESI): m / z 300.1 (M + H) + .

[0349] Step 4: Dissolve (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (300 mg, 1 mmol, 1 eq.), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.5 eq.), cesium carbonate (3 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq.), tris(dibenzylideneacetone)dipalladium (0.1 eq.) in dioxane (6 mL). Under nitrogen protection, react at 100 °C for 3 hours. LC-MS monitoring of the reaction shows the disappearance of the starting material and the discovery of the target compound. Pour the reaction solution into water (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 30%).

[0350] MS (ESI): m / z 459.2 (M + H) + .

[0351] Step 5: Dissolve (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (30 mg, 0.07 mmol, 1 eq.) in hydrochloric acid / dioxane (3 mL) and methanol (3 mL), stir overnight at room temperature. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Pour the reaction solution into saturated sodium bicarbonate solution (80 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by preparative HPLC to obtain methyl (3S,5S)-5-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 41%).

[0352] MS(ESI): m / z 492.2(M + H) + .

[0353] Step 6: Dissolve methyl (3S,5S)-5-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (15 mg, 0.03 mmol, 1 eq.) in water (1 mL) and tetrahydrofuran (3 mL), add lithium hydroxide (3 eq.) at room temperature, then stir at room temperature for 3 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Adjust to pH about 3 with 2 M dilute hydrochloric acid, then pour into water (100 mL) and ethyl acetate (30 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate to obtain (3S,5S)-5-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 86%).

[0354] MS(ESI): m / z 478.2(M + H) + .

[0355] Step 7: Dissolve (3S,5S)-5-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (10 mg, 0.02 mmol, 1 eq.) in acetonitrile (2 mL), add 1-methyl-1H-pyrazol-4-amine (2 eq.) and propylphosphonic anhydride (1.5 eq.) at room temperature, and heat at 80 °C for 6 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was directly purified by reversed-phase preparative HPLC (formic acid) to obtain (2S)-N 2-(3-chloro-2,4-difluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-4-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 30.7%).

[0356] MS(ESI): m / z 557.2 (M+H) + .

[0357] 1 H NMR(400MHz, DMSO-d6) δ 10.26–10.15 (m, 1H), 7.90-7.55 (m, 2H), 7.49–7.31 (m, 2H), 6.75-6.65 (m, 1H), 6.58-6.36 (m, 1H), 4.65-4.40 (m, 1H), 3.96–3.82 (m, 1H), 3.80-3.75 (m, 3H), 3.69–3.55 (m, 1H), 3.10-3.08 (m, 3H), 2.38-2.30 (m, 3H), 2.23–2.11 (m, 1H), 2.10-1.90 (m, 1H).

[0358] Example 23

[0359] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 33) synthesis:

[0360]

[0361] First step: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (200 mg, 0.43 mmol, 1 eq.) in acetonitrile (4 mL), add 1-(2-methoxyethyl)pyrazol-4-amine (1.5 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature, and heat at 80 °C for 1 hour. LC-MS monitoring of the reaction showed that the starting material disappeared and the target compound was found. Pour the reaction solution into sodium bicarbonate solution (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by preparative HPLC (formic acid) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N4 -(1-(2-Methoxyethyl)-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 39.9%).

[0362] MS(ESI): m / z 583.29(M+H) +

[0363] Step 2: Dissolve (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (50.00 mg, 0.09 mmol, 1 eq.) in dichloromethane (4 mL). Add boron tribromide (3 eq.) at 0 °C and stir at room temperature for 1 hour. LC-MS monitoring shows the disappearance of the starting material and the discovery of the target compound. Pour the reaction mixture into sodium bicarbonate solution (100 mL), extract with dichloromethane (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 44.0%).

[0364] MS(ESI): m / z 569.22(M+H) +

[0365] 1 H NMR(400 MHz, DMSO-d6) δ 10.06(s, 1H), 7.90(s, 1H), 7.86(d, J = 4.6 Hz, 1H), 7.65 - 7.55(m, 2H), 7.42(s, 1H), 6.75(s, 1H), 6.55(s, 1H), 4.37(t, J = 9.1 Hz, 1H), 4.09(t, J = 5.3 Hz, 2H), 3.85 - 3.70(m, 1H), 3.68(t, J = 5.3 Hz, 2H), 3.57 - 3.52(m, 1H), 3.15(s, 3H), 3.11–2.98(m, 1H), 2.46(s, 3H), 2.30–2.21(m, 1H), 2.17–2.07(m, 1H).

[0366] Example 24

[0367] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 34) Synthesis:

[0368]

[0369] First step: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq.) in acetonitrile (4 mL). Add 1-[2-(dimethylamino)ethyl]pyrazol-4-amine (1.5 eq.) and 1-propylphosphonic anhydride cyclic (1.5 eq.) at room temperature. Heat at 80 °C for 1 hour. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Pour the reaction solution into sodium bicarbonate solution (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by preparative-HPLC (FA) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 32.2%).

[0370] MS(ESI): m / z 596.35(M + H) +

[0371] 11H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 7.92 (s, 1H), 7.87 (d, J = 6.3 Hz, 1H), 7.60 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 6.75 (s, 1H), 6.55 (s, 1H), 4.37 (t, J = 6.4 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 3.90 - 3.79 (m, 1H), 3.61–3.51 (m, 1H), 3.16 (s, 3H), 3.10 - 2.98 (m, 1H), 2.59 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H), 2.42 - 2.31 (m, 1H), 2.30 - 2.22 (m, 1H), 2.15 (s, 6H).

[0372] Example 25

[0373] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -( 1 H-pyrazol-3-yl)pyrrolidine-2,4-dicarboxamide (Synthesis of Compound 36:

[0374]

[0375] First step: To the N,N-dimethylformamide (10 mL) of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (200 mg, 0.43 mmol, 1.0 eq), add 1H-pyrazol-3-amine (1.0 eq), HATU (1.5 eq) and DIPEA (3.0 eq). Stir at 25 °C for 3 hours. Monitor the disappearance of the starting material by LC-MS and find the target compound. Concentrate the reaction solution, and purify the residue by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(1H-pyrazol-3-yl)pyrrolidine-2,4-dicarboxamide (yield 23.65%).

[0376] MS (ESI): m / z 525.1 (M+1) + .

[0377] 11H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 5.4 Hz, 1H), 7.57 (d, J = 6.8 Hz, 2H), 6.74 (s, 1H), 6.52 (s, 1H), 5.94 (d, J = 2.8 Hz, 1H), 5.67 (s, 2H), 4.45 (t, J = 7.6 Hz, 1H), 4.00–3.93 (m, 2H), 3.62–3.57 (m, 1H), 3.12 (s, 3H), 2.45 (s, 3H), 2.35–2.31 (m, 1H), 2.20–2.12 (m, 1H).

[0378] Example 26

[0379] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(isoxazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 37) Synthesis:

[0380]

[0381] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (25 mg, 0.05 mmol, 1.0 eq) was added to a solvent of DMF (2 mL), then HATU (1.2 eq), DIPEA (2.0 eq) and 1,2-oxazol-3-amine (4.0 eq) were added and the reaction was carried out at 25 °C for 15 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by preparative HPLC (formic acid system) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(isoxazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 8.7%).

[0382] MS (ESI): m / z 526.0 (M+1) + .

[0383] 11H NMR: (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.68 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.50 - 7.42 (m, 2H), 6.81 (d, J = 0.8 Hz, 1H), 6.63 (s, 1H), 6.43 (s, 1H), 4.26 (t, J = 8.0 Hz, 1H), 3.82 - 3.72 (m, 1H), 3.45 (t, J = 9.6 Hz, 1H), 3.12–3.06 (m, 1H), 3.03 (s, 3H), 2.34 (s, 3H), 2.26 - 2.22 (m, 1H), 2.05 - 1.97 (m, 1H).

[0384] Example 27

[0385] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,5-dimethyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 38) synthesis:

[0386]

[0387] (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1.0 eq) was added to the solvent of N,N-dimethylformamide (3 mL). First, 1,5-dimethyl-1H-pyrazol-3-amine (1.5 eq) was added, then HATU (1.5 eq) and DIPEA (3.0 eq). After displacing nitrogen, the mixture was stirred at 25 °C for 16 hours. LC-MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. The reaction solution was separated and purified by preparative HPLC (formic acid system) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,5-dimethyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 21.5%).

[0388] MS (ESI): m / z 553.2 (M+1) + .

[0389] 11H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 6.8 Hz, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.29 (s, 1H), 4.38 - 4.31 (m, 1H), 3.88 - 3.78 (m, 1H), 3.60 (s, 3H), 3.51 (t, J = 9.8 Hz, 1H), 3.15 (s, 3H), 3.12 – 3.03 (m, 1H), 2.46 (s, 3H), 2.31 - 2.24 (m, 1H), 2.21 (s, 3H), 2.15 - 2.05 (m, 1H).

[0390] Example 28

[0391] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-5-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 39) Synthesis:

[0392]

[0393] Step 1: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) in N,N-dimethylformamide (1 ml), add 1-methyl-5-aminopyrazole (1.2 eq), HATU (2 eq) and DIPEA (3 eq). After purging with nitrogen, stir at 20 °C for 12 hours. After filtering the reaction mixture, purify it by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-pyrazol-5-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 20.24%).

[0394] MS (ESI): m / z 539.0 (M+1) + .

[0395] 1HNMR(400MHz,DMSO-d6)δ10.01(s,1H),7.87(d,J=6.6Hz,1H),7.60(d,J=6.6Hz,2H),7.33(d,J=2.0Hz,1H),6.76(s,1H),6.57(s,1H),6.17(d,J=1.6Hz,1H),4.50–4.35(m,1H),3.95–3.85(m,1H),3.65(s,3H),3.63–3.56(m,1H),3.26–3.18(m,1H),3.16(s,3H),2.47(s,3H),2.40–2.25(m,1H),2.22–2.10(m,1H).

[0396] Example 29

[0397] (2S,4R)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2,4-dicarboxamide (Compound 51) synthesis:

[0398]

[0399] First step: Under nitrogen protection at -78 °C, LiHMDS (1M, 2.0 eq.) was added dropwise to a solution of dimethyl (tert-butoxycarbonyl)-L-glutamate (5.00 g, 18.16 mmol, 1.0 eq.) in tetrahydrofuran (50 mL). After the addition was complete, the reaction mixture was stirred at -78 °C for an additional 1 hour. Then benzyl chloromethyl ether (2.0 eq.) was added dropwise to the above reaction system. After the addition was complete, the reaction mixture was stirred at -78 °C for 3 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. At -78 °C, saturated ammonium chloride solution (100 mL) was slowly added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (100 mL * 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain dimethyl (2R,4S)-2-((benzyloxy)methyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (yield 38.85%).

[0400] MS(ESI):m / z 418.3(M+H) + .

[0401] Step 2: At 25 °C, trifluoroacetic acid (20 mL) was added to a solution of dimethyl (2R,4S)-2-((benzyloxy)methyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (2.79 g, 7.06 mmol, 1.0 eq.) in dichloromethane (20 mL). The reaction mixture was stirred at 25 °C for an additional 1 hour. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was concentrated, the pH was adjusted to 8 with saturated NaHCO3 solution, the aqueous phase was extracted with ethyl acetate (100 mL * 3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain dimethyl (2S,4R)-2-amino-4-((benzyloxy)methyl)pentanedioate (yield 76.79%).

[0402] MS(ESI): m / z 296.2(M + H) + .

[0403] Step 3: At 25 °C, dimethyl (2S,4R)-2-amino-4-((benzyloxy)methyl)pentanedioate (1.60 g, 5.42 mmol, 1.0 eq.) was dissolved in toluene (20 mL). The reaction solution was refluxed at 120 °C for 24 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was cooled to 25 °C, concentrated, and the residue was separated and purified by column chromatography (DCM:MeOH = 20:1) to obtain methyl (2S,4R)-4-((benzyloxy)methyl)-5-oxopyrrolidine-2-carboxylate (yield 42.1%).

[0404] MS(ESI): m / z 264.2(M + H) + .

[0405] Step 4: At 25 °C, lithium hydroxide monohydrate (3.0 eq.) was added to a mixed solution of methyl (2S,4R)-4-((benzyloxy)methyl)-5-oxopyrrolidine-2-carboxylate (560 mg, 2.13 mmol, 1.0 eq.) in methanol (8 mL) and water (1 mL). The reaction mixture was stirred at 25 °C for an additional 5 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was concentrated, the pH was adjusted to 2 with HCl (1 M), the aqueous phase was extracted with ethyl acetate (100 mL * 3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude (2S,4R)-4-((benzyloxy)methyl)-5-oxopyrrolidine-2-carboxylic acid, which was used directly in the next step without purification.

[0406] MS(ESI): m / z 250.2(M + H)+.

[0407] Step 5: At 25 °C, to a solution of compound (2S,4R)-4-((benzyloxy)methyl)-5-oxopyrrolidine-2-carboxylic acid (400 mg, crude, obtained from the previous step reaction) and 3-chloro-4-fluoro-N-methylaniline hydrochloride (376 mg) in pyridine (5 mL) was added propylphosphonic anhydride (1.527 g). The reaction mixture was stirred at 25 °C for an additional 16 hours. LC-MS monitoring of the reaction showed disappearance of the starting materials and the discovery of the target compound. The reaction solution was directly separated and purified by a C18 column (0.1% FA in water, MeOH) to obtain (2S,4R)-4-((benzyloxy)methyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-5-oxopyrrolidine-2-carboxamide (yield 80.0%).

[0408] MS(ESI): m / z 391.2 / 393.2 (M+H) + .

[0409] Step 6: At 25 °C under nitrogen protection, to a mixture of compound (2S,4R)-4-((benzyloxy)methyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-5-oxopyrrolidine-2-carboxamide (480 mg, 1.23 mmol, 1.0 eq.), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.5 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq.), tris(dibenzylideneacetone)dipalladium (0.1 eq.) and cesium carbonate (3.0 eq.) was added 1,4-dioxane (20 mL). The mixture was stirred at 80 °C for 1 hour. LC-MS monitoring of the reaction showed disappearance of the starting materials and the discovery of the target compound. The reaction solution was cooled to 25 °C and concentrated. The residue was separated and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain (2S,4R)-4-((benzyloxy)methyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (yield 68.7%).

[0410] MS(ESI): m / z 550.3 / 552.3 (M+H) + .

[0411] 11H NMR: (500 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.89 (d, J = 5.9 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.43 (s, 1H), 7.38 - 7.33 (m, 4H), 7.31 - 7.29 (m, 1H), 4.81 (t, J = 7.9 Hz, 1H), 4.52 (s, 2H), 3.73 - 3.60 (m, 2H), 3.16 (s, 3H), 3.01 - 2.97 (m, 1H), 2.62 (s, 3H), 2.27 - 2.16 (m, 1H), 2.01 - 1.92 (m, 1H).

[0412] Step 7: At 0 °C, boron trichloride (20 eq.) was added dropwise to a solution of compound (2S,4R)-4-((benzyloxy)methyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (450 mg, 0.82 mmol, 1.0 eq.) in dichloromethane (30 mL). The reaction mixture was stirred at 0 °C for an additional 5 minutes. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction was quenched by adding water (10 mL) at 0 °C, and the pH was adjusted to 9 with 5% sodium hydroxide solution. The aqueous phase was extracted with dichloromethane (50 mL * 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (DCM:MeOH = 10:1) to obtain (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (yield 79.73%).

[0413] MS(ESI): m / z 460.2 / 462.2 (M + H) + .

[0414] 1 1H NMR: (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.90 - 7.85 (m, 1H), 7.65 - 7.60 (m, 2H), 7.42 (s, 1H), 4.90 - 4.75 (m, 2H), 3.64 (s, 2H), 3.17 (s, 3H), 2.87 - 2.73 (m, 1H), 2.61 (s, 3H), 2.19 - 2.10 (m, 1H), 2.02 - 1.94 (m, 1H).

[0415] Step 8: At 0 °C, add [ruthenium(III) chloride (0.1 eq.) dissolved in water (1.5 mL)] to a solution of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (50 mg, 0.11 mmol, 1.0 eq.) in acetonitrile (1 mL). The reaction mixture was stirred at 0 °C for an additional 10 minutes. Then, sodium periodate (4.0 eq.) was added portionwise to the reaction system, and the reaction mixture was stirred at 25 °C for 1 hour. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by a C18 column (0.1% FA in water, MeOH) to give (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidine-3-carboxylic acid (yield 36.36%).

[0416] MS(ESI): m / z 474.2 / 476.2 (M+H) + .

[0417] Step 9: At 25 °C, add ammonium chloride (3.0 eq.), HATU (2.0 eq.) and DIEA (4.0 eq.) successively to a solution of (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidine-3-carboxylic acid (17 mg, 0.04 mmol, 1.0 eq.) in N,N-dimethylformamide (1.5 mL). The reaction mixture was stirred at 25 °C for an additional 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by a C18 column (0.1% FA in water, MeOH) to give (2S,4R)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2,4-dicarboxamide (yield 35.37%).

[0418] MS(ESI): m / z 473.2 / 475.2 (M+H) + .

[0419] 11H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.28 (m, 1H), 7.94 - 7.88 (m, 1H), 7.76 (s, 1H), 7.65 - 7.62 (m, 2H), 7.50 - 7.43 (m, 1H), 7.35 (s, 1H), 4.95 - 4.78 (m, 1H), 3.76 (t, J = 9.7 Hz, 1H), 3.19 - 3.16 (m, 3H), 2.62 (s, 3H), 2.45 - 2.25 (m, 2H).

[0420] Example 30

[0421] (2S,4S,5S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,5-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 52) Synthesis:

[0422]

[0423] Dissolve (2S,3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-2-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (40 mg, 0.08 mmol, 1.0 eq), HATU (2.0 eq), ammonium chloride (3.0 eq), DIEA (3 eq) in 1 mL of N,N-dimethylformamide, stir at 10 °C for 16 hours. LC-MS monitoring of the reaction shows the disappearance of the starting material and the discovery of the target compound. Add water (5 ml), extract with dichloromethane (5 mL * 2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by preparative plate separation (DCM:MeOH = 10:1) to obtain (2S,4S,5S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,5-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 49.2%).

[0424] MS (ESI): m / z 473.2 (M+1) + .

[0425] 11H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 5.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.32 (s, 1H), 7.01 (s, 1H), 6.71 (s, 1H), 6.39 (s, 1H), 4.32 - 4.23 (m, 2H), 3.17 (s, 3H), 3.00 – 2.87 (m, 1H), 2.45 (s, 3H), 2.24 - 2.20 (m, 1H), 1.96 - 1.91 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H).

[0426] Example 31

[0427] (2S,4R)-N 2 -(3-chloro-4-fluorophenyl)-4-fluoro-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 53) synthesis:

[0428]

[0429] First step: Add (2S)-1-[(tert-butoxy)carbonyl]-4-oxopyrrolidine-2-carboxylic acid (1 g, 4.36 mmol, 1.0 eq.) to the solvent of N,N-dimethylformamide (15 mL). First add 3-chloro-4-fluoro-N-methylaniline hydrochloride (1.0 eq), then add EDCI (2.0 eq) and pyridine (3.0 eq). After displacing nitrogen, stir at 25 °C for 16 hours. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Quench the reaction solution with water, extract with dichloromethane, combine and concentrate, then prepare a TLC plate (PE:EA = 2:1) for separation and purification to obtain the target compound tert-butyl (2S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-oxopyrrolidine-1-carboxylate (yield 61.9%).

[0430] MS(ESI): m / z 271.0 (M - 100 + H) - .

[0431] 1 1H NMR (400 MHz, CDCl3) δ 7.46 - 7.42 (m, 1H), 7.37 – 7.29 (m, 1H), 7.26 - 7.20 (m, 2H), 4.75 – 4.60 (m, 1H), 4.10 - 4.00 (m, 1H), 3.90 - 3.75 (m, 1H), 3.48 (d, J = 4.0 Hz, 1H), 3.25 (s, 3H), 2.45 - 2.30 (m, 1H), 1.52 - 1.44 (m, 9H).

[0432] Step 2: Add tert-butyl (2S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-oxopyrrolidine-1-carboxylate (3 g, 8.09 mmol, 1.0 eq.) into a solvent of water (30 mL) and tetrahydrofuran (20 mL). Add sodium bisulfate (2.0 eq.) at 0 °C and stir for half an hour. Then add potassium cyanide (2.0 eq.) and stir at 25 °C for 15.5 h. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction mixture with water, then extract it three times with dichloromethane. Combine the organic phases, concentrate, and purify by column chromatography (PE:EA = 2:1) to obtain tert-butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-hydroxypyrrolidine-1-carboxylate (yield 45.7%).

[0433] MS(ESI): m / z 298.0 (M - 100 + H) - .

[0434] Step 3: Add tert-butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-hydroxypyrrolidine-1-carboxylate (800 mg, 2.01 mmol, 1.0 eq.) into a solvent of dichloromethane (10 mL). Dropwise add DAST (2.0 eq.) at -78 °C and stir for 2 h, then raise the temperature to 25 °C and stir for another 14 h. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction mixture with water, then extract it three times with dichloromethane. Combine and concentrate the organic phases, and purify the residue by column chromatography (PE:EA = 2:1) to obtain tert-butyl (2S,4R)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-fluoropyrrolidine-1-carboxylate (yield 49.8%).

[0435] 1 H NMR(400 MHz, CDCl3) δ 7.52 - 7.40 (m, 1H), 7.37–7.29 (m, 1H), 7.25–7.10 (m, 1H), 4.42–3.88 (m, 3H), 3.28 - 3.25 (m, 3H), 2.55 - 2.40 (m, 2H), 1.49 - 1.46 (m, 9H).

[0436] Step 4: To a solution of tert-butyl (2S,4R)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-fluoropyrrolidine-1-carboxylate (350 mg, 0.88 mmol, 1.0 eq.) in dichloromethane (3 mL) was added trifluoroacetic acid (9.97 eq.). The mixture was stirred at 25 °C for 3 h. LC-MS monitoring showed the disappearance of the starting material and the formation of the target compound. The pH was adjusted to 8 with saturated aqueous NaHCO3 solution (10 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methylpyrrolidine-2-carboxamide (yield 83.4%).

[0437] MS(ESI): m / z 300.0 (M+H) + .

[0438] Step 5: To a solution of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methylpyrrolidine-2-carboxamide (200 mg, 0.67 mmol, 1.0 eq.) in dioxane (5 mL) were added 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.0 eq.), cesium carbonate (2.0 eq.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.3 eq.). Under nitrogen protection, tris(dibenzylideneacetone)dipalladium (0.1 eq.) was added, and the mixture was stirred at 100 °C for 6 h. LC-MS monitoring showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: PE / EA = 3 / 1) to give (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 47.8%). MS(ESI): m / z 459.0 (M+H) + .

[0439] Step 6: To a solution of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (115 mg, 0.25 mmol, 1.0 eq.) in dimethyl sulfoxide (2 mL) were added potassium carbonate (2.0 eq.) and 30% H2O2 (0.5 mL). The mixture was stirred at 60 °C for 3 h. LC-MS monitoring showed the disappearance of the starting material and the formation of the target compound. The mixture was filtered by suction, and the filtrate was purified by preparative HPLC to give (2S,4R)-N 2 -(3-chloro-4-fluorophenyl)-4-fluoro-N 2-Methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 58.7%).

[0440] MS(ESI): m / z 477.2 (M+H) + .

[0441] 1 H NMR (400 MHz, DMSO-d6) δ 7.86–7.84 (m, 2H), 7.75 (s, 1H), 7.57 (d, J = 7.2 Hz, 2H), 6.78 (s, 1H), 6.60 (s, 1H), 4.45 (t, J = 8.4 Hz, 1H), 3.95 (s, 1H), 3.90–3.84 (m, 1H), 3.14 (s, 3H), 2.56–2.52 (m, 1H), 2.45 (s, 3H), 2.39–2.31 (m, 1H).

[0442] Example 32

[0443] (2S,4R)-4-(2-Amino-2-oxoethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (Compound 62) synthesis:

[0444]

[0445] First step: In dichloromethane (4 mL) solvent of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (88 mg, 0.19 mmol, 1.0 eq), first add methanesulfonyl chloride (2.0 eq) and then add triethylamine (3.0 eq). After replacing nitrogen, stir at 25 °C for 2 hours. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction solution with water, then extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness by rotary evaporation to obtain [(3R,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidin-3-yl]methyl sulfonate crude product, which is not purified and directly used for the next step.

[0446] MS(ESI): m / z 538.0 (M+1) + .

[0447] Step 2: Sodium cyanide (65 mg) was added to a solution of [(3R,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidin-3-yl]methyl sulfonate (110 mg, crude, obtained from the previous step) in dimethyl sulfoxide (1 mL). After purging with nitrogen, the mixture was stirred at 80 °C for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was quenched with water, then extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give crude (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(cyanomethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide, which was used directly in the next step without purification.

[0448] MS(ESI): m / z 468.6(M+1) + .

[0449] Step 3: Potassium carbonate (53 mg) was added to a solution of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(cyanomethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (90 mg, crude, obtained from the previous step) in dimethyl sulfoxide (5 mL), followed by aqueous hydrogen peroxide solution (0.5 mL). After purging with nitrogen, the mixture was stirred at 60 °C for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was separated and purified by preparative HPLC (formic acid system) to give (2S,4R)-4-(2-amino-2-oxoethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (yield 18.5%);

[0450] MS(ESI): m / z 487.0(M+1) + .

[0451] 1 1H NMR: (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.96 - 7.92 (m, 1H), 7.67–7.61 (m, 2H), 7.42 (s, 2H), 6.90 (s, 1H), 4.85 (d, J = 9.6 Hz, 1H), 3.19 (s, 3H), 3.13–3.05 (m, 1H), 2.62 (s, 3H), 2.46 - 2.43 (m, 1H), 2.35–2.32 (m, 1H), 2.23 - 2.17 (m, 1H), 1.86 - 1.77 (m, 1H).

[0452] Example 33

[0453] Synthesis of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(3-(2-hydroxyethyl)urea)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 65):

[0454]

[0455] First step: Dissolve (2S,4S)-4-amino-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1.5 g, 4.34 mmol, 1 eq.) in tetrahydrofuran (10 mL) and water (10 mL), then add sodium carbonate (3 eq.), and stir for 10 minutes. Slowly add benzyl chloroformate (2 eq.) to the reaction system at 0 °C, and then stir at room temperature for 6 hours. LC-MS monitoring shows that the raw material disappears and the target compound is found. Pour the reaction solution into saturated ammonium chloride solution (150 mL), wash with ethyl acetate (40 mL * 3), and purify the aqueous phase by reverse-phase column (formic acid) to obtain (2S,4S)-4-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (yield 54.8%).

[0456] MS(ESI): m / z 265.2(M + H) + .

[0457] 1 1H NMR(400 MHz, DMSO-d6) δ 12.63(s, 1H), 7.48(d, J = 6.6 Hz, 1H), 7.41–7.28(m, 5H), 5.01(s, 2H), 4.13 - 3.96(m, 2H), 3.73 - 3.60(m, 1H), 3.02(t, J = 9.1 Hz, 2H), 2.48–2.39(m, 1H), 1.84 - 1.66(m, 1H), 1.36(s, 9H).

[0458] Second step: Dissolve (2S,4S)-4-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1 g, 2.74 mmol, 1 eq.) in acetonitrile (10 mL), add 3-chloro-4-fluoro-N-methylaniline hydrochloride (2 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature, heat at 80 °C for 1 hour. LC-MS monitoring shows that the raw material disappears and the target compound is found. Pour the reaction solution into sodium bicarbonate solution (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, then dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by silica gel column (ethyl acetate) to obtain

[0459] ((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)pyrrolidin-3-yl)benzyl carbamate (yield 56%).

[0460] MS(ESI): m / z 406.3(M+H) + .

[0461] Step 3: Dissolve ((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)pyrrolidin-3-yl)benzyl carbamate (200 mg, 0.49 mmol, 1 eq.), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.5 eq.), and DIEA (3 eq.) in N-methylpyrrolidone (2 mL). Under N2 protection, react at 150 °C for 1 hour using microwave. Monitor the disappearance of the starting material by LC-MS to find the target compound. Pour the reaction solution into water (150 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by column chromatography (PE / EtOAc = 3 / 1) to obtain [(3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-yl benzyl carbamate (yield 36.1%).

[0462] MS(ESI): m / z 565.3(M+H) + .

[0463] Step 4: Dissolve [(3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-yl]benzyl carbamate (480 mg, 0.85 mmol, 1 eq.) in dichloromethane (6 mL). Under N2 protection, add palladium dichloride (0.1 eq.) and triethylamine (1.5 eq.). Then add triethylsilane (1.5 eq.) at room temperature and stir for 3 hours. Monitor the reaction by LC-MS to show the disappearance of the starting material and find the target compound. Add trifluoroacetic acid (1 mL) to the reaction solution and stir for 0.5 hour. Then adjust to pH about 10 with 2 M NaOH solution, extract with dichloromethane (20 mL * 3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product of (2S,4S)-4-amino-N-(3-chloro-4-fluorophenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide, which is used directly in the next step without purification.

[0464] 11H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.34 (s, 1H), 7.23 (t, J = 8.6 Hz, 1H), 6.63 (s, 1H), 6.37 (s, 1H), 4.51 (dd, J = 9.2, 4.2 Hz, 1H), 3.72 - 3.62 (m, 2H), 3.56 - 3.46 (m, 1H), 3.29 (s, 3H), 2.50 (s, 3H), 2.31–2.21 (m, 1H), 1.95–1.86 (m, 1H).

[0465] Step 5: Dissolve (2S,4S)-4-amino-N-(3-chloro-4-fluorophenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (100 mg, crude product, obtained from the previous step reaction) and triethylamine (0.5 mL) in dichloromethane (4 mL), add CDI (37 mg) at 0 °C, and stir at low temperature for 0.5 h. Then add 2-methoxyethan-1-amine (17 mg) and stir at room temperature for 3 h. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Concentrate under reduced pressure, and purify the residue by reverse-phase column (FA) to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(3-(2-methoxyethyl)urea)-N-methyl-1-(6-methyl-4-trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (yield 90.5%).

[0466] MS (ESI): m / z 532.3 (M + H) + .

[0467] Step 6: Under ice-water bath conditions, add (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(3-(2-methoxyethyl)urea)-N-methyl-1-(6-methyl-4-trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (20 mg, 0.04 mmol, 1 eq) to dichloromethane (3 mL) of boron tribromide, and raise the temperature to room temperature for reaction for 1 h. Quench the reaction solution with saturated sodium bicarbonate solution (1 mL), concentrate, and separate and purify by preparative HPLC (FA acid) to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-(3-(2-hydroxyethyl)urea)-N-methyl-1-(6-methyl-4-trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (yield 29.0%). MS (ESI): m / z 553.3 (M + H) + . 11H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 5.8 Hz, 1H), 7.58 (d, J = 7.0 Hz, 2H), 6.74 (s, 1H), 6.51 (s, 1H), 6.30 (d, J = 8.4 Hz, 1H), 6.08 (t, J = 5.6 Hz, 1H), 4.64 (t, J = 5.2 Hz, 1H), 4.33 (t, J = 7.3 Hz, 1H), 4.29–4.17 (m, 1H), 3.72 (t, J = 8.0 Hz, 1H), 3.37 (q, J = 5.8 Hz, 2H), 3.24–3.20 (m, 1H), 3.18 (s, 3H), 3.05 (q, J = 5.8 Hz, 2H), 2.46 (s, 3H), 2.27 (dt, J = 15.0, 7.7 Hz, 1H), 1.81–1.69 (m, 1H).

[0468] Example 34

[0469] (2S,4S)-N 2 -(3-Chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-Methyl-1H-imidazol-2-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 79) Synthesis:

[0470]

[0471] First step: Add (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1.0 eq) to the solvent of N,N-dimethylformamide (3 mL). First add 1-methyl-1H-imidazol-2-amine (3.0 eq), then add pyridine (2.0 eq) and EDCI (3.0 eq). After displacing nitrogen, stir at 25 °C for 16 hours. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. The reaction solution is separated and purified by preparative HPLC (formic acid system) to obtain (2S,4S)-N 2 -(3-Chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-Methyl-1H-imidazol-2-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 2.9%).

[0472] MS (ESI): m / z 539.0 (M+1) + .

[0473] 1 1H NMR: (400 MHz, MeOD) δ 7.84 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 7.42 (t, J = 8.8 Hz, 1H), 6.97 (s, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.70 (s, 1H), 6.51 (s, 1H), 4.54 (t, J = 8.0 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.88 - 3.77 (m, 2H), 3.53 (s, 3H), 3.26 (s, 3H), 2.51 (s, 3H), 2.40 - 2.28 (m, 2H).

[0474] Example 35

[0475] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -{1-[2-(dimethylamino)ethyl]-1H-pyrazol-3-yl}-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 84) synthesis:

[0476]

[0477] First step: Dissolve 3-nitro-1H-pyrazole (200 mg, 1.77 mmol, 1 eq) in N,N-dimethylformamide (2 ml). At 0 °C, add sodium hydride (60%, 2.0 eq), and then add 2-chloro-N,N-dimethylethylamine hydrochloride (1.5 eq). Stir at 80 °C for 2 hours. Cool the reaction solution to room temperature, add water (2 mL) to the reaction solution, then extract with ethyl acetate (6 mL). Wash the organic phase three times with saturated brine (12 mL * 3). After rotary evaporation, purify by preparative TLC (PE:EA = 2:1) to obtain N,N-dimethyl-2-(3-nitropyrazol-1-yl)ethylamine (yield 15.35%).

[0478] MS(ESI): m / z 185.2 (M+1) + .

[0479] 1 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 4.29 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.28 (s, 6H).

[0480] Step 2: Dissolve N,N-dimethyl-2-(3-nitropyrazol-1-yl)ethanamine (50 mg, 0.17 mmol, 1 eq) in methanol (2 mL), then add palladium on carbon (10%, 50 mg). After displacing with hydrogen three times, stir at 20 °C for two hours. Filter the reaction solution, and rotary evaporate the filtrate to obtain 1-[2-(dimethylamino)ethyl]-1H-pyrazol-3-amine (yield 84.1%).

[0481] MS(ESI): m / z 155.2(M+1) + .

[0482] Step 3: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (100 mg, 0.22 mmol, 1 eq) in N,N-dimethylformamide (2 mL), add 1-[2-(dimethylamino)ethyl]-1H-pyrazol-3-amine (1.2 eq), HATU (2 eq) and DIEA (3 eq). After displacing with nitrogen, stir at 20 °C for 12 hours. Filter the reaction solution, and separate and purify the filtrate by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -{1-[2-(dimethylamino)ethyl]-1H-pyrazol-3-yl}-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 27.3%).

[0483] MS(ESI): m / z 596.2(M+1) + .

[0484] 1 1H NMR(400 MHz, DMSO-d6) δ 10.53(s, 1H), 7.88(d, J = 5.6 Hz, 1H), 7.65–7.57(m, 3H), 6.76(s, 1H), 6.56(s, 1H), 6.46(d, J = 2.0 Hz, 1H), 4.37(t, J = 7.6 Hz, 1H), 4.09(t, J = 6.4 Hz, 2H), 3.91–3.81(m, 1H), 3.55(t, J = 9.6 Hz, 1H), 3.17(s, 3H), 3.15–3.12(m, 1H), 2.61(t, J = 6.4 Hz, 2H), 2.48(s, 3H), 2.36–2.25(m, 1H), 2.17(s, 6H), 2.15–2.10(m, 1H).

[0485] Example 36

[0486] (2S,4S)-N 2 -(3-Chloro-4-fluorophenyl)-N 4 -[1-(2-Hydroxyethyl)-1H-pyrazol-3-yl]-N 2 -Methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 85) Synthesis:

[0487]

[0488] First step: (3S,5S)-5-[(3-Chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) and HATU (1.5 eq) were successively added to a solution of N,N-dimethylformamide (2 mL). DIPEA (3 eq) was added, and under nitrogen protection, the mixture was stirred at 25 °C for 16 hours. LC-MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. The reaction solution was filtered and concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-Chloro-4-fluorophenyl)-N 4 -[1-(2-Hydroxyethyl)-1H-pyrazol-3-yl]-N 2 -Methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 5.9%).

[0489] MS (ESI): m / z 569.32 (M+1) + .

[0490] 1 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.65 - 7.63 (m, 1H), 7.33 – 7.32 (m, 2H), 7.25 - 7.23 (m, 1H), 6.68 (s, 1H), 6.61 (d, J = 1.6 Hz, 1H), 6.42 (s, 1H), 4.56 – 4.52 (m, 1H), 4.14 – 4.12 (m, 2H), 3.98 – 3.92 (m, 3H), 3.82 – 3.77 (m, 1H), 3.29 (s, 3H), 3.25 – 3.19 (m, 1H), 2.51 (s, 3H), 2.46 – 2.36 (m, 2H).

[0491] Example 37

[0492] Synthesis of (3S,5S)-5-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (Compound 88):

[0493]

[0494] Step 1: Sodium methoxide (10.0 eq) was added to a solution of methanol (30 mL). 3-Chloro-2,4-difluoroaniline (5 g, 30.57 mmol, 1 eq), paraformaldehyde (1.5 eq) were added. After reacting at 25 °C for 12 hours, sodium borohydride (2 eq) was added, and then stirred at 25 °C for 2 hours. The reaction mixture was monitored by LC-MS until the starting materials disappeared and the target compound was found. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE:EA = 1:1) to obtain 3-chloro-2,4-difluoro-N-methylaniline (yield 84.7%).

[0495] MS(ESI): m / z 178.0 (M+H) + .

[0496] Step 2: A solution of lithium hydroxide (3.0 eq) in water (50 mL) was slowly added to a solution of (2S,4S)-1-tert-butyl 2-methyl 4-cyanopyrrolidine-1,2-dicarboxylate (25 g, 98.32 mmol, 1.0 eq) in tetrahydrofuran (250 mL). The mixture was stirred at 25 °C for 5 hours. The reaction mixture was monitored by LC-MS until the starting materials disappeared and the target compound was found. The pH of the reaction solution was adjusted to 5 with 1 M dilute HCl (80 mL), and the mixture was extracted with ethyl acetate (600 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain (2S,4S)-1-(tert-butoxycarbonyl)-4-cyanopyrrolidine-2-carboxylic acid (yield 97.5%).

[0497] MS(ESI): m / z 185.0 (M - 55) + .

[0498] Step 3: (2S,4S)-1-[(tert-Butoxy)carbonyl]-4-cyanopyrrolidine-2-carboxylic acid (1 g, 4.16 mmol, 1.0 eq), 3-chloro-2,4-difluoro-N-methylaniline (1.2 eq), and 1-propylphosphonic anhydride (3 eq, 50% DMF solution) were successively added to a pyridine (15 mL) solution. Under nitrogen protection, the mixture was stirred at 25 °C for 16 h. The disappearance of the starting materials was monitored by LC-MS, and the target compound was found. Ethyl acetate (30 mL) was added, and the mixture was washed with aqueous lithium chloride solution (20 mL × 2), washed with aqueous sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then loaded onto a column for purification by column chromatography (DCM:MeOH = 10:1) to obtain tert-butyl (2S,4S)-2-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (yield 6.5%).

[0499] MS(ESI): m / z 300.0 (M + H - 100) + .

[0500] Step 4: tert-Butyl (2S,4S)-2-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (108 mg, 0.27 mmol, 1 eq) was added to dichloromethane (2.5 mL), and trifluoroacetic acid (16.24 eq) was added. Under nitrogen protection, the mixture was stirred at 25 °C for 2 h. The disappearance of the starting materials was monitored by LC-MS, and the target compound was found. The pH of the reaction solution was adjusted to 8 with aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried by rotary evaporation to obtain (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (yield 98.8%).

[0501] MS(ESI): m / z 300.0 (M + H) + .

[0502] Step 5: (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (100 mg, 0.33 mmol, 1.0 eq), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.1 eq), [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (0.2 eq), tris(dibenzylideneacetone)dipalladium (0.1 eq) and cesium carbonate (3 eq) were successively added to dioxane (10 mL) under nitrogen protection. The temperature was raised to 100 °C and stirred for 4 hours. LC-MS monitored the disappearance of the raw materials and the target compound was found. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated and purified by column chromatography (PE:EA = 2:1) to obtain (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 39.2%)

[0503] MS(ESI): m / z 459.0 (M+H) + .

[0504] Step 6: (2S,4S)-N-(3-chloro-2,4-difluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (70 mg, 0.15 mmol, 1 eq) and sodium hydroxide (2 eq) were successively added to tetrahydrofuran (5 mL) under nitrogen protection and stirred at 25 °C for 2 hours. LC-MS monitored the disappearance of the raw materials and the target compound was found. The pH value of the reaction solution was adjusted to 5 with 1 M dilute HCl, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and purified by preparative HPLC to obtain (3S,5S)-5-[(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 13.1%).

[0505] MS(ESI): m / z 477.6 (M+H) + .

[0506] 1HNMR(400MHz,DMSO-d6)δ7.80-7.76(m,1H),7.60-7.34(m,2H),6.73-6.70(m,1H),6.52-6.43(m,1H),4.42-4.32(m,1H),3.86-3.78(m,1H),3.60-3.52(m,2H),3.11(s,4H),2.49-2.37(m,3H),2.32-2.21(m,1H).

[0507] Example 38

[0508] (2S,3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-2-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (Compound 89) synthesis:

[0509]

[0510] First step: At 20 °C, potassium carbonate (1.26 eq) and methyl iodide (1.0 eq) were added to a solution of [(3S)-3-{[(benzyloxy)carbonyl]amino}-4-(tert-butoxy)-4-oxobutoxy](hydroxy)methylene (10.0 g, 29.64 mmol, 1.0 eq) in N,N-dimethylformamide (20 ml). After stirring for 18 hours, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, washed successively with water and saturated brine, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain 1-tert-butyl 5-methyl (2S)-2-{[(benzyloxy)carbonyl]amino}pentanedioate (yield 96.0%).

[0511] 1 H NMR(400MHz,CDCl3)δ7.45–7.27(m,5H),5.41(d,J=7.6Hz,1H),5.10(s,2H),4.30-4.27(m,1H),3.65(s,3H),2.51–2.29(m,2H),2.20-2.15(m,1H),1.99-1.91(m,1H),1.46(s,9H).

[0512] Step 2: At -78 °C, a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.7 eq) was added dropwise to a solution of 1-tert-butyl 5-methyl (2S)-2-{[(benzyloxy)carbonyl]amino}pentanedioate (4.1 g, 11.67 mmol, 1.0 eq) in anhydrous tetrahydrofuran (40 mL). After stirring for 30 min, acetyl chloride (2.98 eq) was added, and the reaction mixture was stirred at -78 °C for one hour. The reaction mixture was quenched with glacial acetic acid (31.5 eq), heated to 50 °C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed successively with saturated NaHCO3 and saturated brine, then dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the resulting residue was separated by column chromatography to obtain 1-benzyl 2-tert-butyl 4-methyl (2S)-5-methyl-2,3-dihydro-1H-pyrrole-1,2,4-tricarboxylate (yield 31.0%).

[0513] MS(ESI): m / z 276.0 (M - 100 + 1) + .

[0514] 1 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.25 (m, 5H), 5.16 (s, 2H), 4.68 - 4.60 (m, 1H), 3.71 (s, 3H), 3.09–3.04 (m, 1H), 2.73–2.67 (m, 1H), 2.66 (s, 3H), 1.38 (s, 9H).

[0515] Step 3: To a solution of 1-benzyl 2-tert-butyl 4-methyl (2S)-5-methyl-2,3-dihydro-1H-pyrrole-1,2,4-tricarboxylate (3.8 g, 10.12 mmol, 1.0 eq) in acetic acid (20 mL) was added platinum dioxide (0.1 eq). The mixture was stirred under hydrogen at 20 °C for 16 hours, filtered through diatomaceous earth, and the diatomaceous earth was washed with 10 mL of ethyl acetate. The filtrate was concentrated in vacuo, adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography to obtain 2-tert-butyl 4-methyl (2S,4S,5S)-5-methylpyrrolidine-2,4-dicarboxylate (yield 52.8%).

[0516] MS(ESI): m / z 244.2 (M - 100 + 1) + .

[0517] Step 4: 2-tert-Butyl 4-methyl (2S,4S,5S)-5-methylpyrrolidine-2,4-dicarboxylate (1.2 g, 4.93 mmol, 1.0 eq) was added to a mixture of trifluoroacetic acid (8 mL) and water (2 mL). The resulting mixture was stirred at 20 °C for 16 h. TLC (EA / PE = 1:4) monitoring showed that the reaction was almost complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product of (2S,4S,5S)-4-(methoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid, which was used directly in the next step without purification.

[0518] Step 5: (2S,4S,5S)-4-(Methoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (850 mg, crude product, obtained from the previous step) was added to a stirred solution of THF (4 mL) and water (4 mL). A solution of NaHCO3 (1.527 g) and di-tert-butyl dicarbonate (1.387 g) in THF (4 mL) was then added. After stirring at room temperature for 16 h, ethyl acetate (30 mL) was added for extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (2S,4S,5S)-1-[(tert-butoxy)carbonyl]-4-(methoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (yield 56.7%).

[0519] MS (ESI): m / z 188.0 (M - 100 + 1) + .

[0520] 1 1H NMR (400 MHz, CDCl3) δ 4.42–4.21 (m, 2H), 3.73 (s, 3H), 3.19–3.11 (m, 1H), 2.69 - 2.41 (m, 2H), 1.48 (s, 9H), 1.12 (d, J = 6.4 Hz, 3H).

[0521] Step 6: (2S,4S,5S)-1-[(tert-Butoxy)carbonyl]-4-(methoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (490 mg, 1.71 mmol, 1 eq) and 3-chloro-4-fluoro-N-methylaniline hydrochloride (1 eq) were dissolved in pyridine (10 mL). Under nitrogen protection, a DMF solution of 50% propylphosphonic anhydride (1.84 eq) was added. The mixture was stirred at 20 °C for 16 h. LC-MS monitoring showed the disappearance of the starting materials and the formation of the target compound. The reaction mixture was concentrated under reduced pressure directly and then purified by column chromatography (EA / PE = 1:4) to obtain 1-tert-butyl 3-methyl (2S,3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-2-methylpyrrolidine-1,3-dicarboxylate (yield 75%).

[0522] MS(ESI): m / z 429.2 (M+1) + .

[0523] 1 H NMR(400 MHz, CDCl3) δ 7.47 - 7.16 (m, 3H), 4.37–4.05 (m, 2H), 3.69 (s, 3H), 3.26 (s, 3H), 2.96 - 2.91 (m, 1H), 2.36 - 2.26 (m, 1H), 1.96 - 1.91 (m, 1H), 1.47 (d, J = 9.6 Hz, 9H), 1.20 (t, J = 6.8 Hz, 3H).

[0524] Step 7: Add 1-tert-butyl 3-methyl (2S,3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-2-methylpyrrolidine-1,3-dicarboxylate (100 mg, 0.23 mmol, 1 eq) to dichloromethane (3 mL), then add trifluoroacetic acid (1 mL), stir at room temperature for 3 hours, and directly rotary evaporate the reaction solution under reduced pressure to obtain the crude product of methyl (2S,3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-2-methylpyrrolidine-3-carboxylate, which is used directly in the next step without purification.

[0525] MS(ESI): m / z 329.2 (M+1) + .

[0526] Step 8: Dissolve methyl (2S,3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-2-methylpyrrolidine-3-carboxylate (70 mg, crude product, obtained from the previous step reaction), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (41 mg), and N,N-diisopropylethylamine (3 mL) in N-methylpyrrolidone (1.5 ml) solution, react at 150 °C under microwave for 6 hours, monitor the reaction by LC-MS, and it shows that the raw materials disappear and the target compound is found. Add water (10 mL) and ethyl acetate (10 mL) for liquid separation, rotary evaporate the organic phase, and purify it by preparative plate TLC separation (P:E = 3:1) to obtain methyl (2S,3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-2-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 12.7%).

[0527] MS(ESI): m / z 488.2 (M+1) + .

[0528] 11H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.37 (s, 1H), 7.22 (t, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.36 (s, 1H), 4.41 (dd, J = 10.0, 8.0 Hz, 1H), 4.33–4.22 (m, 1H), 3.73 (s, 3H), 3.28 (s, 3H), 3.13–3.04 (m, 1H), 2.48 (s, 3H), 2.18–2.08 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.25 - 1.22 (m, 1H).

[0529] Step 9: Dissolve methyl (2S,3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-2-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (90 mg, 0.18 mmol, 1.0 eq) in 2 mL of tetrahydrofuran. While stirring, add 1 mL of an aqueous solution of sodium hydroxide (5.56 eq). Stir at room temperature for 16 hours. LC-MS monitoring of the reaction shows that the starting material has disappeared and the target compound is found. Rotate the flask under reduced pressure to remove tetrahydrofuran. Adjust the residual solution to acidic pH = 2 with dilute hydrochloric acid, then add ethyl acetate (5 mL * 2) for extraction and liquid separation. Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by preparative plate TLC separation (DCM:MeOH = 15:1) to obtain (2S,3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-2-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (yield 85.3%).

[0530] MS (ESI): m / z 474.0 (M+1) + .

[0531] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 6.4 Hz, 2H), 6.71 (s, 1H), 6.49 (s, 1H), 4.30 - 4.26 (m, 2H), 3.17 (s, 3H), 3.15 - 3.11 (m, 1H), 2.45 (s, 3H), 2.17 - 2.12 (m, 2H), 1.15 (d, J = 6.4 Hz, 3H).

[0532] Example 39

[0533] Synthesis of (3S,5S)-5-[(5-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (Compound 90):

[0534]

[0535] Step 1: To a solution of (2S,4S)-1-[(tert-butoxy)carbonyl]-4-cyanopyrrolidine-2-carboxylic acid (2 g, 8.32 mmol, 1 eq) in pyridine (10 mL) at 20 °C was added 5-chloro-2,4-difluoro-N-methylaniline hydrochloride (1.2 eq) and a solution of 50% propylphosphonic anhydride (3 eq) in N,N-dimethylformamide. Under nitrogen protection, after stirring at 20 °C for 6 hours, LC-MS monitoring showed the disappearance of the starting material and the discovery of the target compound. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed successively with saturated lithium chloride solution (50 mL × 3), saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and then the organic phase was concentrated. Purification by column chromatography (PE:EA = 64:36) gave tert-butyl (2S,4S)-2-[(5-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (yield 12.0%).

[0536] MS(ESI): m / z 300.1 (M - 100 + 1) + .

[0537] Step 2: To a solution of tert-butyl (2S,4S)-2-[(5-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (100 mg, 0.25 mmol, 1 eq) in dichloromethane (2 mL) at 20 °C was added trifluoroacetic acid (0.2 mL). Under nitrogen protection, after stirring at 20 °C for 3 hours, LC-MS monitoring showed the disappearance of the starting material and the discovery of the target compound. Water (8 mL) was added to the reaction solution, and the pH was adjusted to weakly basic with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated. Purification by preparative TLC plate (PE:EA = 3:1) gave (2S,4S)-N-(5-chloro-2,4-difluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (yield 40.0%).

[0538] MS(ESI): m / z 300.1 (M + 1) + .

[0539] Step 3: To a solution of (2S,4S)-N-(5-chloro-2,4-difluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (310 mg, 1.03 mmol, 1.0 eq) in dioxane (5 mL), add 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.1 eq), cesium carbonate (3.0 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq). Under nitrogen displacement protection, add tris(dibenzylideneacetone)dipalladium (0.1 eq), and stir the reaction at 100 °C for 4 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Add water (8 mL) to the reaction solution, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated sodium chloride solution (15 mL×3), dry over anhydrous sodium sulfate, concentrate the organic phase, and separate and purify by column chromatography (MeOH:DCM = 7:93) to obtain (2S,4S)-N-(5-chloro-2,4-difluorophenyl)-4-cyano-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide (yield 46.4%).

[0540] MS(ESI): m / z 459.0(M+1) + .

[0541] Step 4: To (2S,4S)-N-(5-chloro-2,4-difluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (180 mg, 0.39 mmol, 1 eq), add 2.5 mL of methanol and dioxane hydrochloride (52.6 eq), and stir at 20 °C for 16 hours under nitrogen protection. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Dropwise add saturated sodium bicarbonate solution to the reaction solution to adjust the pH of the reaction solution to neutral, extract with dichloromethane (15 mL×3), combine the organic phases, concentrate and rotary evaporate to obtain methyl (3S,5S)-5-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylate (yield 93.8%).

[0542] MS(ESI): m / z 492.0(M+1) + .

[0543] Step 5: Dissolve methyl ((3S,5S)-5-[(5-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate) (60 mg, 0.12 mmol, 1 eq) in tetrahydrofuran (4 mL) at 15 °C, and add aqueous sodium hydroxide solution (3.33 eq). Stir at 15 °C for 16 h under nitrogen protection. LC-MS monitoring of the reaction shows that the starting material has disappeared and the target compound is found. Add aqueous hydrochloric acid solution (1 M) to the reaction solution to adjust the reaction solution to pH = 5, extract with ethyl acetate (5 mL × 3), combine the organic phases, concentrate the organic phases, and separate and purify by preparative TLC plate (MeOH:DCM = 1:10) to obtain (3S,5S)-5-[(5-chloro-2,4-difluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 16.4%).

[0544] MS(ESI): m / z 478.0(M+1) + .

[0545] 1 H NMR(400 MHz, DMSO-d6) δ 8.05 - 8.00(m, 1H), 7.97 - 7.92(m, 1H), 7.87 - 7.81(m, 2H), 7.66–7.56(m, 1H), 6.76(s, 1H), 6.75 - 6.71(m, 1H), 6.57(s, 1H), 6.43(s, 1H), 4.48 - 4.43(m, 1H), 4.31 - 4.26(m, 1H), 3.80 - 3.74(m, 1H), 3.66–3.53(m, 2H), 3.49(s, 1H), 3.16 - 3.13(m, 1H), 3.11(s, 3H), 3.09(s, 2H), 2.39 - 2.35(m, 3H), 2.27 - 2.20(m, 3H), 2.08 - 2.03(m, 1H).

[0546] Example 40

[0547] (2S,4S)-4-(2-Amino-2-oxoethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (Compound 91) Synthesis:

[0548]

[0549] Step 1: (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(cyanomethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (90 mg, 0.19 mmol, 1.0 eq) was added to a solvent of dimethyl sulfoxide (5 mL) in a 50 mL single-necked flask. First, potassium carbonate (2.0 eq) was added, followed by aqueous hydrogen peroxide solution (20 eq). After purging with nitrogen, the mixture was stirred at 60 °C for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by preparative HPLC (formic acid system) to obtain (2S,4S)-4-(2-amino-2-oxoethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (yield 18.6%).

[0550] MS(ESI): m / z 487.0 (M+1) + .

[0551] 1 1H NMR: (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.45 - 7.40 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 6.58 (s, 1H), 4.75 - 4.66 (m, 1H), 3.14 (s, 3H), 2.70 - 2.63 (m, 3H), 2.33 (s, 3H), 2.07 - 1.98 (m, 1H), 1.73 - 1.65 (m, 1H).

[0552] Example 41

[0553] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(oxetan-3-yl)pyrrolidine-2,4-dicarboxamide (Compound 92) Synthesis:

[0554]

[0555] Step 1: To a solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) in N,N-dimethylformamide (2 ml) was added oxetan-3-amine (1.2 eq), HATU (1.5 eq), DIPEA (3 eq). Under nitrogen protection, the mixture was stirred at 20 °C for 16 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was filtered and concentrated, dissolved in DMSO, and then separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(oxetan-3-yl)pyrrolidine-2,4-dicarboxamide (yield 14.6%).

[0556] MS(ESI): m / z 515.2 (M+1) + .

[0557] 1 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.33 (s, 1H), 7.22 - 7.30 (m, 1H), 6.72 (s, 1H), 6.44 (s, 1H), 5.00 - 4.93 (m, 1H), 4.92 - 4.86 (m, 2H), 4.63 - 4.57 (m, 2H), 4.51 - 4.47 (m, 1H), 3.88 (dd, J = 10.0, 4.4 Hz, 1H), 3.65 (t, J = 9.2 Hz, 1H), 3.32 (s, 3H), 3.20 – 3.14 (m, 1H), 2.52 (s, 3H), 2.45 – 2.37 (m, 1H), 2.30 - 2.10 (m, 1H).

[0558] Example 42

[0559] (2S,4S)-N 4 -(azetidin-3-yl)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 93) Synthesis:

[0560] Step 1: To a solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (100 mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 ml), add tert-butyl 3-aminoazetidine-1-carboxylate (1.2 eq), HATU (1.5 eq), and DIPEA (3 eq). Stir at 20 °C for 16 h under nitrogen protection. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Add water (20 mL) to the reaction solution, extract with ethyl acetate (10 mL * 3), combine the organic phases, wash successively with saturated lithium chloride solution (3 * 10 ml), saturated sodium chloride solution (10 mL * 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate in vacuo to obtain tert-butyl 3-((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)aminocarbonyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxamido)azetidine-1-carboxylate (yield 72.7%).

[0561] MS(ESI): m / z 614.2 (M+1) + .

[0562] Step 2: At 20 °C, add trifluoroacetic acid (0.5 ml) to a solution of tert-butyl 3-((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)aminocarbonyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxamido)azetidine-1-carboxylate (100 mg, 0.16 mmol, 1.0 eq) in dichloromethane (5 ml). Stir at 20 °C for 3 h under nitrogen protection. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Filter and concentrate the reaction solution, dissolve it in DMF, and purify it by preparative HPLC to obtain (2S,4S)-N 4 -(azetidin-3-yl)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 60.8%).

[0563] MS(ESI): m / z 514.2 (M+1) + .

[0564] 11H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 7.2 Hz, 1H), 8.58 (s, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 7.24 - 7.21 (m, 1H), 6.67 (s, 1H), 6.43 (s, 1H), 4.76 (s, 1H), 4.49–4.44 (m, 1H), 4.22 - 4.15 (m, 2H), 3.89–3.86 (m, 2H), 3.70–3.62 (m, 2H), 3.27 (s, 3H), 3.12–3.06 (m, 1H), 2.50 (s, 3H), 2.36 - 2.31 (m, 2H).

[0565] Example 43

[0566] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 4 -(piperidin-4-yl)pyrrolidine-2,4-dicarboxamide (Compound 94) Synthesis:

[0567]

[0568] First step: (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (100 mg, 0.22 mmol, 1 eq), tert-butyl 4-aminopiperidine-1-carboxylate (1.2 eq), HATU (1.5 eq) were added successively to a solution of N,N-dimethylformamide (2 mL), then DIPEA (3 eq) was added, protected by nitrogen, and stirred at 25 °C for 16 h. LC-MS monitoring of the reaction showed that the raw materials disappeared and the target compound was found. The reaction solution was added with ethyl acetate (30 mL), washed with saturated lithium chloride aqueous solution (10 mL * 3), washed with saturated sodium chloride aqueous solution (10 mL * 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then separated and purified by column chromatography (PE:EA = 1:1) to obtain tert-butyl 4-[(3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-ylamino]piperidine-1-carboxylate (yield 60%).

[0569] MS (ESI): m / z 642.2 (M + 1) + .

[0570] Step 2: tert-Butyl 4-[(3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-ylamino]piperidine-1-carboxylate (100 mg, 0.16 mmol, 1 eq) and trifluoroacetic acid (56.31 eq) were successively added to a solution of dichloromethane (3 mL). Under nitrogen protection, the mixture was stirred at 25 °C for 4 hours. LC-MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(piperidin-4-yl)pyrrolidine-2,4-dicarboxamide (yield 23.7%).

[0571] MS (ESI): m / z 542.2 (M+1) + .

[0572] 1 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.65 (s, 1H), 7.30 - 7.29 (m, 1H), 7.26 - 7.22 (m, 1H), 6.69 (s, 1H), 6.41 (s, 1H), 4.50 - 4.47 (m, 1H), 3.93 - 3.83 (m, 1H), 3.84 - 3.80 (m, 1H), 3.69 - 3.65 (m, 1H), 3.28 (s, 3H), 3.26–3.25 (m, 1H), 3.10 - 3.08 (m, 1H), 2.88 - 2.82 (m, 4H), 2.50 (s, 3H), 2.42 - 2.34 (m, 1H), 2.23–2.17 (m, 1H), 2.06–2.02 (m, 2H), 1.71–1.65 (m, 2H).

[0573] Example 44

[0574] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -{1-(2-morpholinoethyl)-1H-pyrazol-3-yl}pyrrolidine-2,4-dicarboxamide (Compound 95) synthesis:

[0575]

[0576] Step 1: Dissolve 3-nitro-1H-pyrazole (1 g, 8.84 mmol, 1 eq) in N,N-dimethylformamide (10 mL). At 0 °C, add sodium hydride (60%, 2.0 eq), and then add 4-(2-chloroethyl)morpholine (1.2 eq). Stir at 80 °C for 2 hours. Cool the reaction mixture to room temperature, add water (10 mL) to the reaction mixture, and then extract with ethyl acetate (30 mL). Combine the organic phases, wash three times with saturated brine (60 mL * 3), and then concentrate under reduced pressure. Purify by normal-phase column chromatography (PE:EA = 2:1) to obtain 4-[2-(3-nitro-1H-pyrazol-1-yl)ethyl]morpholine (yield 43%).

[0577] MS(ESI): m / z 227.1 (M+1) + .

[0578] 1 HNMR(400 MHz, DMSO-d6) δ 8.04 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 4.36 (t, J = 6.4 Hz, 2H), 3.61–3.48 (m, 4H), 2.74 (t, J = 6.4 Hz, 2H), 2.45–2.36 (m, 4H).

[0579] Step 2: Dissolve 4-[2-(3-nitro-1H-pyrazol-1-yl)ethyl]morpholine (860 mg, 3.8 mmol, 1 eq) in methanol (10 mL). Add palladium on carbon (10%, 80 mg), displace with hydrogen, and then stir at room temperature (20 °C) for 3 hours. Filter the reaction mixture, and rotary evaporate the filtrate to obtain 1-(2-morpholinoethyl)-1H-pyrazol-3-amine (yield 94.6%).

[0580] MS(ESI): m / z 197.2 (M+1) + .

[0581] 1 HNMR(400 MHz, DMSO-d6) δ 7.29 (d, J = 2.4 Hz, 1H), 5.34 (d, J = 2.4 Hz, 1H), 4.48 (s, 2H), 3.92 (t, J = 6.8 Hz, 2H), 3.58–3.48 (m, 4H), 2.59 (t, J = 6.8 Hz, 2H), 2.40–2.33 (m, 4H).

[0582] Step 3: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) in N,N-dimethylformamide (1 mL), add 1-(2-morpholinoethyl)-1H-pyrazol-3-amine (1.2 eq), HATU (2 eq) and DIPEA (3 eq). After purging with nitrogen, stir at 20 °C for 12 h. After filtering the reaction mixture, purify it by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -{1-(2-morpholinoethyl)-1H-pyrazol-3-yl}pyrrolidine-2,4-dicarboxamide (yield 20.4%).

[0583] MS(ESI): m / z 638.2 (M+1) + .

[0584] 1 HNMR(400 MHz, DMSO_d6) δ 10.52 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.68–7.53 (m, 3H), 6.75 (s, 1H), 6.53 (s, 1H), 6.46 (s, 1H), 4.40–4.30 (m, 1H), 4.11 (s, 2H), 3.90–3.75 (m, 1H), 3.65–3.45 (m, 6H), 3.15 (s, 3H), 3.13–3.08 (m, 1H), 2.75–2.60 (m, 2H), 2.46 (s, 3H), 2.40–2.30 (m, 3H), 2.29–2.22 (m, 1H), 2.18–2.06 (m, 1H).

[0585] Example 45

[0586] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -(methyl-d3)-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 96) Synthesis:

[0587]

[0588] Step 1: Dissolve 3-chloro-4-fluoroaniline (60 mg, 0.12 mmol, 1 eq) in tetrahydrofuran (4 mL) at 15 °C, and add aqueous sodium hydroxide solution (1 M, 3.33 eq), di-tert-butyl dicarbonate (1.2 eq). Under nitrogen protection, stir at 15 °C for 16 hours. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Add aqueous hydrochloric acid solution (1 M) to the reaction solution to adjust the reaction solution to pH = 5, and extract with ethyl acetate (5 mL × 3). Combine the organic phases. Through preparative TLC plate (MeOH:DCM = 1:10), tert-butyl (3-chloro-4-fluorophenyl)carbamate (yield 16.4%) is obtained.

[0589] MS(ESI): m / z 190.0(M - 56) + .

[0590] Step 2: Dissolve tert-butyl (3-chloro-4-fluorophenyl)carbamate (2.5 g, 10.18 mmol, 1 eq) in DMF (20 mL), add sodium hydride (60%, 1.5 eq) at 0 °C, then displace nitrogen, stir at 0 °C for 1 hour, and then dropwise add iodomethane-d3 (1.2 eq). Slowly warm up to 20 °C and stir for 2 hours. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction solution with water, extract with ethyl acetate (30 ml × 3), wash the combined organic phases with saturated lithium chloride solution (10%), and then concentrate and spin dry to obtain tert-butyl-(3-chloro-4-fluorophenyl)(methyl-d3)carbamate (yield 74.8%).

[0591] MS(ESI): m / z 207.0(M - 56) + .

[0592] Step 3: Dissolve tert-butyl-(3-chloro-4-fluorophenyl)(methyl-d3)carbamate (2 g, 7.61 mmol, 1 eq) in dioxane hydrochloride (4 M, 5.3 eq) at 0 °C. Under nitrogen protection, stir for 1 hour and then naturally rise to room temperature 20 °C and react for 2 hours. Filter the reaction solution under reduced pressure, and dry the filter cake in vacuo to obtain 3-chloro-4-fluoro-N-(methyl-d3)aniline hydrochloride (yield 49.5%).

[0593] MS(ESI): m / z 163.0(M + H) + .

[0594] Step 4: A solution of lithium hydroxide (3.0 eq) in water (20 mL) was slowly added to a solution of (2S,4S)-1-tert-butyl 2-methyl 4-cyanopyrrolidine-1,2-dicarboxylate (10 g, 39.33 mmol, 1.0 eq) in tetrahydrofuran (50 mL). The mixture was stirred at 25 °C for 5 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was adjusted to pH 5 with 2 M dilute HCl (15 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give (2S,4S)-1-(tert-butoxycarbonyl)-4-cyanopyrrolidine-2-carboxylic acid (yield 97.4%).

[0595] MS(ESI): m / z 141.20 (M - 100) + .

[0596] Step 5: Compound (2S,4S)-1-(tert-butoxy)carbonyl-4-cyanopyrrolidine-2-carboxylic acid (1.12 g, 4.66 mmol, 1 eq), 3-chloro-4-fluoro-N-(methyl-d3)aniline hydrochloride (1.1 eq), N'-(ethylpropionamido)-N,N-dimethylpropane-1,3-diamine hydrochloride (1.5 eq), and pyridine (1.5 eq) were successively added to a solution of N,N-dimethylformamide (10 mL). The reaction was carried out under nitrogen protection and stirred at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with saturated lithium chloride aqueous solution (30 mL×2) and saturated brine (20 mL×2). The organic phase was concentrated and then purified by column chromatography (PE:EA = 2:1) to give tert-butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl-d3)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (yield 51.5%).

[0597] MS(ESI): m / z 284.8 (M - 100) + .

[0598] Step 6: tert-Butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl-d3)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (916 mg, 2.38 mmol, 1 eq) was added to dichloromethane (9 mL), and trifluoroacetic acid (11.05 eq) was added. Under nitrogen protection, the mixture was stirred at 25 °C for 2 h. LC-MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. The reaction solution was concentrated, dichloromethane (20 mL) and water (10 mL) were added, and the pH was adjusted to 8 - 9 with saturated sodium bicarbonate solution. Then, extraction was carried out with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-(methyl-d3)pyrrolidine-2-carboxamide (yield 97.7%).

[0599] MS(ESI): m / z 285.2(M + H) + .

[0600] Step 7: Compound (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-(methyl-d3)pyrrolidine-2-carboxamide (500 mg, 1.76 mmol, 1 eq), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.1 eq), [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (0.2 eq), tris(dibenzylideneacetone)dipalladium (1 eq) and cesium carbonate (3 eq) were successively added to a mixed solution of dioxane (20 mL). Under nitrogen protection, the temperature was raised to 100 °C and stirred for 4 h. LC-MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. The mixture was filtered, the filtrate was concentrated, and the residue was separated and purified by column chromatography (PE:EA = 2:1) to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-(methyl-d3)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 53.8%).

[0601] MS(ESI): m / z 444.2(M + H) + .

[0602] 11H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.34 - 7.31 (m, 1H), 7.24 (m, 1H), 6.70 (s, 1H), 6.40 (s, 1H), 4.60 (t, J = 7.8 Hz, 1H), 3.96 (t, J = 8.6 Hz, 1H), 3.88 (t, J = 9.4 Hz, 1H), 3.12 - 3.07 (m, 1H), 2.50 (m, 3H), 2.49 - 2.44 (m, 1H), 2.39 - 2.29 (m, 1H)

[0603] Step 8: (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-(methyl-d3)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (150 mg, 0.34 mmol, 1 eq) was added to methanol (2 mL), and dioxane hydrochloride (4 M, 2 mL) was added. The mixture was stirred at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction solution was concentrated to obtain methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)((methyl-d3)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 92.5%).

[0604] MS (ESI): m / z 477.2 (M + H) + .

[0605] Step 9: Compound methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)((methyl-d3)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (150 mg, 0.31 mmol, 1 eq) was added to a solution of tetrahydrofuran (2 mL). Sodium hydroxide (3 eq) dissolved in water (0.5 mL) was added dropwise to the reaction solution under nitrogen protection, and the mixture was stirred at 25 °C for 2 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. Dichloromethane (20 mL) and water (10 mL) were added, and the pH was adjusted to 5 - 6 with 1 M hydrochloric acid solution. Then, extraction was performed with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain (3S,5S)-5-[(3-chloro-4-fluorophenyl)((methyl-d3)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 89.3%).

[0606] MS (ESI): m / z 462.2 (M + H) + .

[0607] Step 10: (3S,5S)-5-[(3-chloro-4-fluorophenyl)((methyl-d3)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (130 mg, 0.28 mmol, 1 eq), 1-methyl-1H-pyrazol-3-amine (1 eq), HATU (3 eq), and DIPEA (3 eq) were successively added to a solution of N,N-dimethylformamide (3 mL). Under nitrogen protection, the mixture was stirred at 25 °C for 4 hours. LC-MS monitoring of the reaction showed the disappearance of the starting materials, and the target compound was found. The reaction solution was concentrated, and the residue was separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -(methyl-d3)-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 28.57%).

[0608] MS (ESI): m / z 542.0 (M+H) + .

[0609] 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.59 - 7.55 (m, 3H), 6.74 (s, 1H), 6.54 (s, 1H), 6.45 (d, J = 1.6 Hz, 1H), 4.36 (t, J = 8.0 Hz, 1H), 3.86 - 3.83 (m, 1H), 3.73 (s, 3H), 3.53 (t, J = 9.8 Hz, 1H), 3.14–3.10 (m, 1H), 2.46 (m, 3H), 2.29 - 2.24 (m, 1H), 2.16–2.12 (m, 1H).

[0610] Example 46

[0611] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(5-ethyl-1-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 97) synthesis:

[0612]

[0613] Step 1: To a solution of 5-ethyl-1H-pyrazol-3-amine (100 mg, 0.9 mmol, 1.0 eq) in glacial acetic acid (5 mL) was added phthalic anhydride (1.5 eq), and the mixture was stirred at 120 °C for 5 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was concentrated to obtain 2-(5-ethyl-1H-pyrazol-3-yl)isoindoline-1,3-dione (yield 82.9%).

[0614] MS(ESI): m / z 242.0 (M+H) + .

[0615] Step 2: To a solution of 2-(5-ethyl-1H-pyrazol-3-yl)isoindoline-1,3-dione (250 mg, 1.04 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL) were added cesium carbonate (2.0 eq) and methyl iodide (2.0 eq), and the mixture was stirred at 25 °C for 3 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The mixture was extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain 2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)isoindoline-1,3-dione (yield 60.9%).

[0616] MS(ESI): m / z 256.2 (M+H) + .

[0617] Step 3: To a solution of 2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)isoindoline-1,3-dione (230 mg, 0.9 mmol, 1.0 eq) in ethanol (2 mL) was added hydrazine hydrate (2.0 eq), and the mixture was stirred at 90 °C for 2 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was filtered, the filter cake was washed with ethanol (10 mL), the filtrates were combined, and the filtrate was concentrated in vacuo to obtain 5-ethyl-1-methyl-1H-pyrazol-3-amine (yield 59.0%).

[0618] MS(ESI): m / z 126.2 (M+H) + .

[0619] Step 4: To a solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (150 mg, 0.33 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL) was added 5-ethyl-1-methyl-1H-pyrazol-3-amine (2.0 eq), HATU (1.5 eq) and DIPEA (3.0 eq). The reaction mixture was stirred at 25 °C for 3 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the formation of the target compound. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(5-ethyl-1-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 36.9%).

[0620] MS (ESI): m / z 567.0 (M+H) + .

[0621] 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.86 (d, J = 5.2 Hz, 1H), 7.59 (d, J = 6.8 Hz, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.30 (s, 1H), 4.34 (t, J = 8.0 Hz, 1H), 3.86–3.80 (m, 1H), 3.61 (s, 3H), 3.52 (t, J = 10.0 Hz, 1H), 3.15 (s, 3H), 3.10–3.05 (m, 1H), 2.61–2.55 (m, 2H), 2.46 (s, 3H), 2.29–2.22 (m, 1H), 2.14–2.26 (m, 1H), 1.17 (t, J = 7.6 Hz, 3H).

[0622] Examples 47 and 48

[0623] Synthesis of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (Example 47, Compound 98) and (3R,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (Example 48, Compound 99):

[0624]

[0625] Step 1: Add (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (200 mg, 0.45 mmol, 1 eq) to tetrahydrofuran (10 mL). Under nitrogen protection, dropwise add lithium bis(trimethylsilyl)amide (2 eq, 1 M) at -78 °C. After stirring for half an hour, add methyl iodide (2 eq). React at -78 °C for 3.5 hours. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction solution with saturated ammonium chloride solution (10 mL), extract with ethyl acetate (10 mL * 2), combine the organic phases, wash with saturated aqueous sodium chloride solution (20 mL * 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify by preparative TLC plate (PE:EA = 1:1) to obtain (2S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N,4-dimethyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 48.5%).

[0626] MS(ESI): m / z 455.0 (M+H) + .

[0627] Step 2: Add (2S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N,4-dimethyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (40 mg, 0.09 mmol, 1 eq) to methanol (2 mL), add dioxane hydrochloride (4 M, 6 mL), and stir at 25 °C for 16 hours. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Rotavaporize the reaction solution to obtain methyl (5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 93.2%).

[0628] MS(ESI): m / z 488.2 (M+H) + .

[0629] Step 3: Methyl (5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (40 mg, 0.08 mmol, 1 eq) was added to a mixed solution of tetrahydrofuran (1 mL) and methanol (1 mL). Lithium hydroxide (3 eq) dissolved in water (0.5 mL) was added dropwise to the reaction solution under nitrogen protection, and the mixture was stirred at 25 °C for 2 h. LC-MS monitoring of the reaction showed that the starting material disappeared and the target compound was found. Hydrochloric acid (1 mol / L) was added to the reaction solution to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then separated and purified by preparative HPLC to obtain (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 23.9%.) (Example 47) and (3R,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 16.0%) (Example 48).

[0630] Example 47: MS(ESI): m / z 474.0 (M+H) + .

[0631] 1 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 7.70 (s, 1H), 7.48 - 7.45 (m, 2H), 6.62 (s, 1H), 6.40 (s, 1H), 4.20 - 4.16 (m, 1H), 3.84 - 3.79 (m, 2H), 3.03 (s, 3H), 2.32 (s, 3H), 1.71 - 1.64 (m, 2H), 1.23 (s, 3H).

[0632] Example 48: MS(ESI): m / z 474.0 (M+H) + .

[0633] 1HNMR(400MHz,DMSO-d6)δ12.52(s,1H),7.72-7.70(m,1H),7.46-7.44(m,2H),6.62(s,1H),6.40(s,1H),4.33-4.30(m,1H),3.72-3.69(m,1H),3.39-3.21(m,1H),3.01(s,3H),2.33(s,3H),2.26-2.21(m,1H),1.81–1.76(m,1H),1.02(s,3H).

[0634] Example 49

[0635] (2S,4S)-N 4 -[(azetidin-3-yl)methyl]-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 100) synthesis:

[0636]

[0637] First step: Add (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1 eq), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (1.2 eq), HATU (1.5 eq), DIEA (3 eq) and dichloromethane (2 mL) into a single-necked flask, and react at room temperature for 2 hours. LC-MS monitoring of the reaction showed that the raw materials disappeared and the target compound was found. Quench the reaction with saturated ammonium chloride aqueous solution, extract with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify by flash column chromatography (DCM:MeOH = 20:1) to obtain tert-butyl 3-({[(3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-yl]carbamoyl}methyl)azetidine-1-carboxylate (yield 84%).

[0638] MS(ESI):m / z 628.4(M+H) + .

[0639] Step 2: Add tert-butyl 3-({[(3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-yl]methyl}carbamoyl)azetidine-1-carboxylate (70 mg, 0.11 mmol, 1 eq), trifluoroacetic acid (1 mL) and dichloromethane (2 mL) to a single-necked flask, and react at room temperature for 0.5 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash column chromatography (DCM:MeOH:TEA = 10:1:0.5% - 5:5:0.5%) to obtain (2S,4S)-N 4 -[(azetidin-3-yl)methyl]-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 31.2%).

[0640] MS(ESI): m / z 528.3(M+H) + .

[0641] 1 H NMR(400 MHz, DMSO-d6) δ8.19(s, 1H), 7.85(d, J = 5.3 Hz, 1H), 7.58(d, J = 6.4 Hz, 2H), 6.73(s, 1H), 6.52(s, 1H), 4.32(t, J = 8.3 Hz, 1H), 3.90–3.69(m, 2H), 3.69–3.58(m, 2H), 3.47(t, J = 9.8 Hz, 1H), 3.42–3.33(m, 2H), 3.25(m, 2H), 3.15(s, 3H), 2.98–2.86(m, 1H), 2.83–2.70(m, 1H), 2.45(s, 3H), 2.19(dt, J = 13.8, 7.8 Hz, 1H), 2.11–2.00(m, 1H).

[0642] Example 50

[0643] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-imidazol-4-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 101) Synthesis:

[0644]

[0645] Step 1: Add (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (200 mg, 0.44 mmol, 1 eq), 4-iodo-1-methylimidazole (1.1 eq), copper(I) iodide (0.1 eq), cesium carbonate (2 eq), N,N'-dimethylethylenediamine (0.4 eq) and dioxane (5 mL) into a single-necked flask. Flush with nitrogen three times and react at 110 °C for 16 h. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Rotate to dry the solvent, dissolve with water, extract with ethyl acetate. The organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and then separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-N 4 -(1-methyl-1H-imidazol-4-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 17.3%).

[0646] MS(ESI): m / z 539.2 (M+H) + .

[0647] 1 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.86 (d, J = 5.4 Hz, 1H), 7.59 (d, J = 6.7 Hz, 2H), 7.39 (s, 1H), 7.21 (s, 1H), 6.74 (s, 1H), 6.55 (s, 1H), 4.34 (t, J = 8.2 Hz, 1H), 3.90–3.76 (m, 1H), 3.62 (s, 3H), 3.52 (t, J = 9.9 Hz, 1H), 3.15 (s, 3H), 3.14–3.01 (m, 1H), 2.46 (s, 3H), 2.25 (dd, J = 13.3, 6.1 Hz, 1H), 2.11 (dd, J = 19.1, 9.5 Hz, 1H).

[0648] Example 51

[0649] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1H-imidazol-5-yl)-N 2Synthesis of N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 102):

[0650]

[0651] Step 1: Add (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (100 mg, 0.22 mmol, 1 eq), 4-iodo-1-tritylimidazole (1 eq), copper(I) iodide (0.1 eq), cesium carbonate (2 eq), N,N'-dimethylethylenediamine (0.4 eq) and dioxane (3 mL) into a single-necked flask. Purge with nitrogen three times and react at 110 °C for 16 h. LC-MS monitoring of the reaction showed that the starting material disappeared and the target compound was found. Rotate to dry the solvent, dissolve in water, extract with ethyl acetate. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[1-(trityl)-1H-imidazol-4-yl]pyrrolidine-2,4-dicarboxamide (yield 36.5%).

[0652] MS(ESI): m / z 767.5 (M+H) + .

[0653] Step 2: Add (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[1-(trityl)-1H-imidazol-4-yl]pyrrolidine-2,4-dicarboxamide (51 mg, 0.07 mmol, 1 eq) and acetic acid (10 ml) into a single-necked flask and react at 120 °C overnight. LC-MS monitoring of the reaction showed that the starting material disappeared and the target compound was found. Rotate to dry the solvent, dissolve in water, extract with ethyl acetate. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1H-imidazol-5-yl)-N 2-Methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 21.8%).

[0654] MS(ESI): m / z 525.2 (M+H) + .

[0655] 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.39 (s, 1H), 8.21 (s, 1H), 7.86 (d, J = 5.6 Hz, 1H), 7.59 (d, J = 6.6 Hz, 2H), 7.44 (s, 1H), 7.18 (s, 1H), 6.74 (s, 1H), 6.54 (s, 1H), 4.34 (t, J = 8.0 Hz, 1H), 3.91–3.77 (m, 1H), 3.51 (d, J = 9.8 Hz, 1H), 3.15 (s, 3H), 3.13–3.05 (m, 1H), 2.46 (s, 3H), 2.31–2.21 (m, 1H), 2.18–2.06 (m, 1H).

[0656] Example 52

[0657] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(1,3-oxazol-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 103) synthesis:

[0658]

[0659] First step: Add (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1 eq), 1,3-oxazol-2-amine (1.2 eq), N-methylimidazole (3.1 eq) and acetonitrile (1 ml) into a single-necked flask. While stirring, add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 eq), and react at room temperature overnight. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Quench the reaction with saturated ammonium chloride aqueous solution, extract with ethyl acetate. The organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and then separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2-Methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(1,3-oxazol-2-yl)pyrrolidine-2,4-dicarboxamide (yield 38.0%).

[0660] MS (ESI): m / z 526.2 (M+H) + .

[0661] 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.89 (s, 1H), 7.87 (d, J = 6.4 Hz, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.11 (s, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 4.38 (t, J = 8.1 Hz, 1H), 3.89 (m, 1H), 3.56 (t, J = 9.8 Hz, 1H), 3.17 (m, 1H), 3.15 (s, 3H), 2.46 (s, 3H), 2.33 (m, 1H), 2.12 (m, 1H).

[0662] Example 53

[0663] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(1,3-thiazol-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 104) synthesis:

[0664]

[0665] First step: Add (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1 eq), 1,3-thiazol-2-amine (1 eq), N-methylimidazole (3.1 eq) and acetonitrile (1 ml) to a single-necked flask. While stirring, add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 eq), and react at room temperature overnight. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Quench the reaction with saturated ammonium chloride aqueous solution, extract with ethyl acetate. The organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and then separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4-(1,3-Thiazol-2-yl)pyrrolidine-2,4-dicarboxamide (yield 36.9%).

[0666] MS(ESI): m / z 542.2(M+H) + .

[0667] 1 H NMR(400MHz, DMSO-d6) δ 12.25(s, 1H), 7.87(d, J = 5.8Hz, 1H), 7.60(d, J = 7.7Hz, 2H), 7.49(d, J = 3.5Hz, 1H), 7.25(d, J = 3.5Hz, 1H), 6.77(s, 1H), 6.57(s, 1H), 4.40(t, J = 8.1Hz, 1H), 3.92(m, 1H), 3.60(t, J = 9.8Hz, 1H), 3.28(m, 1H), 3.15(s, 3H), 2.47(s, 3H), 2.38–2.31(m, 1H), 2.17(m, 1H).

[0668] Example 54

[0669] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(1,3-thiazol-5-yl)pyrrolidine-2,4-dicarboxamide (Compound 105) synthesis:

[0670]

[0671] First step: Add (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1 eq), 1,3-thiazol-5-amine (1.2 eq), N-methylimidazole (3.1 eq) and acetonitrile (1 ml) into a single-necked flask. While stirring, add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 eq), and react at room temperature overnight. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. Quench the reaction with saturated ammonium chloride aqueous solution, extract with ethyl acetate. The organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and then separated and purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4-(1,3-Thiazol-5-yl)pyrrolidine-2,4-dicarboxamide (yield 55.8%).

[0672] MS(ESI): m / z 542.2 (M+H) + .

[0673] 1 H NMR(400MHz, DMSO-d6) δ 11.51(s, 1H), 8.60(s, 1H), 7.87(d, J = 5.9Hz, 1H), 7.62–7.59(d, J = 10.7Hz, 3H), 6.76(s, 1H), 6.56(s, 1H), 4.41(t, J = 8.2Hz, 1H), 3.93–3.84(m, 1H), 3.60(t, J = 9.8Hz, 1H), 3.25–3.21(m, 1H), 3.15(s, 3H), 2.47(s, 3H), 2.37–2.29(m, 1H), 2.19–2.11(m, 1H).

[0674] Example 55

[0675] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[(oxetan-3-yl)methyl]pyrrolidine-2,4-dicarboxamide (Compound 106) synthesis:

[0676]

[0677] First step: Under the condition of an ice-water bath at 0 °C, in an acetonitrile (3 mL) solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) and 3-aminomethyloxetane (1.2 eq), add N-methylimidazole (3.5 eq) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.2 eq), raise the temperature to 25 °C at room temperature, and react for 4 hours. The reaction solution is filtered, and the filtrate is separated and purified by preparative HPLC (FA acid) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[(oxetan-3-yl)methyl]pyrrolidine-2,4-dicarboxamide (yield 34.4%).

[0678] MS(ESI): m / z 529.3 (M+H) + .

[0679] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (t, J = 5.5 Hz, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.66–7.53 (m, 2H), 6.74 (s, 1H), 6.48 (s, 1H), 4.63–4.55 (m, 2H), 4.51 (d, J = 7.5 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 3.73 (t, J = 8.7 Hz, 1H), 3.42 (t, J = 8.6 Hz, 1H), 3.35 (s, 2H), 3.27 (dd, J = 13.3, 6.2 Hz, 1H), 3.15 (s, 3H), 3.01 (dt, J = 13.7, 6.8 Hz, 1H), 2.45 (s, 3H), 2.25–2.13 (m, 1H), 2.05 (dt, J = 28.9, 8.4 Hz, 1H).

[0680] Example 56

[0681] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(tetrahydrofuran-3-yl)pyrrolidine-2,4-dicarboxamide (Compound 107) Synthesis:

[0682]

[0683] First step: In a solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) and 3-aminotetrahydrofuran hydrochloride (1.2 eq) in acetonitrile (3 mL), add N-methylimidazole (3.5 eq) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.2 eq), at room temperature 25 °C, react for 4 hours. The reaction solution is diluted with water (10 mL), extracted with ethyl acetate (50 mL * 3), the organic phases are combined, concentrated, and then separated and purified by preparative HPLC (FA acid) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(tetrahydrofuran-3-yl)pyrrolidine-2,4-dicarboxamide (yield 20.6%).

[0684] MS(ESI): m / z 529.3 (M+H) + .

[0685] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 6.5 Hz, 1H), 7.87 (d, J = 5.7 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 6.74 (s, 1H), 6.48 (s, 1H), 4.50 (d, J = 8.2 Hz, 1H), 4.19 (s, 1H), 3.82–3.62 (m, 4H), 3.47–3.37 (m, 2H), 3.31–3.24 (m, 1H), 3.15 (s, 3H), 2.45 (s, 3H), 2.16 (d, J = 6.3 Hz, 1H), 2.12–1.98 (m, 2H), 1.78–1.61 (m, 1H).

[0686] Example 57

[0687] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[5-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 108) Synthesis:

[0688]

[0689] First step: In a pyridine (0.5 mL) solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) and 5-(trifluoromethyl)pyridin-2-amine (1.0 eq), 1-propylphosphonic anhydride (50% wt) ethyl acetate solution (3.0 eq) was added. At room temperature of 25 °C, the reaction was carried out for 12 hours. The reaction solution was quenched with water (50 mL), extracted with ethyl acetate (100 mL). After concentration of the organic phase, it was separated and purified by preparative HPLC (FA acid) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -[5-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 52.7%).

[0690] MS(ESI): m / z 604.3 (M+H)+ .

[0691] 1 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.74 (s, 1H), 8.30 (d, J = 8.9 Hz, 1H), 8.22 (dd, J = 8.9, 2.2 Hz, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 7.0 Hz, 2H), 6.76 (s, 1H), 6.57 (s, 1H), 4.38 (t, J = 8.2 Hz, 1H), 3.92 (s, 1H), 3.59 (t, J = 9.9 Hz, 2H), 3.15 (s, 3H), 2.47 (s, 3H), 2.37 (dd, J = 12.7, 7.8 Hz, 1H), 2.16 (dd, J = 21.0, 11.5 Hz, 1H).

[0692] Example 58

[0693] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(pyrimidin-4-yl)pyrrolidine-2,4-dicarboxamide (Compound 109) synthesis:

[0694]

[0695] First step: In a pyridine (0.5 mL) solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (20 mg, 0.04 mmol, 1.0 eq) and 4-aminopyrimidine (1.5 eq), add ethyl 1-propylphosphonic anhydride acetate solution (50% wt) (3.0 eq), react at 25 °C for 12 hours. Quench the reaction solution with water (50 mL), extract with ethyl acetate (100 mL), concentrate the organic phase, and separate and purify by preparative HPLC (FA acid) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(pyrimidin-4-yl)pyrrolidine-2,4-dicarboxamide (yield 60.5%).

[0696] MS (ESI): m / z 537.2 (M+H) + .

[0697] 11H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.90 (s, 1H), 8.68 (d, J = 5.8 Hz, 1H), 8.09 (dd, J = 5.8, 1.1 Hz, 1H), 7.87 (d, J = 5.9 Hz, 1H), 7.60 (d, J = 7.6 Hz, 2H), 6.76 (s, 1H), 6.56 (s, 1H), 4.38 (t, J = 8.1 Hz, 1H), 3.91 (s, 1H), 3.58 (t, J = 9.8 Hz, 2H), 3.15 (s, 3H), 2.47 (s, 3H), 2.39–2.31 (m, 1H), 2.14 (dd, J = 20.7, 11.0 Hz, 1H).

[0698] Example 59

[0699] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-isopropyl-5-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 110) Synthesis:

[0700]

[0701] First step: At 25 °C, add 2-bromopropane (2.0 eq.) and cesium carbonate (3.0 eq.) to a solution of compound 5-methyl-3-nitro-1H-pyrazole (2.00 g, 15.74 mmol, 1.0 eq.) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at 60 °C for an additional 16 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was quenched by pouring it into water (300 mL), extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain 1-isopropyl-5-methyl-3-nitro-1H-pyrazole 1a (yield 60.1%) and 1-isopropyl-3-methyl-5-nitro-1H-pyrazole 1b (yield 31.9%).

[0702] MS (ESI): m / z 170.1 (M+H) + .

[0703] 1a: 11H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 4.56 - 4.48 (m, 1H), 2.36 (s, 3H), 1.53 (d, J = 6.6 Hz, 6H).

[0704] 1b: 1 1H NMR (400 MHz, CDCl3) δ 6.81 (s, 1H), 5.44 - 5.33 (m, 1H), 2.30 (s, 3H), 1.51 (d, J = 6.6 Hz, 6H).

[0705] Step 2: At 25 °C, to a solution of 1 - isopropyl - 5 - methyl - 3 - nitro - 1H - pyrazole (500 mg, 2.96 mmol, 1.0 eq.) in methanol (10 mL) was added 10% palladium on carbon (100 mg). The hydrogen was displaced three times, and the reaction was continued to stir for 1 hour under a hydrogen (1 atm) atmosphere. LC - MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain 1 - isopropyl - 5 - methyl - 1H - pyrazol - 3 - amine

[0706] as a crude product, without purification, and was directly used for the next step.

[0707] MS (ESI): m / z 140.1 (M + H)+.

[0708] Step 3: At 25 °C, to a solution of compound (3S,5S) - 5 - ((3 - chloro - 4 - fluorophenyl)(methyl)carbamoyl) - 1 - (6 - methyl - 4 - (trifluoromethyl)pyridin - 2 - yl)pyrrolidine - 3 - carboxylic acid (70 mg, 0.15 mmol, 1.0 eq.) in acetonitrile (2 mL) was added 1 - isopropyl - 5 - methyl - 1H - pyrazol - 3 - amine (30 mg, crude product, obtained from the previous step reaction) and 1 - propylphosphonic anhydride (50% wt ethyl acetate solution, 3.0 eq.). The reaction mixture was continued to stir at 25 °C for 2 hours. LC - MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to obtain (2S,4S) - N 2 -(3 - chloro - 4 - fluorophenyl) - N 4 -(1 - isopropyl - 5 - methyl - 1H - pyrazol - 3 - yl) - N 2 -methyl - 1 - (6 - methyl - 4 - (trifluoromethyl)pyridin - 2 - yl)pyrrolidine - 2,4 - dicarboxamide (yield 32.8%).

[0709] MS (ESI): m / z 581.2 / 583.2 (M + H) + .

[0710] 1 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.59 (d, J = 6.6 Hz, 2H), 6.74 (s, 1H), 6.55 (s, 1H), 6.28 (s, 1H), 4.46 - 4.38 (m, 1H), 4.36 - 4.31 (m, 1H), 3.90 - 3.77 (m, 1H), 3.51 (t, J = 9.8 Hz, 1H), 3.21 - 3.05 (m, 4H), 2.46 (s, 3H), 2.29 - 2.19 (m, 4H), 2.15 - 2.05 (m, 1H), 1.31 (d, J = 5.9 Hz, 6H).

[0711] Example 60

[0712] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-isopropyl-3-methyl-1H-pyrazol-5-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 111) synthesis:

[0713]

[0714] First step: At 25 °C, add 10% palladium on carbon (80 mg) to a methanol (10 mL) solution of compound 1-isopropyl-3-methyl-5-nitro-1H-pyrazole (400 mg, 2.36 mmol, 1.0 eq.). Replace hydrogen three times, and continue to stir the reaction for 1 hour under a hydrogen atmosphere (1 atmosphere). LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Filter the reaction solution through diatomaceous earth, and rotary evaporate the filtrate to obtain the crude product of 1-isopropyl-3-methyl-1H-pyrazol-5-amine, which is used directly in the next step without purification.

[0715] MS (ESI): m / z 140.1 (M + H) + .

[0716] Step 2: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1.0 eq.) in acetonitrile (2 mL) were successively added compound 1-isopropyl-3-methyl-1H-pyrazol-5-amine (30 mg, crude product, obtained from the previous step reaction), 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 3.0 eq.) and DIEA (4.0 eq.). The reaction mixture was continuously stirred at 25 °C for 2 h. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-isopropyl-3-methyl-1H-pyrazol-5-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 55.5%).

[0717] MS(ESI): m / z 581.3.2 / 583.3 (M + H) + .

[0718] 1 H NMR(400 MHz, DMSO-d6) δ 9.82(s, 1H), 7.88(d, J = 6.3 Hz, 1H), 7.61(d, J = 6.7 Hz, 2H), 6.76(s, 1H), 6.58(s, 1H), 5.92(d, J = 1.9 Hz, 1H), 4.44 - 4.30(m, 2H), 3.88(t, J = 7.3 Hz, 1H), 3.58(t, J = 9.8 Hz, 1H), 3.27 - 3.10(m, 4H), 2.47(s, 3H), 2.36 - 2.27(m, 1H), 2.19 - 2.07(m, 4H), 1.30(d, J = 6.5 Hz, 6H).

[0719] Example 61

[0720] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,3-dimethyl-1H-pyrazol-5-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 112) synthesis:

[0721]

[0722] Step 1: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1.0 eq.) in acetonitrile (2 mL) were successively added compound 1,3-dimethyl-1H-pyrazol-5-amine (1.2 eq.), 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 3.0 eq.) and DIEA (4.0 eq.). The reaction mixture was continuously stirred at 25 °C for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,3-dimethyl-1H-pyrazol-5-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 46.0%).

[0723] MS(ESI): m / z 553.2 / 555.2 (M + H) + .

[0724] 1 H NMR(400 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 6.6 Hz, 2H), 6.76 (s, 1H), 6.58 (s, 1H), 5.97 (s, 1H), 4.39 (t, J = 8.1 Hz, 1H), 3.88 (t, J = 8.6 Hz, 1H), 3.60 - 3.58 (m, 1H), 3.56 (s, 3H), 3.25 - 3.13 (m, 4H), 2.47 (s, 3H), 2.37 - 2.28 (m, 1H), 2.19 - 2.11 (m, 1H), 2.09 (s, 3H).

[0725] Example 62

[0726] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,4-dimethyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 113) synthesis:

[0727]

[0728] Step 1: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1.0 eq.) in acetonitrile (2 mL) were successively added compound 1,4-dimethyl-1H-pyrazol-3-amine (1.2 eq.), 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 3.0 eq.) and DIEA (4.0 eq.). The reaction mixture was stirred at 25 °C for an additional 2 hours. LC-MS monitoring of the reaction showed disappearance of the starting material and the formation of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to give (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,4-dimethyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 44.0%).

[0729] MS (ESI): m / z 553.2 / 555.2 (M+H) + .

[0730] 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 6.9 Hz, 2H), 7.39 (s, 1H), 6.75 (s, 1H), 6.58 (s, 1H), 4.37 (t, J = 8.1 Hz, 1H), 3.86 (t, J = 9.9 Hz, 1H), 3.70 (s, 3H), 3.55 (t, J = 9.9 Hz, 1H), 3.20 - 3.04 (m, 4H), 2.47 (s, 3H), 2.36 - 2.25 (m, 1H), 2.16 - 2.06 (m, 1H), 1.82 (s, 3H).

[0731] Example 63

[0732] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(4-cyano-1-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 114) synthesis:

[0733]

[0734] Step 1: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1.0 eq.) in acetonitrile (2 mL) were successively added compound 1-methyl-3-aminopyrazole-4-carbonitrile (1.2 eq.), 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 3.0 eq.) and DIEA (4.0 eq.). The reaction mixture was stirred at 25 °C for an additional 2 hours. LC-MS monitoring of the reaction showed disappearance of the starting material and formation of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to give (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(4-cyano-1-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 32.3%).

[0735] MS (ESI): m / z 564.2 / 566.2 (M+H) +.

[0736] 1 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.43 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 6.7 Hz, 2H), 6.76 (s, 1H), 6.58 (s, 1H), 4.38 (t, J = 8.1 Hz, 1H), 3.96 - 3.85 (m, 1H), 3.82 (s, 3H), 3.56 (t, J = 9.8 Hz, 1H), 3.24 - 3.11 (m, 4H), 2.47 (s, 3H), 2.36 - 2.28 (m, 1H), 2.16 - 2.07 (m, 1H).

[0737] Example 64

[0738] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 115) synthesis:

[0739]

[0740] Step 1: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1.0 eq.) in acetonitrile (2 mL) were successively added compound 2-(3-amino-5-methyl-1H-pyrazol-1-yl)ethan-1-ol (1.2 eq.), 1-propylphosphonic anhydride (50% wt solution in ethyl acetate, 3.0 eq.) and DIEA (4.0 eq.). The reaction mixture was continuously stirred at 25 °C for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 19.1%).

[0741] MS(ESI): m / z 583.2 / 585.2 (M + H) + .

[0742] 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.59 (d, J = 6.6 Hz, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.28 (s, 1H), 4.34 (t, J = 8.0 Hz, 1H), 3.94 (t, J = 5.7 Hz, 2H), 3.88 - 3.77 (m, 1H), 3.65 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 9.9 Hz, 1H), 3.21 - 3.02 (m, 4H), 2.46 (s, 3H), 2.32 - 2.20 (m, 4H), 2.15 - 2.05 (m, 1H).

[0743] Examples 65 and 66

[0744] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-yl)-N 2-Methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Example 65, Compound 116) and (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-5-yl)-N 2 -Methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Example 66, Compound 117) Synthesis:

[0745]

[0746] First step: Under nitrogen protection at 0 °C, diisopropyl azodicarboxylate (1.5 eq.) was added dropwise to a solution of 2-(dimethylamino)ethan-1-ol (1.00 g, 11.12 mmol, 1.0 eq.), 5-methyl-3-nitro-1H-pyrazole (1.2 eq.) and triphenylphosphine (1.5 eq.) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 25 °C for an additional 16 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain a mixture of N,N-dimethyl-2-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethan-1-amine and N,N-dimethyl-2-(3-methyl-5-nitro-1H-pyrazol-1-yl)ethan-1-amine, as a crude product, unpurified, and directly used in the next step.

[0747] MS(ESI): m / z 199.17(M+H) + .

[0748] Step 2: At 25 °C, 10% palladium on carbon (120 mg) was added to a methanol (10 mL) solution of a mixture of compound N,N-dimethyl-2-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethan-1-amine and N,N-dimethyl-2-(3-methyl-5-nitro-1H-pyrazol-1-yl)ethan-1-amine (600 mg, crude product, obtained from the previous step). The hydrogen was displaced three times, and the reaction was continued under a hydrogen atmosphere (1 atmosphere) for 1 hour. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain a mixture of 1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-amine and 1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-5-amine, crude product, which was not purified and directly used in the next step.

[0749] MS(ESI): m / z 169.17(M+H) + .

[0750] Step 3: At 25 °C, to an acetonitrile (2 mL) solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1.0 eq.) were successively added a mixture of compound 1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-amine and 1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-5-amine (38 mg, crude product, obtained from the previous step), 1-propylphosphonic anhydride (50% wt in ethyl acetate solution, 3.0 eq.) and DIEA (4.0 eq.). The reaction mixture was continuously stirred at 25 °C for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Example 65) (yield 35%) and (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-5-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Example 66) (yield 23%).

[0751] Example 65: MS(ESI): m / z 610.3 / 612.3 (M+H) + .

[0752] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.59 (d, J = 6.9 Hz, 2H), 6.74 (s, 1H), 6.55 (s, 1H), 6.29 (s, 1H), 4.34 (t, J = 8.3 Hz, 1H), 3.98 (t, J = 6.6 Hz, 2H), 3.89 - 3.78 (m, 1H), 3.51 (t, J = 9.9 Hz, 1H), 3.21 - 3.03 (m, 4H), 2.57 (t, J = 6.1 Hz, 2H), 2.46 (s, 3H), 2.31 - 2.21 (m, 4H), 2.20 - 2.05 (m, 7H).

[0753] Example 66: MS(ESI): m / z 610.3 / 612.3 (M+H) + .

[0754] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 7.86 (d, J = 5.9 Hz, 1H), 7.60 (d, J = 7.7 Hz, 2H), 6.76 (s, 1H), 6.54 (s, 1H), 6.06 (s, 1H), 4.40 (t, J = 8.1 Hz, 1H), 4.03 (t, J = 6.1 Hz, 2H), 3.88 - 3.84 (m, 1H), 3.59 (t, J = 9.7 Hz, 1H), 3.16 - 3.10 (m, 4H), 2.68 - 2.59 (m, 2H), 2.47 (s, 3H), 2.34 - 2.19 (m, 7H), 2.17 - 2.04 (m, 4H).

[0755] Example 67

[0756] Synthesis of 2-(3-((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxamido)-1H-pyrazol-1-yl)acetic acid (Compound 118):

[0757]

[0758] Step 1: At 0 °C, sodium hydride (1.1 eq., 60%) was added portionwise to a solution of 3-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1.0 eq.) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 0 °C for 30 minutes, and then tert-butyl 2-bromoacetate (1.3 eq.) was added dropwise to the reaction solution. The reaction mixture was continuously stirred at 25 °C for 16 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate (150 mL * 3). The combined organic phases were washed with saturated sodium bicarbonate (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain tert-butyl 2-(3-nitro-1H-pyrazol-1-yl)acetate (yield 53.9%).

[0759] MS(ESI): m / z 228.1(M+H) +

[0760] Step 2: At 25 °C, 10% palladium on carbon (72 mg) was added to a solution of tert-butyl 2-(3-nitro-1H-pyrazol-1-yl)acetate (360 mg, 1.58 mmol, 1.0 eq.) in methanol (10 mL). The hydrogen was displaced 3 times, and the reaction was continuously stirred for 2 hours under a hydrogen atmosphere (1 atm). LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness to obtain the crude product of tert-butyl 2-(3-amino-1H-pyrazol-1-yl)acetate, which was used directly in the next step without purification.

[0761] MS(ESI): m / z 198.1(M+H) +

[0762] Step 3: At 25 °C, to a solution of compound (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (150 mg, 0.33 mmol, 1.0 eq.) in acetonitrile (3 mL) were successively added tert-butyl 2-(3-amino-1H-pyrazol-1-yl)acetate (100 mg, crude product, obtained from the previous step reaction), 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 3.0 eq.), and DIEA (4.0 eq.). The reaction mixture was continuously stirred at 25 °C for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to obtain tert-butyl 2-(3-((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxamido)-1H-pyrazol-1-yl) (yield 48.0%).

[0763] MS(ESI): m / z 639.3 / 641.3(M+H) +

[0764] 1 H NMR(400 MHz, DMSO-d6) δ 10.58(s, 1H), 7.86(d, J = 6.0 Hz, 1H), 7.61 - 7.56(m, 3H), 6.75(s, 1H), 6.56 - 6.50(m, 2H), 4.83(s, 2H), 4.36(t, J = 8.1 Hz, 1H), 3.85(t, J = 7.7 Hz, 1H), 3.54(t, J = 9.9 Hz, 1H), 3.20 - 3.06(m, 4H), 2.46(s, 3H), 2.35 - 2.23(m, 1H), 2.19 - 2.07(m, 1H), 1.42(s, 9H).

[0765] Step 4: At 25 °C, trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 2-(3-((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-carboxamido)-1H-pyrazol-1-yl)acetate (80 mg, 0.13 mmol, 1.0 eq.) in dichloromethane (6 mL). The reaction mixture was stirred at 25 °C for an additional 2 h. LC-MS monitoring of the reaction showed disappearance of the starting material and the formation of the target compound. The reaction solution was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to give 2-(3-((3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-carboxamido)-1H-pyrazol-1-yl)acetic acid (yield 77.49%).

[0766] MS(ESI): m / z 583.2 / 585.2 (M+H) +

[0767] 1 H NMR(400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.62 - 7.56 (m, 3H), 6.75 (s, 1H), 6.56 - 6.50 (m, 2H), 4.84 (s, 2H), 4.36 (t, J = 8.2 Hz, 1H), 3.92 - 3.80 (m, 1H), 3.54 (t, J = 9.9 Hz, 1H), 3.16 - 3.08 (m, 4H), 2.46 (s, 3H), 2.35 - 2.23 (m, 1H), 2.17 - 2.08 (m, 1H).

[0768] Example 68

[0769] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,3-dimethyl-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 119) Synthesis:

[0770]

[0771] Step 1: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq.) in acetonitrile (4 mL). Add 1,3-dimethylpyrazol-4-amine (1.5 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature, and stir at 80 °C for 1 hour. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Pour the reaction solution into saturated NaHCO3 solution (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative HPLC (FA) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,3-dimethyl-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 25.6%).

[0772] MS(ESI): m / z 553.27(M+H) +

[0773] 1 1H NMR(400 MHz, DMSO-d6) δ 9.45(s, 1H), 7.98 - 7.78(m, 2H), 7.60(s, 1H), 7.59(s, 1H), 6.74(s, 1H), 6.56(s, 1H), 4.36(t, J = 8.4 Hz, 1H), 3.89–3.79(m, 1H), 3.71(s, 3H), 3.59 - 3.49(m, 1H), 3.24 - 3.06(m, 4H), 2.46(s, 3H), 2.34–2.22(m, 1H), 2.17–2.05(m, 4H).

[0774] Example 69

[0775] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(3-cyano-1-methyl-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 120) synthesis:

[0776]

[0777] Step 1: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq.) in dichloromethane (3 mL). Add 4-amino-1-methylpyrazole-3-carbonitrile (1.5 eq.), DIEA (3 eq.) and HATU (2 eq.) at room temperature. Stir at room temperature for 3 hours. LC-MS monitoring of the reaction shows that the starting material has disappeared and the target compound is found. Pour the reaction solution into saturated sodium bicarbonate solution (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column (DCM / MeOH = 10 / 1) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(3-cyano-1-methyl-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 47.9%).

[0778] MS(ESI): m / z 564.23 (M+H) +

[0779] 1 H NMR(400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.25 (s, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.60 (s, 1H), 7.59 (s, 1H), 6.75 (s, 1H), 6.56 (s, 1H), 4.37 (t, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.87 - 3.82 (m, 1H), 3.59 - 3.51 (m, 1H), 3.27 - 3.19 (m, 1H), 3.15 (s, 3H), 2.46 (s, 3H), 2.34–2.27 (m, 1H), 2.15 - 2.05 (m, 1H).

[0780] Example 70

[0781] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-ethyl-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 121) Synthesis:

[0782]

[0783] Step 1: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq.) in acetonitrile (4 mL). Add 1-ethyl-1H-pyrazol-4-amine (1.5 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature, and heat at 80 °C for 1 hour. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Pour the reaction solution into saturated sodium bicarbonate solution (100 mL), extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative HPLC (FA) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1-ethyl-1H-pyrazol-4-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 14.1%).

[0784] MS(ESI): m / z 553.25(M + H) +

[0785] 1 1H NMR(400 MHz, DMSO-d6) δ 10.07(s, 1H), 7.91(s, 1H), 7.86(d, J = 6.0 Hz, 1H), 7.66 - 7.55(m, 2H), 7.40(s, 1H), 6.75(s, 1H), 6.55(s, 1H), 4.37(t, J = 8.2 Hz, 1H), 4.08(q, J = 7.2 Hz, 2H), 3.87 - 3.78(m, 1H), 3.55(t, J = 9.8 Hz, 1H), 3.15(s, 3H), 3.10–2.99(m, 1H), 2.46(s, 3H), 2.31–2.21(m, 1H), 2.18 - 2.06(m, 1H), 1.32(t, J = 7.2 Hz, 3H).

[0786] Example 71

[0787] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(tetrahydro-2H-pyran-4-yl)pyrrolidine-2,4-dicarboxamide (Compound 122) synthesis:

[0788]

[0789] Step 1: In a solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) and 4-aminotetrahydropyran hydrochloride (1.2 eq) in acetonitrile (3 mL), N-methylimidazole (3.5 eq) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.2 eq) were added. The reaction was carried out at room temperature (25 °C) for 4 hours. The reaction mixture was filtered, and the filtrate was separated and purified by preparative HPLC (FA acid) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N 4 -(tetrahydro-2H-pyran-4-yl)pyrrolidine-2,4-dicarboxamide (yield 27.6%).

[0790] MS (ESI): m / z 543.3 (M+H) + .

[0791] 1 1H NMR (400 MHz, DMSO-d6) δ 8.12 (t, J = 6.3 Hz, 1H), 7.88 (d, J = 6.3 Hz, 1H), 7.59 (d, J = 7.3 Hz, 2H), 6.74 (s, 1H), 6.49 (s, 1H), 4.50 (d, J = 8.0 Hz, 1H), 3.89–3.77 (m, 2H), 3.73 (t, J = 8.6 Hz, 2H), 3.42 (t, J = 8.5 Hz, 1H), 3.35 (d, J = 3.3 Hz, 1H), 3.32 (t, J = 4.6 Hz, 4H), 2.52 (d, J = 2.5 Hz, 1H), 2.45 (s, 3H), 2.24–2.13 (m, 1H), 2.07 (dd, J = 19.8, 11.1 Hz, 1H), 1.67 (d, J = 9.9 Hz, 2H), 1.46–1.27 (m, 2H).

[0792] Example 72

[0793] Synthesis of (pivaloyloxy)methyl (3S,5S)-5-(((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylate (Compound 123):

[0794]

[0795] Step 1: In a solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq) and potassium carbonate (2 eq) in N,N-dimethylformamide (3 mL), add pivaloyl chloride methyl ester (1.5 eq), and react at room temperature for 12 hours. Dilute the reaction solution with water (20 mL), extract with ethyl acetate (50 mL * 3), combine the organic phases, concentrate, and separate and purify by preparative HPLC (FA acid) to obtain (pivaloyloxy)methyl (3S,5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (yield 80.1%).

[0796] MS(ESI): m / z 574.2(M + H) + .

[0797] 1 1H NMR(400 MHz, DMSO-d6) δ 7.85(d, J = 5.0 Hz, 1H), 7.67–7.49(m, 2H), 6.77(s, 1H), 6.55(s, 1H), 5.74(s, 2H), 4.42(t, J = 7.3 Hz, 1H), 3.83(t, J = 8.7 Hz, 1H), 3.62(t, J = 8.9 Hz, 1H), 3.43–3.23(m, 3H), 2.55–2.51(m, 1H), 2.45(s, 3H), 2.29(dt, J = 12.6, 8.2 Hz, 1H), 2.18–2.08(m, 1H), 1.16(s, 9H).

[0798] Example 73

[0799] (2S,4S)-N 4 -(5-chloro-1-methyl-1H-pyrazol-3-yl)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 124) synthesis:

[0800]

[0801] Step 1: (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (70 mg, 0.15 mmol, 1 eq.), 5-chloro-1-methyl-1H-pyrazol-3-amine (1 eq.), HATU (3 eq.), and DIPEA (3 eq.) were successively added to a solution of N,N-dimethylformamide (5 mL). Under nitrogen protection, the mixture was stirred at 25 °C for 16 h. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the formation of the target compound. The reaction solution was filtered, and the filtrate was separated and purified by preparative HPLC to obtain (2S,4S)-N 4 -(5-chloro-1-methyl-1H-pyrazol-3-yl)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 11.9%).

[0802] MS (ESI): m / z 573.2 (M + H) + .

[0803] 1 HNMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.86 - 7.84 (m, 1H), 7.59 - 7.58 (m, 2H), 6.74 (s, 1H), 6.57 (s, 1H), 6.54 (s, 1H), 4.36 (t, J = 8.0 Hz, 1H), 3.87 - 3.83 (m, 1H), 3.70 (s, 3H), 3.53 (t, J = 9.8 Hz, 1H), 3.15 (s, 4H), 2.46 (s, 3H), 2.29 - 2.25 (m, 1H), 2.15–2.10 (m, 1H).

[0804] Example 74

[0805] Synthesis of 2,3-dihydro-1H-inden-5-yl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (Compound 125):

[0806]

[0807] Step 1: In a DMF (3 mL) solution of (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-carboxylic acid (50 mg, 0.11 mmol, 1 eq), 2,3-dihydro-1H-inden-5-ol (1.5 eq) and dicyclohexylcarbodiimide (1.5 eq), 4-dimethylaminopyridine (2 eq) was added, and the reaction was carried out at room temperature for 12 h. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed three times with saturated brine, concentrated, and separated and purified by preparative HPLC (FA acid) to obtain 2,3-dihydro-1H-inden-5-yl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-carboxylic acid (yield 31.6%).

[0808] MS(ESI): m / z 576.3(M+H) + .

[0809] 1 H NMR(400MHz, DMSO-d6)δ7.90(d, J = 6.1Hz, 1H), 7.61(d, J = 6.8Hz, 2H), 7.24(d, J = 8.1Hz, 1H), 7.03(s, 1H), 6.90(d, J = 7.4Hz, 1H), 6.78(s, 1H), 6.61(s, 1H), 4.49(t, J = 6.9Hz, 1H), 3.87(dt, J = 17.1, 9.5Hz, 2H), 3.55(dd, J = 17.5, 10.0Hz, 1H), 3.16(s, 3H), 2.86(dd, J = 14.7, 7.3Hz, 4H), 2.48(s, 3H), 2.43–2.32(m, 2H), 2.05(p, J = 7.4Hz, 2H).

[0810] Example 75

[0811] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 4 -(4-methyloxazol-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 126) synthesis:

[0812]

[0813] Step 1: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (130 mg, 0.28 mmol, 1 equiv.) in acetonitrile (4 mL). Add 4-methyl-1,3-oxazol-2-amine (1.5 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature. Heat the mixture at 80 °C for 1 hour. LC-MS monitoring of the reaction shows the disappearance of the starting material and the formation of the target compound. Pour the reaction solution into NaHCO3 solution (100 mL), extract with ethyl acetate (30 mL * 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by preparative HPLC (FA) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N 4 -(4-methyloxazol-2-yl)pyrrolidine-2,4-dicarboxamide (yield 8.5%).

[0814] MS(ESI): m / z 540.2(M + H) + .

[0815] 1 1H NMR(400 MHz, DMSO-d6) δ 11.19(s, 1H), 7.86(d, J = 5.9 Hz, 1H), 7.65 - 7.48(m, 3H), 6.75(s, 1H), 6.55(s, 1H), 4.37(t, J = 8.0 Hz, 1H), 3.87(t, J = 8.2 Hz, 1H), 3.55(t, J = 9.8 Hz, 2H), 3.15(s, 4H), 2.46(s, 3H), 2.38 - 2.25(m, 1H), 2.17–2.06(m, 1H), 2.03(d, J = 1.0 Hz, 3H).

[0816] Example 76

[0817] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -isopropyl-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 127) synthesis:

[0818]

[0819] Step 1: (2S,4S)-1-[(tert-Butoxy)carbonyl]-4-cyanopyrrolidine-2-carboxylic acid (1 g, 4.16 mmol, 1 eq.), 3-chloro-4-fluoro-N-(propan-2-yl)aniline (1.5 eq.), and triethylamine (3 eq.) were added to dichloromethane (10 mL). 2-Chloro-1,3-dimethylimidazolinium chloride (1.5 eq.) was added at room temperature, and the mixture was stirred for 1 hour. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. The reaction mixture was poured into water (100 mL), and the product was extracted with dichloromethane (30 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(propan-2-yl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (yield 6%).

[0820] MS(ESI): m / z 432.2 (M+Na) + .

[0821] Step 2: tert-Butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(propan-2-yl)carbamoyl]-4-cyanopyrrolidine-1-carboxylate (100 mg, 0.24 mmol, 1 eq.) was added to a mixture of trifluoroacetic acid (1.5 mL) and dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. The reaction mixture was poured into saturated NaHCO3 solution (100 mL), and the product was extracted with dichloromethane (30 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-(propan-2-yl)pyrrolidine-2-carboxamide (yield 95%).

[0822] MS(ESI): m / z 310.1 (M+H) + .

[0823] Step 3: Add (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-(propan-2-yl)pyrrolidine-2-carboxamide (60 mg, 0.19 mmol, 1 eq.), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.5 eq.), cesium carbonate (3 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.1 eq.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq.) into dioxane (4 mL), and stir at 100 °C for 6 hours under nitrogen protection. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. Pour the reaction solution into water (100 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by flash silica gel column (PE / EtOAc = 3 / 1) to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N-(propan-2-yl)pyrrolidine-2-carboxamide (yield 98%).

[0824] MS(ESI): m / z 469.2 (M+H) + .

[0825] Step 4: Dissolve (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-N-(propan-2-yl)pyrrolidine-2-carboxamide (90 mg, 0.19 mmol, 1 eq.) in hydrochloric acid / dioxane (3 mL) and methanol (3 mL), and stir at room temperature for 6 hours. LC-MS monitoring of the reaction showed the disappearance of the starting materials and the discovery of the target compound. Pour the reaction solution into saturated NaHCO3 solution (100 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(propan-2-yl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 29%).

[0826] MS(ESI): m / z 502.2 (M+H) + .

[0827] Step 5: Dissolve methyl (3S,5S)-5-[(3-chloro-4-fluorophenyl)(propan-2-yl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (30 mg, 0.06 mmol, 1 eq.) in water (1 mL) and tetrahydrofuran (3 mL), add lithium hydroxide (3 eq.) at room temperature, and stir overnight. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. Pour the reaction solution into water (80 mL), adjust to pH = 2 with 2 M dilute hydrochloric acid, extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under reduced pressure to obtain (3S,5S)-5-[(3-chloro-4-fluorophenyl)(propan-2-yl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 90%).

[0828] MS(ESI): m / z 488.2(M+H) + .

[0829] Step 6: Dissolve (3S,5S)-5-[(3-chloro-4-fluorophenyl)(propan-2-yl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (20 mg, 0.04 mmol, 1 eq.) in acetonitrile (1 mL), add 1-methyl-1H-pyrazol-3-amine (2 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature, and heat at 80 °C for 6 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was directly separated and purified by reversed-phase preparative HPLC (formic acid) to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 -isopropyl-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 28.8%).

[0830] MS(ESI): m / z 567.3(M+H) + .

[0831] 11H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.80 - 7.72 (m, 0.5H), 7.69–7.51 (m, 3H), 7.45 - 7.37 (m, 0.5H), 6.74 (d, J = 6.5 Hz, 1H), 6.60 - 6.46 (m, 1H), 6.47 - 6.40 (m, 1H), 4.80 - 4.67 (m, 1H), 4.15 - 4.05 (m, 1H), 3.92–3.78 (m, 1H), 3.73 (s, 3H), 3.57 - 3.45 (m, 1H), 3.15–3.02 (m, 1H), 2.46 (d, J = 10.2 Hz, 3H), 2.24 - 2.15 (m, 1H), 2.14 - 2.04 (m, 1H), 1.10 - 0.90 (m, 6H).

[0832] Example 77

[0833] Synthesis of (2S)-4-(3-Amino-3-oxopropyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (Compound 128):

[0834]

[0835] First step: Add (2S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (500 mg, 1.16 mmol, 1 eq), hexamethylphosphoramide (1.3 eq) and tetrahydrofuran (1 mL) into a single-necked flask. Replace the air with nitrogen three times. Dropwise add LiHMDS (1.2 eq) at -78 °C and react at -78 °C for 30 minutes. Then add 3-bromopropionitrile (1 eq) and react at -78 °C for 1 hour. Monitor the reaction by LC-MS. When the raw material disappears, the target compound is found. Quench the reaction with water, extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify by preparative HPLC to obtain (2S)-N-(3-chloro-4-fluorophenyl)-4-(2-cyanoethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (yield 61.8%).

[0836] MS (ESI): m / z 483.1 (M + H) + .

[0837] Step 2: Add (2S)-N-(3-chloro-4-fluorophenyl)-4-(2-cyanoethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (150 mg, 0.31 mmol, 1 eq), hydrogen peroxide (19 eq), potassium carbonate (2 eq) and DMSO (3 mL) into a single-necked flask, and react at 60 °C overnight. LC-MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. Quench the reaction with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and rotary evaporate to obtain (4S)-2-(3-amino-3-oxopropyl)-5-((3-chloro-4-fluorophenyl)(methyl)amino)-4-((6-methyl-4-(trifluoromethyl)pyridin-2-yl)amino)-5-oxopentanoic acid (yield 61.1%).

[0838] MS(ESI): m / z 519.2(M+H) + .

[0839] Step 3: Add (4S)-2-(3-amino-3-oxopropyl)-5-((3-chloro-4-fluorophenyl)(methyl)amino)-4-((6-methyl-4-(trifluoromethyl)pyridin-2-yl)amino)-5-oxopentanoic acid (135 mg, 0.26 mmol, 1 eq.), HATU (1.5 eq.), DIEA (3 eq.) and dichloromethane (2 mL) into a single-necked flask, and react at room temperature for half an hour. LC-MS monitoring of the reaction showed that the raw material disappeared and the target compound was found. Dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and then separate and purify to obtain Compound A (yield 10.0%) and Compound B (yield 26.9%).

[0840] A: MS(ESI): m / z 501.1(M+H) + .

[0841] A: 1 1H NMR(400 MHz, DMSO-d6) δ 8.42(s, 1H), 7.90(dd, J = 6.5, 1.6 Hz, 1H), 7.74–7.56(m, 2H), 7.43(s, 1H), 7.33(s, 1H), 6.78(s, 1H), 4.82(dd, J = 8.5, 6.7 Hz, 1H), 3.19(s, 3H), 2.70(t, J = 6.3 Hz, 1H), 2.63(s, 3H), 2.37–2.26(m, 1H), 2.25–2.17(m, 2H), 2.06–1.98(m, 1H), 1.73–1.63(m, 2H).

[0842] B: MS (ESI): m / z 501.1 (M+H) + .

[0843] B: 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.66 (d, J = 6.9 Hz, 2H), 7.43 (s, 1H), 7.31 (s, 1H), 6.78 (s, 1H), 4.88 (d, J = 9.2 Hz, 1H), 3.21 (s, 3H), 2.86–2.75 (m, 1H), 2.63 (s, 3H), 2.42–2.34 (m, 1H), 2.21–2.12 (m, 2H), 2.07–1.98 (m, 1H), 1.81–1.73 (m, 1H), 1.57–1.41 (m, 1H).

[0844] Example 78

[0845] (2S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,5-dimethyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2,4-dicarboxamide (Compound 129) synthesis:

[0846]

[0847] First step: Dissolve (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (100 mg) in tetrahydrofuran (5 mL), dropwise add lithium bis(trimethylsilyl)amide (0.28 mL) at -70 °C, stir for 0.5 hour, then pour the reaction solution into dry ice and wait for the dry ice to evaporate completely. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Rotate the reaction solution to dryness and separate and purify it by preparative HPLC (FA) to obtain (S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidine-3-carboxylic acid (yield 38%).

[0848] MS (ESI): m / z 474.2 (M+H) + .

[0849] Step 2: Dissolve (S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidine-3-carboxylic acid (50 mg, 0.02 mmol, 1 eq.) in acetonitrile (1 mL). Add 1,5-dimethyl-1H-pyrazol-3-amine (1.5 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature, and stir at 80 °C for 6 hours. LC-MS monitoring of the reaction showed the disappearance of the starting material and the discovery of the target compound. The reaction solution was directly separated and purified by preparative HPLC (FA) to obtain (2S)-N 2 -(3-chloro-4-fluorophenyl)-N 4 -(1,5-dimethyl-1H-pyrazol-3-yl)-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2,4-dicarboxamide (yield 22.9%).

[0850] MS (ESI): m / z 567.2 (M+H) + .

[0851] 1 1H NMR (400 MHz, DMSO-d6) δ 10.65 - 10.40 (m, 1H), 8.42 - 8.25 (m, 1H), 7.97–7.85 (m, 1H), 7.65 - 7.58 (m, 2H), 7.50 - 7.42 (m, 1H), 6.32 - 6.24 (m, 1H), 5.02–4.85 (m, 1H), 4.10 - 3.75 (m, 1H), 3.65 - 3.55 (m, 3H), 3.25 - 3.15 (m, 3H), 2.65 - 2.55 (m, 3H), 2.47–2.30 (m, 2H), 2.25 - 2.15 (m, 3H).

[0852] Example 79

[0853] Synthesis of (2S)-N-(3-chloro-4-fluorophenyl)-4-(2-(1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (Compound 130):

[0854]

[0855] Step 1: Dissolve (2S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (100 mg, 0.23 mmol, 1 eq.) in tetrahydrofuran (2 mL). Dropwise add lithium bis(trimethylsilyl)amide (0.28 mL) at -70 °C and stir for 0.5 h. Then add 2-bromoacetonitrile (2 eq.) to the reaction solution and slowly warm up to room temperature and continue stirring for 1 h. LC-MS monitoring of the reaction shows that the starting material disappears and the target compound is found. Pour the reaction solution into water (100 mL) to quench, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate in vacuo to obtain (2S)-N-(3-chloro-4-fluorophenyl)-4-(cyanomethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (yield 92%).

[0856] Step 2: Dissolve (2S)-N-(3-chloro-4-fluorophenyl)-4-(cyanomethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (120 mg, 0.26 mmol, 1 eq.) in hydrochloric acid / dioxane (3 mL) and methanol (3 mL), and stir at room temperature overnight. LC-MS monitoring of the reaction shows that the starting material disappears and the target compound is found. Pour the reaction solution into saturated NaHCO3 solution (80 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain methyl 2-[(5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidin-3-yl]acetate (yield 95.5%).

[0857] MS(ESI): m / z 502.2(M + H) + .

[0858] Step 3: Dissolve methyl 2-[(5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidin-3-yl]acetate (130 mg, 0.26 mmol, 1 eq.) in water (1 mL) and tetrahydrofuran (3 mL), then add lithium hydroxide (3 eq.), and stir at room temperature for 6 hours. Pour the reaction solution into water (100 mL), adjust the pH to ~3 with 2 M hydrochloric acid, extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 2-[(5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidin-3-yl]acetic acid (yield 89.1%).

[0859] MS(ESI): m / z 488.1(M + H) + .

[0860] Step 4: Dissolve 2-[(5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2-oxopyrrolidin-3-yl]acetic acid (120 mg, 0.25 mmol, 1 eq.) in acetonitrile (1 mL), add 1,5-dimethyl-1H-pyrazol-3-amine (1.5 eq.) and 1-propylphosphonic anhydride (1.5 eq.) at room temperature, heat at 80 °C for 6 hours. LC-MS monitoring of the reaction shows the disappearance of the starting material and the discovery of the target compound. The reaction solution is directly separated and purified by preparative HPLC (formic acid) in the reverse phase to obtain (2S)-N-(3-chloro-4-fluorophenyl)-4-(2-(1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (yield 5.4%).

[0861] MS(ESI): m / z 581.2(M + H) + .

[0862] 11H NMR (400 MHz, DMSO-d6) δ 10.43 - 10.30 (m, 1H), 8.49 – 8.34 (m, 1H), 7.96 – 7.84 (m, 1H), 7.68 – 7.57 (m, 2H), 7.45 - 7.37 (m, 1H), 6.30 - 6.20 (m, 1H), 5.02 – 4.76 (m, 1H), 3.62 - 3.58 (m, 3H), 3.20 - 3.15 (m, 3H), 2.85 - 2.72 (m, 1H), 2.62 (s, 3H), 2.46 – 2.31 (m, 2H), 2.20 - 2.15 (m, 2H).

[0863] Example 80

[0864] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-4-fluoro-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (Compound 131) Synthesis:

[0865]

[0866] First step: Add (2S)-1-[(tert-butoxy)carbonyl]-4-oxopyrrolidine-2-carboxylic acid (5 g, 21.81 mmol, 1.0 eq.) to the solvent of N,N-dimethylformamide (40 mL). First add 3-chloro-4-fluoro-N-methylaniline hydrochloride (1.0 eq), then add EDCI (2.0 eq), pyridine (3.0 eq). After displacing nitrogen, stir at 25 °C for 16 hours. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction solution with water and extract with dichloromethane. Concentrate the organic phase under reduced pressure and purify by column (PE:EA = 2:1) to obtain the target compound tert-butyl (2S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-oxopyrrolidine-1-carboxylate (yield 91.7%).

[0867] MS (ESI): m / z 271.0 (M+H) + .

[0868] Step 2: Add tert-butyl (2S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-oxopyrrolidine-1-carboxylate (2 g, 5.39 mmol, 1.0 eq.) to a solvent of water (15 mL) and tetrahydrofuran (10 mL). Add sodium bisulfate (1.5 eq.) at 0 °C and stir for 0.5 h, then add potassium cyanide (1.5 eq.) and stir at 25 °C for 15.5 h. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction mixture with water, extract with dichloromethane three times, combine the organic phases, concentrate by rotary evaporation, and obtain crude tert-butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-hydroxypyrrolidine-1-carboxylate, which is used directly in the next step without purification.

[0869] MS(ESI): m / z 297.8(M-100+H) + .

[0870] Step 3: Add tert-butyl (2S,4S)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-hydroxypyrrolidine-1-carboxylate (2 g, crude product, obtained from the previous step) to a solvent of dichloromethane (10 mL). Add diethylaminosulfur trifluoride (1.62 g) dropwise at -78 °C and stir for 2 h, then raise the temperature to 25 °C and continue to stir for 14 h. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction mixture with water, extract with dichloromethane three times, combine the organic phases, concentrate under reduced pressure, and obtain tert-butyl (2S,4R)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-fluoropyrrolidine-1-carboxylate (yield 64.7%) by column chromatography (PE:EA = 2:1).

[0871] MS(ESI): m / z 300.0(M-100+H)+.

[0872] Step 4: Add trifluoroacetic acid (146.17 eq.) to dichloromethane (5 mL) containing tert-butyl (2S,4R)-2-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-4-cyano-4-fluoropyrrolidine-1-carboxylate (1.3 g, 3.25 mmol, 1.0 eq.). Stir at 25 °C for 3 h. LC-MS shows that the raw material disappears and the target compound is found. Adjust the pH to about 8 with saturated aqueous sodium bicarbonate solution (10 mL), extract with ethyl acetate (20 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methylpyrrolidine-2-carboxamide, which is used directly in the next step without purification.

[0873] MS(ESI): m / z 300.0 (M+H)+.

[0874] Step 5: To a solution of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methylpyrrolidine-2-carboxamide (555 mg, crude, obtained from the previous step reaction) in dioxane (5 mL), add 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (362 mg), cesium carbonate (1.206 g), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (214 mg). Under nitrogen displacement protection, add tris(dibenzylideneacetone)dipalladium (169 mg), and stir the reaction at 100 °C for 3 hours. LC-MS monitoring of the reaction shows the disappearance of the starting material and the discovery of the target compound. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure and purified by preparative HPLC to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 14.6%).

[0875] Step 6: To a solution of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-4-fluoro-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (33 mg, 0.07 mmol, 1.0 eq.) in dimethyl sulfoxide (2 mL), add potassium carbonate (2.0 eq.) and 30% H2O2 (0.21 mL), and stir the reaction at 60 °C for 2 hours. LC-MS monitoring of the reaction shows the disappearance of the starting material and the discovery of the target compound. The reaction solution is filtered, and the filtrate is purified by preparative HPLC to obtain (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-4-fluoro-N 2 -methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2,4-dicarboxamide (yield 4.8%).

[0876] MS(ESI): m / z 477.0 (M+H) + .

[0877] 1 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.30 (s, 1H), 7.22–7.21 (m, 1H), 6.68 (s, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.68 (s, 1H), 4.92 (d, J = 9.2 Hz, 1H), 4.14–3.99 (m, 2H), 3.28 (s, 3H), 2.80–2.66 (m, 1H), 2.50 (s, 3H), 2.43–2.33 (m, 1H).

[0878] Example 81

[0879] (2S,4S)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,4-dimethyl-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (Compound 132) Synthesis:

[0880]

[0881] First step: Under nitrogen protection, in a solution of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methylpyrrolidine-2-carboxamide (1.00 g, 3.55 mmol, 1 eq), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (0.2 eq) and cesium carbonate (2 eq) in dioxane (30 mL), tris(dibenzylideneacetone)dipalladium (0.1 eq) was added, and the temperature was raised to 100 °C for reaction for 12 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (300 mL), the organic phase was concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0 - 50%) to obtain (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 32.0%).

[0882] MS(ESI): m / z 441.2(M + H) + .

[0883] Second step: Under the condition of -78 °C, in (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (100 mg, 0.23 mmol, 1 eq) in tetrahydrofuran (5 mL), LiHMDS (2 eq) was added dropwise, stirred for 1 hour, and methyl iodide (1.1 eq) was added dropwise, and reacted at -78 °C for 2 hours. Quenched with water (5 mL), diluted with ethyl acetate (50 mL) and water (10 mL), separated, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product obtained was purified by column chromatography (ethyl acetate / petroleum ether = 0 - 50%) to obtain (2S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N,4-dimethyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (yield 47.8%).

[0884] MS(ESI): m / z 455.2 (M+H) +

[0885] Step 3: To a solution of (2S)-N-(3-chloro-4-fluorophenyl)-4-cyano-N,4-dimethyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (600 mg, 1.32 mmol, 1 eq) in methanol (2.5 mL), hydrochloric acid / dioxane solution (1.44 mL, 4 M) was added dropwise. The reaction was heated to 50 °C for 3 hours. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (300 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 0 - 50%) to obtain methyl (5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (yield 62.2%).

[0886] MS(ESI): m / z 488.2 (M+H) +

[0887] Step 4: To a solution of methyl (5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylate (400 mg, 0.82 mmol, 1 eq) in MeOH (10 mL) and THF (10 mL), an aqueous solution of lithium hydroxide (2 eq) in water (10 mL) was added dropwise. The reaction was carried out at room temperature for 12 hours. The reaction solution was concentrated, diluted with water (10 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure and separated and purified by reverse-phase column (C18, FA) to obtain (5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (yield 51.5%).

[0888] MS(ESI): m / z 474.2 (M+H) + .

[0889] Step 5: To a solution of (5S)-5-[(3-chloro-4-fluorophenyl)(methyl)carbamoyl]-3-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (40 mg, 0.08 mmol, 1 eq), 1-methyl-1H-pyrazol-3-amine (1.5 eq) and N-methylimidazole (3.5 eq) in acetonitrile (2 mL) was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.2 eq), and the reaction was carried out at room temperature for 4 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, concentrated under reduced pressure and purified by preparative HPLC (FA) to give (2S,4R)-N 2 -(3-chloro-4-fluorophenyl)-N 2 ,4-dimethyl-N 4 -(1-methyl-1H-pyrazol-3-yl)-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2,4-dicarboxamide (yield 67.8%).

[0890] MS(ESI): m / z 553.3(M+H) + .

[0891] 1 H NMR(400 MHz, DMSO-d6) δ10.10(s, 1H), 7.83(d, J = 4.6 Hz, 1H), 7.58(dd, J = 15.1, 5.4 Hz, 3H), 6.76(s, 1H), 6.49(s, 1H), 6.44(d, J = 2.2 Hz, 1H), 4.45(t, J = 7.1 Hz, 1H), 3.76(s, 1H), 3.75(s, 3H), 3.65(d, J = 9.9 Hz, 1H), 3.13(s, 3H), 2.46(s, 3H), 2.33–2.22(m, 1H), 2.17–2.04(m, 1H), 1.18(s, 3H).

[0892] Examples 82 and 83

[0893] (2S,4R)-N-(3-chloro-4-fluorophenyl)-N-methyl-4-{[(1-methyl-1H-pyrazol-3-yl)amino]methyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (Example 82, Compound 133) and (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-4-{[(1-methyl-1H-pyrazol-3-yl)amino]methyl]-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (Example 83, Compound 134) were synthesized as follows:

[0894]

[0895] Step 1: To a solution of (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (50 mg, 0.11 mmol, 1 eq) in dichloromethane (1 mL) was added Dess-Martin periodinane (3 eq), and the reaction was carried out at room temperature for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain (2S)-N-(3-chloro-4-fluorophenyl)-4-formyl-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (yield 92%).

[0896] MS(ESI): m / z 458.1(M+H) + .

[0897] Step 2: To a solution of (2S)-N-(3-chloro-4-fluorophenyl)-4-formyl-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (50 mg, 0.11 mmol, 1 eq), 1-methyl-1H-pyrazol-3-amine (1 eq) and acetic acid (10 eq) in methanol (3 mL) was added sodium cyanoborohydride (3 eq), and the reaction was carried out at 25 °C at room temperature for 16 h. After the reaction mixture was concentrated under reduced pressure, it was diluted with water (5 mL) and ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by preparative HPLC (FA) to obtain (2S,4R)-N-(3-chloro-4-fluorophenyl)-N-methyl-4-{[(1-methyl-1H-pyrazol-3-yl)amino]methyl}-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (Example 82) and (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-4-{[(1-methyl-1H-pyrazol-3-yl)amino]methyl}-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (Example 83) (yield 22.1%).

[0898] Example 82 or Example 83: MS(ESI): m / z 539.2(M+H) + .

[0899] 11H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.88–7.80 (m, 1H), 7.64 (t, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 1.9 Hz, 1H), 5.43 (d, J = 1.9 Hz, 1H), 5.27 (t, J = 6.2 Hz, 1H), 4.82 (dd, J = 9.0, 5.5 Hz, 1H), 3.60 (s, 3H), 3.49–3.39 (m, 2H), 3.18 (s, 3H), 3.06–2.95 (m, 1H), 2.62 (d, J = 7.3 Hz, 3H), 2.18 (dt, J = 19.1, 9.5 Hz, 1H), 2.00–1.87 (m, 1H).

[0900] Example 83 or Example 82: MS (ESI): m / z 539.22 (M+H) + .

[0901] 1 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.91 (d, J = 6.2 Hz, 1H), 7.63 (d, J = 6.8 Hz, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 5.38 (s, 1H), 5.19 (s, 1H), 4.86 (d, J = 9.2 Hz, 1H), 3.58 (s, 3H), 3.42 (d, J = 8.8 Hz, 2H), 3.17 (s, 3H), 3.15–3.09 (m, 1H), 2.61 (s, 3H), 2.32–2.23 (m, 1H), 2.01–1.85 (m, 1H).

[0902] Example 84

[0903] Synthesis of (2S)-N-(3-chloro-4-fluorophenyl)-4-{[(1,5-dimethyl-1H-pyrazol-3-yl)amino]methyl}-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (Compound 135):

[0904]

[0905] Step 1: Add (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (200 mg, 0.43 mmol, 1 eq), Dess-Martin oxidant (1.1 eq) and dichloromethane (4 mL) into a single-necked flask, and react at room temperature overnight. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction with water, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate by rotary evaporation to obtain the crude product of (2S)-N-(3-chloro-4-fluorophenyl)-4-formyl-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide, which is used directly in the next step without purification.

[0906] MS(ESI): m / z 458.1(M+H) + .

[0907] Step 2: Add (2S)-N-(3-chloro-4-fluorophenyl)-4-formyl-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (199 mg, crude product, obtained from the previous step reaction), 1,5-dimethyl-1H-pyrazol-3-amine (72.47 mg,), AcOH (0.5 mL) and MeOH (5 mL) into a single-necked flask, and add sodium cyanoborohydride (135 mg) in batches. React overnight. LC-MS monitoring of the reaction shows that the raw material disappears and the target compound is found. Quench the reaction with water, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and after concentration, separate and purify by preparative HPLC to obtain (2S)-N-(3-chloro-4-fluorophenyl)-4-{[(1,5-dimethyl-1H-pyrazol-3-yl)amino]methyl}-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (A: yield 0.49%; B: yield 3.7%).

[0908] A: MS(ESI): m / z 553.2(M+H) + .

[0909] A: 1 1H NMR(400MHz, DMSO-d6) δ8.42(s,1H),7.85(dd,J=6.7,2.3Hz,1H),7.65(t,J=8.9

[0910] Hz, 1H), 7.61–7.54 (m, 1H), 7.42 (s, 1H), 5.28 (s, 1H), 5.14 (t, J = 6.5 Hz, 1H), 4.82 (dd, J = 9.1, 5.4 Hz, 1H), 3.49 (s, 3H), 3.41 (dd, J = 13.0, 5.6 Hz, 1H), 3.18 (d, J = 7.6 Hz, 3H), 3.16–3.08 (m, 1H), 3.00 (dq, J = 6.3, 5.8 Hz, 1H), 2.62 (s, 3H), 2.22–2.13 (m, 1H), 2.11 (s, 3H), 1.97–1.87 (m, 1H).

[0911] B: MS(ESI): m / z 553.2 (M + H) + .

[0912] B: 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.98–7.88 (m, 1H), 7.70–7.61 (m, 2H), 7.43 (s, 1H), 5.25 (s, 1H), 5.08 (t, J = 6.3 Hz, 1H), 4.88 (d, J = 8.8 Hz, 1H), 3.48 (s, 3H), 3.46–3.39 (m, 1H), 3.19 (s, 3H), 3.16–3.02 (m, 2H), 2.63 (s, 3H), 2.31–2.26 (m, 1H), 2.11 (s, 3H), 1.98–1.90 (m, 1H).

[0913] Example 85

[0914] (2S)-N-(3-chloro-4-fluorophenyl)-N-methyl-4-(3-((1-methyl-1H-pyrazol-3-yl)amino)-3-oxopropyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (Compound 136) Synthesis:

[0915]

[0916] Step 1: Add (2S)-N-(3-chloro-4-fluorophenyl)-4-(2-cyanoethyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-5-oxopyrrolidine-2-carboxamide (175 mg, 0.36 mmol, 1 eq) and MeOH (4 mL) into a single-necked flask, stir to dissolve, then add HCl / dioxane (4 mL), and react overnight. LC-MS monitoring of the reaction shows the disappearance of the raw material and the discovery of the target compound. The reaction solution is concentrated under reduced pressure, the pH is adjusted to 8 - 9 with saturated aqueous NaHCO3, extracted with ethyl acetate, the organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and then separated and purified by column chromatography (PE:EA = 3:1) to obtain methyl 3-((5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)propionate (yield 78.2%).

[0917] MS(ESI): m / z 516.2(M + H) + .

[0918] Step 2: Add methyl 3-((5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)propionate (146 mg, 0.28 mmol, 1 eq), MeOH (2 mL) and THF (2 mL) into a single-necked flask, stir to dissolve, then add an aqueous solution of LiOH (3 eq) (0.5 mL), and react overnight. LC-MS monitoring of the reaction shows the disappearance of the raw material and the discovery of the target compound. The reaction solution is concentrated under reduced pressure, the pH is adjusted to 3 - 4 with dilute hydrochloric acid, extracted with ethyl acetate, the organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and evaporated to dryness to obtain 3-((5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)propanoic acid (yield 91%).

[0919] MS(ESI): m / z 502.1(M + H) + .

[0920] Step 3: Add 3-((5S)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)propanoic acid (130 mg, 0.26 mmol, 1 eq), 1-methyl-1H-pyrazol-3-amine (1.2 eq), HATU (1.3 eq), DIEA (3 eq) and DMF (3 mL) into a single-necked flask, and react overnight. LC-MS monitoring of the reaction shows that the raw materials disappear and the target compound is found. The reaction solution is diluted with ethyl acetate, washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The product is separated and purified by preparative HPLC to obtain (2S)-N-(3-chloro-4-fluorophenyl)-N-methyl-4-(3-((1-methyl-1H-pyrazol-3-yl)amino)-3-oxopropyl)-1-(6-methyl-4-trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (A: 7 mg, yield 4.6%; B: 19 mg, yield 12.6%).

[0921] A: MS(ESI): m / z 581.2(M+H) + .

[0922] A: 1 1H NMR(400 MHz, DMSO-d6) δ10.37(s, 1H), 8.42(s, 1H), 7.88(dd, J = 6.6, 2.1 Hz, 1H),

[0923] 7.70–7.57(m, 2H), 7.54(d, J = 2.1 Hz, 1H), 7.44(s, 1H), 6.45(d, J = 2.2 Hz, 1H), 4.83(dd, J = 8.6, 6.5 Hz, 1H), 3.75(s, 3H), 3.20(s, 3H), 2.75–2.66(m, 1H), 2.63(s, 3H), 2.48–2.38(m, 2H), 2.30(ddd, J = 18.6, 13.6, 6.5 Hz, 1H), 2.10(td, J = 13.5, 7.5 Hz, 1H), 1.82–1.66(m, 2H).

[0924] B: MS(ESI): m / z 581.2(M+H) + .

[0925] B: 11H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.47 (s, 1H), 7.91–7.89 (m, 1H), 7.64–7.62 (m, 2H), 7.53 (d, J = 2.1 Hz, 1H), 7.42 (s, 1H), 6.43 (d, J = 2.2 Hz, 1H), 4.87 (d, J = 9.2 Hz, 1H), 3.73 (s, 3H), 3.19 (s, 3H), 2.86–2.78 (m, 1H), 2.62 (s, 3H), 2.40–2.33 (m, 3H), 2.13–2.05 (m, 1H), 1.82–1.74 (m, 1H), 1.63–1.53 (m, 1H).

[0926] Referring to the preparation methods of Reference Examples 1-85, the following compounds were prepared:

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933] Biological test evaluation

[0934] POLQ is expressed at low levels in normal tissues but is upregulated in many tumor types, such as breast, ovarian, HNSCC, and lung. POLQ inhibitors have the potential to be used in a wide range of clinical settings, particularly in HR-deficient tumors, such as breast and ovarian cancer, or in combination with DNA-damaging agents (chemotherapy and radiotherapy). Mechanistically, they can also be used in combination with PARP1 inhibitors to expand the indication.

[0935] The present invention will be further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0936] Test Example 1

[0937] 1. Experimental purpose:

[0938] The purpose of this experiment is to detect the ability of the invented compound to inhibit the activity of PolQ polymerase. The template and primer were mixed at a ratio of 1:1.1, heat-treated at 95°C for 5 minutes in the reaction buffer, and after slow cooling, the PolQ protein was treated with compounds at different concentrations. After incubation at room temperature, the fluorescence was measured at the 525 / 598nm module on an Envision instrument, and the data was read. The data was processed by four-parameter fitting to obtain the IC 50 value, thereby calculating the biological activity of the compound.

[0939] 2. Experimental materials and equipment:

[0940] 1) Materials

[0941]

[0942] 2) Reagents & manufacturers

[0943] dNTP Sigma#D7295-5ML, 10 mM; <![CDATA[MgCl2]]> Thermo Fisher#R0971; NaCl Sigma#10708976001 BSA Sigma#A70828-25G; DTT Sigma#10197777001;

[0944] 3) Consumables

[0945]

[0946] 4) Equipment

[0947]

[0948] 3. Experimental procedures

[0949] The polymerase active fragment of PolQ (amino acids 1792 - 2590) was synthesized by Shanghai RunNuo Biotechnology Co., Ltd., and after aliquoting, it was stored in a -80°C refrigerator. The reaction was carried out in a 1× buffer system (20 mM Tris pH 7.8, 10 mM MgCl2, 50 mM KCl, 1 mM DTT, 0.01% Tween-20, and 0.01% BSA).

[0950] The compound powder was dissolved in DMSO to a concentration of 10 mM. The compound was serially diluted 3-fold, with 11 test concentrations. 150 nL of the compound was transferred to a 384-well reaction plate (Corning 4514) using ECHO. The highest final concentration of the compound in the reaction system was 10 μM. 150 nL of DMSO was added to the positive control and negative control respectively. The content of DMSO in the final reaction system was 1%.

[0951] Mix the template 5-TAMRA-CCTTCCTCCCGTGTCTTGTACCTTCCCGT CAGGAGGAAGG-BHQ-3′ (SEQ ID NO 1) and the primer 5′-GACGGGAAGG-3′ (SEQ ID NO 2) at a ratio of 1:1.1, heat-treat in a heat-treatment reaction buffer (10 mM Tris (pH 8.0), 100 mM NaCl and H2O) at 95 °C for 5 minutes, and cool down slowly. Add 10 μL of the mixture of PolQ protein and dNTPs to the reaction plate (final concentration of PolQ protein is 2.5 nM, and final concentration of dNTPs is 48 μM), and incubate at room temperature for 15 minutes. Prepare a DNA mixture (final reaction system is 96 nM), transfer 5 μL to the reaction plate, and incubate at room temperature for 60 minutes. After incubation, measure the fluorescence intensity at the 525 / 598 nm module on Envision and record the data. The IC 50 value is determined by a four-parameter dose-response equation.

[0952] 4. Experimental results:

[0953]

[0954]

[0955]

[0956] Note: A represents IC 50 < 10 nM; B represents 10 nM < IC 50 < 50 nM

[0957] Test Example 2

[0958] 1. Experimental purpose:

[0959] The purpose of this experiment is to detect the ability of the inventive compound to inhibit the proliferation of MDA-MB-436 cells. Culture MDA-MB-436 cells, then plate them at a density of 1000 cells / well, incubate the culture plate overnight in an incubator at 37 °C, 5% CO2, and 100% relative humidity, and then treat the MDA-MB-436 cells with different concentrations of the compound, and incubate in an incubator at 37 °C, 5% CO2, and 100% relative humidity for 144 hours. Take out the culture plate and equilibrate to room temperature, add 50 μL / well of CellTiter-Glo working solution, avoid light, incubate at room temperature for 10 minutes, and then measure the fluorescence on the chemiluminescence module of a TECAN microplate reader and read the data. Process the data by four-parameter fitting to obtain the IC50 value, and thus calculate the biological activity of the compound.

[0960] 2. Experimental materials and equipment:

[0961] (1) Materials

[0962] Cells: HTB - 130 (ATCC)

[0963] (2) Reagents & Manufacturers:

[0964]

[0965] (3) Consumables:

[0966]

[0967]

[0968] (4) Equipment:

[0969]

[0970] 4. Experimental Procedures

[0971] (4.1) Cell Culture

[0972] Culture the tumor cell line in an incubator at 37 °C and 5% CO2 according to the culture conditions shown in Table 2. Passage regularly and use cells in the logarithmic growth phase for plating.

[0973] (4.2) Cell Plating

[0974] Stain the cells with trypan blue and count the viable cells.

[0975] Adjust the concentration of MDA - MB - 436 cells to an appropriate concentration of 1000 cells / well.

[0976] Add 195 μL of cell suspension to each well in the culture plate according to the Platemap, and add 200 μL / well of cell - free culture medium to the blank control wells.

[0977] Incubate the culture plate overnight in an incubator at 37 °C, 5% CO2, and 100% relative humidity.

[0978] (4.3) Compound Treatment of Cells

[0979] Preparation of 40X compound working solution: In a 96 - well plate with a V - bottom, add 10 mM compound and DMSO according to the volume of the first well. From wells 2 - 9, take 20 μL of the compound from the previous well + 40 μL of DMSO for 3 - fold dilution. Dilute all compounds: medium = 1:4 by volume and mix well to prepare the 40X compound solution.

[0980] Drug addition: Take 5 μL of the 40X compound working solution and add it to the cell culture plate. Add 5 μL of DMSO-cell culture medium mixture to the vehicle control. The final concentration of DMSO is 0.5%.

[0981] Place the 96-well cell plate back into the incubator and culture for 6 days.

[0982] (4.4)Cell viability detection by CellTiter-Glo luminescence assay

[0983] The following steps are carried out according to the instructions of the Promega CellTiter-Glo luminescence cell viability detection kit (Promega-G7573).

[0984] Melt the CellTiter-Glo buffer and let it stand at room temperature.

[0985] Let the CellTiter-Glo substrate stand at room temperature.

[0986] Add the CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate, thus preparing the CellTiter-Glo working solution.

[0987] Take out the CellTiter-Glo working solution from the -20 °C refrigerator.

[0988] Take out the cell culture plate and let it equilibrate to room temperature for 10 minutes.

[0989] Use a multichannel pipette to aspirate 100 μL of the culture medium from each well and discard it.

[0990] Add 50 μL (equal to half the volume of the cell culture medium in each well) of the CellTiter-Glo working solution to each well. Wrap the cell plate with aluminum foil to avoid light.

[0991] Shake the culture plate on an orbital shaker for 10 minutes to induce cell lysis.

[0992] Measure the fluorescence intensity on the chemiluminescence module of a TECAN microplate reader and record the data. The IC 50 value is determined by a four-parameter dose-response equation.

[0993] 5. Experimental results:

[0994] Compound number MDA-MB-436 IC50 (μM) ART812 >10 Example 1 (Compound 1) 3.2 Example 16 (Compound 56) 0.45 Example 52 (Compound 103) 2.9 Example 62 (Compound 113) 3.5

Claims

1. A compound represented by formula (I-A), its stereoisomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt: n1 is 0 or 1; R1 is independently -OH; n2 is 1 or 2; R2, each occurrence of which is independently R h -SO2-, carboxyl, -C(O)-NR b -SO2-R a , -C(O)-OR a , -C(O)-O(CH2) w -O-C(O)-R a , -C(O)-R a , -C(O)-NR b R c , -C(O)-NR b -(CH2) w -C(O)R a , -C(O)-NR b -(CH2) w -C(O)NR b R c ; OH provided that n2 is 2 and one of the R2s is -C(O)-NR b -SO2-R a , -C(O)-OR a , -C(O)-R a , -C(O)-NR b R c , -C(O)-NR b -(CH2) w -C(O)R a , or -C(O)-NR b -(CH2) w -C(O)NR b R c ); halogen provided that n2 is 2 and one of the R2s is -C(O)-NR b -SO2-R a , -C(O)-OR a , -C(O)-R a , -C(O)-NR b R c , -C(O)-NR b -(CH2) w -C(O)R a , -C(O)-NR b -(CH2) w -C(O)NR b R c ); -CH3 provided that n2 is 2 and one of the R2s is -C(O)-NR b -SO2-R a , -C(O)-OR a , -C(O)-R a , -C(O)-NR b R c , -C(O)-NR b -(CH2) w -C(O)R a , or -C(O)-NR b -(CH2) w -C(O)NR b R c ); -C(O)-(CH2) w -O-C(O)-R a or -C(O)-NR b -(CH2) w -O-(CH2) w -O-(CH2) w -NR b R c ; When n2 = 2, each R2 is different; R a Each, independently at each occurrence, is a 4- to 8-membered heterocyclic group or a 5- to 6-membered heteroaryl group, which heterocyclic group or heteroaryl group may optionally be substituted by one or more substituents selected from halogen, hydroxy, -NR b R c , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, halo-C 1-3 alkyl, halo-C 1-3 alkylthio, -C(O)C 1-3 alkyl, and -C(O)C 1-3 alkoxy; R b and R c each independently, at each occurrence, is a 3- to 6-membered cycloalkyl or a 5- to 6-membered heteroaryl, wherein said cycloalkyl and heteroaryl may optionally be substituted with one or more substituents selected from R a2 , halogen, hydroxy, di(C 1-3 alkyl)amino, mono(C 1-3 alkyl)amino, amino, C 1-3 alkyl, and 3- to 6-membered heterocyclic groups; R a2 each independently represents ethyl or propyl each time it appears; R h Each, independently at each occurrence, is halogen, hydroxy, bis(C 1-3 alkyl)amino, mono(C 1-3 alkyl)amino, amino, mercapto, C 1-3 alkyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl, haloC 1-3 alkyl, or substituted with a 3- to 8-membered heterocyclic group; n3 is independently 0, 1 or 2 each time it appears; Each occurrence of R3 is independently deuterium, tritium, a halogen, C 1-6 alkyl, C 1-6 alkoxy or -CH2-R 13 , where R 13 is C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or hydroxy C 1-6 alkyl; When n3 = 2, each R3 may be the same or different; Or R2 is linked to R3 to form a 2-fused heterocycle with the pyrrolidine ring, and the 2-fused heterocycle is selected from R4 is absent or is cyano; R5 is methyl; m is independently 0, 1, 2, 3, 4 or 5 each time it appears; When m > 1, each R6 may be the same or different; R6, each occurrence independently, is halogen, hydroxy, amino, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, or halo-C 1-3 alkoxy; w is independently 1, 2 or 3; R7 is CF3; R8 is absent; R9 does not exist or is C 1-6 alkyl, halo-C 1-6 alkyl; Wherein 1, 2 or 3 ring atoms in the heteroaryl or heterocyclic group are selected from N, O or S, and the remaining ring atoms are C.

2. The compound according to claim 1, its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts, wherein: (R2) n2 For 3. A compound, its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein, The compound is selected from:

4. A pharmaceutical composition comprising a compound represented by any one of claims 1-3, its stereoisomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient and / or adjuvant.

5. Use of a compound represented by any one of claims 1-3, its stereoisomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt or the pharmaceutical composition of claim 4 in the preparation of a drug for the treatment of POLQ-mediated diseases.

6. The use according to claim 5, wherein the POLQ-mediated disease is a tumor.

7. The use according to claim 6, wherein the tumor is a solid tumor.

8. The use according to claim 7, wherein the solid tumor is breast cancer.

9. A drug combination comprising a compound represented by any one of claims 1-3, its stereoisomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt, and an additional anti-cancer agent or immune checkpoint inhibitor for the treatment of tumors.

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