WO2025242055A1

WO2025242055A1 - Inhibitors of lactate dehydrogenase, compositions comprising the inhibitor, and methods of use thereof

Info

Publication number: WO2025242055A1
Application number: PCT/CN2025/095852
Authority: WO
Inventors: Ke Xu; Anjin XIANYU; Helmut Haning; Shiqiang ZHOU
Original assignee: Meta Pharmaceuticals Hk Ltd; Shenzhen Moyuan Pharmaceuticals
Current assignee: Meta Pharmaceuticals Hk Ltd; Shenzhen Moyuan Pharmaceuticals
Priority date: 2024-05-20
Filing date: 2025-05-19
Publication date: 2025-11-27
Anticipated expiration: 2026-11-20
Also published as: WO2025241048A1

Abstract

The present disclosure provides novel small molecule compounds with six-membered aromatic substituents that can serve as inhibitors of lactate dehydrogenase. The present disclosure also provides pharmaceutical compositions, comprising at least one of such novel substituted compounds, and methods of using at least one of such compounds or compositions in treating or preventing diseases associated with lactate dehydrogenase activities, such as autoimmune diseases.

Description

Inhibitors of Lactate Dehydrogenase, Compositions Comprising the Inhibitor, and Methods of Use Thereof

Technical Field

The present disclosure relates to novel compounds that can serve as inhibitors of lactate dehydrogenase, pharmaceutical compositions, comprising at least one of such compounds, and methods of using at least one of such compounds in treating or preventing diseases associated with lactate dehydrogenase activities, such as autoimmune diseases.

Background

Lactate dehydrogenase (LDH) is an important enzyme of the glucose metabolism. It belongs to the class of oxidoreductases and functions to catalyze the reversible conversion of lactate to pyruvate with the reduction of NAD+ to NADH and vice versa. LDH is a tetrameric protein composed of the products of the LDHA (subunit M) and LDHB (subunit H) genes. The tetrameric combination of these gene products generates 5 LDH isoforms with different combinations of subunits depending on the cell type. All LDH isoforms catalyze the last step in the glycolytic pathway converting pyruvate to lactate while regenerating NAD+from NADH. This reaction is important for the production of ATP through glycolysis.

Lactate dehydrogenase inhibition has been considered as a therapeutic option for cancer treatment. Cancer cells exhibit metabolic characteristics that are different from normal cells. Cancer cells prefer glycolysis over mitochondrial oxidative phosphorylation to regenerate NAD+ and produce essential cellular building blocks, such as amino acids, lipids, and nucleotides that are needed to support rapid cell growth. While aerobic glycolysis is an inefficient way to generate ATP in comparison with oxidative phosphorylation, it generates ATP rapidly. Many non-cancer cells use a combination of oxidative phosphorylation and glycolysis to achieve the metabolic plasticity that is needed to serve their biological functions. The preference of cancer cells for aerobic glycolysis and the enzymes in glycolysis have long been recognized as potential targets for the selective killing of cancer cells. Cancer cells overexpress many glycolytic enzymes, including lactate dehydrogenase (LDH) enzymes A (LDHA) and B (LDHB) .

Lactate dehydrogenase A (LDHA) inhibition attracts more attention, since it can help regulate the metabolic activity of cells. Genetic knockdown of LDHA has been shown to elicit cell death or delay cell growth in various cell lines, while knockdown of lactate dehydrogenase B (LDHB) has been reported to be less effective in impacting survival of tumor cells. Inhibition of LDHA can lead to a decrease in lactate production and an increase in oxidative phosphorylation, which can help regulate cellular metabolism. Therefore, LDHA inhibition is not only considered as a potential treatment of cancers, but in general a potential treatment of metabolic disorders and other diseases that are associated with altered cellular functions.

Various pyrazolyl-based compounds substituted with a thiazolyl group that is substituted or unsubstituted for use in inhibiting lactase dehydrogenase activity and for the treatment of one or more symptoms of hyperoxaluria, including primary hyperoxaluria and stone formation in the kidney and urinary tract, were known. See WO2021234543A1 and WO2021234547A1. In addition, thiazole carboxylic acid was considered as a critical substitute, and replacement of the thiazole carboxylic acid with other rings, such as oxazole, pyridine, and other heterocycles, was reported to be markedly detrimental to the activity of compounds. See J. Med. Chem., 60 (22) , pp. 9184-9204 (2017) .

In addition, substituted pyrazolyl compounds, which inhibit lactase dehydrogenase activity and could be used for treating cancer, have also been known. See J. Med. Chem. 63 (19) , pp. 10984-11011 (2020) ; J. Med. Chem., 60 (22) , pp. 9184-9204 (2017) ; Bioorg. Med. Chem. Lett. 41, Article 127974 (2021) ; WO2016109559A2; and WO2018005807A1.

However, those LDHA inhibitors do not meet the various needs of the patients. Therefore, there is still a need for better LDHA inhibitors.

Summary of the Present Disclosure

The present disclosure relates to compounds that can serve as inhibitors of lactate dehydrogenase A, compositions comprising at least one of such compounds, and methods of uses thereof.

One objective of the present disclosure is to provide a compound of formula I, a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof:

in which:

Z₁ and Z₂ are each independently selected from CH and N;

ring A is not a pyrazole ring

ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:

X₁, X₂, X₃, X₄, and X₅ are each independently selected from CR₅ and NR₅;

wherein three or four of X₁, X₂, X₃, X₄, and X₅ are CR₅;

wherein each R₅ is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl,

and wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably, ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:

X₁, X₂, X₃ and X₅ are each independently selected from C or N;

X₄ is selected from CR₅ and NR₅;

three or four ring atoms in ring A are carbon atoms;

wherein each R₅ is independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl;

wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably, ring A comprises a structure selected from:

*is the position connecting Ar₁.

Ar₁ is a substituted or unsubstituted six-membered aromatic ring, preferably Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 hetero atoms, such as nitrogen atom; in which each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR_c, -CONR_dR_e, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and SO₂NR_dR_e; and wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

preferably, Ar₁ is a substituted six-membered aromatic ring, preferably Ar₁ is selected from substituted phenyl and substituted six-membered heteroaryl groups with 1 to 3 hetero atoms, such as nitrogen atom; each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably, Ar₁ has a structure selected from: in which R₆ is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR_c, -CONR_dR_e, and -SO₂NR_dR_e, wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups, and m is 0, 1 or 2;

preferably, Ar₁ iswherein E₁, E₂, E₃ and E₄ are each independently selected from N and CR_f, and at least one of E₁, E₂, E₃ and E₄ is N; R_f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R_c is hydrogen or C1-C6 alkyl groups.

R₃ is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and substituted or unsubstituted five-to ten-membered heteroaryloxy groups with one or two or three heteroatoms each independently selected from N, O, and S; or R₃ and X₂ together form

wherein the substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups;

L₁ is selected from -CR₁R₂-, -CO-, -O-, -NH-, and -S-;

in which R₁ and R₂ are each independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and in which the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R₁ and R₂, together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;

ring B is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic alkyl, substituted or unsubstituted six-to ten-membered aryl, and substituted or unsubstituted five-to ten-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S;

in which each substituent group is independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably ring B is selected from a substituted or unsubstituted C4-C8 cycloalkyl, a substituted or unsubstituted C4-C8 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S, a substituted or unsubstituted six-to ten-membered aryl, and a substituted or unsubstituted five-to eight-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

more preferably ring B is selected from:

optionally ring B is substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;

R₄ is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO₂NR_aR_b, -CONR_aR_b, and -N (C1-C6 alkyl) (C1-C6 alkyl) ; in which R_a and R_b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups;

wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH₂, -NH-COOH, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; and n is an integer selected from 0, 1, 2, 3, and 4;

preferably, R₄ is each independently selected from fluorine, chlorine, and -SO₂NH₂;

L₂ is a linker comprising an unsaturated or aromatic moiety, preferably L₂ is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S;in which, optionally each hydrogen in L₂ is independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;

preferably, L₂ is selected from in which R’ is selected from a halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;

optionally, hydrogen in L₂ is each independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;

Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with 1 to 3 hetero atoms each independently selected from N, O and S; in which the substituent group is each independently selected from oxo, halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, amino group, -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , and -N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, -CH₃, -CF₃, -CF₂H, -CH₂-CF₃, -O-CH₃, -O-CF₃, -O-CF₂H, -O-CH₂-CF₃, -CD₃, -CN,

In some embodiments, ring B comprises an aliphatic ring, an aromatic ring, or a partially saturated ring. In some embodiments, ring B is an aliphatic ring, an aromatic ring, or a partially saturated ring.

In some embodiments, ring B is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic alkyl, substituted or unsubstituted six-to ten-membered aryl, and substituted or unsubstituted five-to ten-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) .

In some embodiments, ring B is selected from a substituted or unsubstituted C4-C8 cycloalkyl, a substituted or unsubstituted C4-C8 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S, a substituted or unsubstituted six-to ten-membered aryl, and a substituted or unsubstituted five-to eight-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) .

In some embodiments, ring B is selected from a substituted or unsubstituted C5-C7 cycloalkyl, a substituted or unsubstituted C5-C7 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S, a substituted or unsubstituted six-membered aryl, and a substituted or unsubstituted five-to six-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) .

In some embodiments, ring B is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) .

In some embodiments, ring B is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups.

In some embodiments, ring B comprises a structure selected from optionally ring B is substituted by one or more substituents independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups.

In some embodiments, ring B comprises a structure selected from

In some embodiments, ring A is an heteroaromatic ring, or a partially saturated ring, with the proviso that ring A is not a pyrazole ring.

In some embodiments, ring A is not

In some embodiments, ring A is a five-membered heteroaromatic ring, or a five-membered partially saturated ring, with the proviso that ring A is not a pyrazole ring.

In some embodiments, ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:

three or four of X₁, X₂, X₃, X₄, and X₅ are CR₅;

each R₅ is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl, wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) .

In some embodiments, ring A comprises a structure selected from:

*is the position connecting Ar₁.

In some embodiments, Ar₁ is a six-membered aromatic or partially saturated ring.

In some embodiments, Ar₁ is a six-membered aromatic or partially saturated ring, comprising 0 to 3 heteroatoms selected from N, S, and O.

In some embodiments, Ar₁ is a six-membered aromatic or partially saturated ring which is optionally substituted by halogen, hydroxyl, cyano, carboxyl, -COOR_c, -CONR_dR_e, and -SO₂NR_dR_e, wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups.

In some embodiments, Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 hetero atoms.

In some embodiments, Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 nitrogen atoms.

In some embodiments, Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 nitrogen atom; in which each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR_c, -CONR_dR_e, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and SO₂NR_dR_e; and wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups.

In some embodiments, Ar₁ has a structure selected from:

wherein R₆ is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR_c, -CONR_dR_e, and -SO₂NR_dR_e, wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

wherein m is 0, 1 or 2.

In some embodiments, Ar₁ iswherein E₁, E₂, E₃ and E₄ are each independently selected from N and CR_f, and at least one of E₁, E₂, E₃ and E₄ is N; R_f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R_c is hydrogen or C1-C6 alkyl groups.

In some embodiments, L₂ is a linker comprising an unsaturated or aromatic moiety, preferably L₂ is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, three-to six-membered aromatic groups, and three-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S.

Optionally, each hydrogen in L₂ is each independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.

In some embodiments, L₂ is selected from in which R’ is selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.

In some embodiments, Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with 1 to 3 hetero atoms each independently selected from N, O and S; in which the substituent group is each independently selected from oxo, halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, amino group, -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , and -N (C1-C6 alkyl) (C1-C6 alkyl) .

In some embodiments, Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, -CH₃, -CF₃, -CF₂H, -CH₂-CF₃, -O-CH₃, -O-CF₃, -O-CF₂H, -O-CH₂-CF₃, -CD₃, -CN,

In some embodiments, R₃ is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and substituted or unsubstituted five -to ten-membered heteroaryloxy groups with one or two or three heteroatoms each independently selected from N, O, and S; or R₃ and X₂ together form

in which the substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups.

In some embodiments, R₃ is substituted C1-C6 alkyl groups, C6-C10 aryloxy, C3-C6 cycloalkoxy or substituted C1-C6 alkoxyl groups, wherein the substituent group is independently selected from hydroxyl, halogen, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or R₃ and X₂ together form

In some embodiments, R₃ is selected fromor R₃ and X₂ together form

In some embodiments, R₄ is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO₂NR_aR_b, -CONR_aR_b, and -N (C1-C6 alkyl) (C1-C6 alkyl) ; in which R_a and R_b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups; wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH₂, -NH-COOH, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; and n is an integer selected from 0, 1, 2, 3, and 4.

In some embodiments, R₄ is each independently selected from fluorine, chlorine, and -SO₂NH₂.

In some embodiments, n is 0, 1, 2, or 3.

In some embodiments, L₁ is selected from -CR₁R₂-, -CO-, -O-, -NH-, and -S-; in which R₁ and R₂ are each independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and wherein the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or R₁ and R₂, together with the atom to which they are bound, to form a C3-C6 cycloalkyl group.

In some embodiments, L₁ is selected from -CH₂-, -CHF-, -CHOH-, -CO-, -O-, -NH-, and -S-.

In some embodiments, L₁ can be absent.

In some embodiments, a compound of the present disclosure has a structure of any one of Formula II,

in which:

Z₁ and Z₂ are each independently selected from CH and N;

ring A is not a pyrazole ring;

wherein three or four of X₁, X₂, X₃, X₄, and X₅ are CR₅;

wherein each R₅ is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl, wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

X₁, X₂, X₃ and X₅ are each independently selected from C or N;

X₄ is selected from CR₅ and NR₅;

three or four ring atoms in ring A are carbon atoms;

preferably, ring A comprises a structure selected from:

*is the position connecting Ar₁.

in ring B, Y₁, Y₂, Y₃, and Y₄ of ring B are each independently selected from CR₇ and NR₇;

Y₅ is absent, CR₇ or NR₇;

each R₇ is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably, in ring B, Y₁, Y₂, Y₃, Y₄ and Y₅ of ring B are each independently selected from CR₇ and N;

or Y₅ is absent; isY₁, Y₂, Y₃ and Y₄ of ring B, are each independently selected from CR₇, N, NR₇, O and S; and only one of Y₁, Y₂, Y₃ and Y₄ is NR₇, O or S;

each R₇ is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino, four-to six-membered heterocycloalkyl groups optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano and oxo, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably, each R₇ is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;

more preferably, each R₇ is independently absent or selected from hydrogen, halogen, and oxo;

preferably ring B is selected from substituted or unsubstituted six-to ten-membered aryl, and substituted or unsubstituted five-to eight-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

more preferably ring B is selected from:

ring B is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;

Ar₁ is a substituted or unsubstituted six-membered aromatic ring, preferably Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 hetero atoms, such as nitrogen atoms; in which each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR_c, -CONR_dR_e, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and SO₂NR_dR_e; and wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

preferably, Ar₁ iswherein E₁, E₂, E₃ and E₄ are each independently selected from N and CR_f, and at least one of E₁, E₂, E₃ and E₄ is N; R_f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R_c is hydrogen or C1-C6 alkyl groups;

L₁ is selected from -CR₁R₂-, -CO-, -O-, -NH-, and -S-;

in which R₁ and R₂ are each independently selected from H, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and in which the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R₁ and R₂, together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;

R₄ is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO₂NR_aR_b, -CONR_aR_b, and -N (C1-C6 alkyl) (C1-C6 alkyl) ; in which R_a and R_b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups; wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH₂, -NH-COOH, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; and n is an integer selected from 0, 1, 2, 3, and 4;

L₂ is a linker comprising an unsaturated or aromatic moiety, preferably L₂ is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S;

In some embodiments, X₁, X₂, X₃, X₄, X₅, L₁, L₂, Ar₁, R₃, R₄, and Q of Formula II are defined as disclosed above for Formula I.

In some embodiments, Formula II comprises the following Formula II-1 and II-2:

in which each of X₁, X₂, X₃, X₄, X₅, Y₁, Y₂, Y₃, Y₄, L₁, L₂, Ar₁, R₃, R₄, and Q are defined as disclosed above.

In some embodiments, Formula II comprises the following Formula II-3, II-4, and II-5

in which each of X₁, X₂, X₃, X₄, X₅, Y₁, Y₂, Y₃, Y₄, Y₅, L₁, L₂, Ar₁, R₃, R₄, and Q are defined as disclosed above.

In some embodiments, a compound of the present disclosure has a structure of any one of Formulae II-1, II-2, II-3, II-4, and II-5.

In some embodiments, a compound of the present disclosure has a structure of Formula III

in which:

Z₁ and Z₂ are each independently selected from CH and N;

ring A is not a pyrazole ring;

wherein three or four of X₁, X₂, X₃, X₄, and X₅ are CR₅;

X₁, X₂, X₃ and X₅ are each independently selected from C or N;

X₄ is selected from CR₅ and NR₅;

three or four ring atoms in ring A are carbon atoms;

preferably, ring A comprises a structure selected from:

*is the position connecting Ar₁.

in ring B, Y₁, Y₂, Y₃, and Y₄ of ring B are each independently selected from C (R₇) ₂ and NR₇;

Y₅ and Y₆ of ring B are each independently absent, C (R₇) ₂ or NR₇;

preferably, each R₇ is independently absent or selected from hydrogen, halogen, and oxo;

preferably ring B is selected from a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

preferably ring B is selected from

R₃ is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and substituted or unsubstituted five -to ten-membered heteroaryloxy groups with one or two or three heteroatoms each independently selected from N, O, and S; or R₃ and X₂ together form

L₁ is selected from -CR₁R₂-, -CO-, -O-, -NH-, and -S-;

L₂ is a linker comprising an unsaturated or aromatic moiety, preferably L₂ is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S;in which, optionally each hydrogen in L₂ is independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group

In some embodiments, X₁, X₂, X₃, X₄, X₅, L₁, L₂, Ar₁, R₃, R₄, and Q of Formula III are defined as disclosed above for Formula I or II.

In some embodiments, Formula III comprises the following Formula III-1 and Formula III-2:

In some embodiments, Formula III comprises the following Formula III-3, Formula III-4, and Formula III-5:

In some embodiments, Formula III comprises the following Formula III-6, Formula III-7, and Formula III-8:

in which each of X₁, X₂, X₃, X₄, X₅, Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, L₁, L₂, Ar₁, R₃, R₄, and Q are defined as disclosed above.

In some embodiments, a compound of the present disclosure has a structure of any one of Formulae III-1, III-2, III-3, III-4, III-5, III-6, III-7, and III-8.

In some embodiments, a compound of the present disclosure comprises a structure selected from:

One objective of the present disclosure is to provide a pharmaceutical composition comprising at least one compound as described above, a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof.

Another objective of the present disclosure is to provide a method of inhibiting lactate dehydrogenase A activity in a cell, comprising: administering to a subject an effective amount of at least one compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof.

Another objective of the present disclosure is to provide a method of treating or preventing a disease associated with lactate dehydrogenase A activity, comprising administering to a subject an effective amount of at least one compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof.

In some embodiments, a disease associated with lactate dehydrogenase A activity is an autoimmune disorder.

In some embodiments, the autoimmune disorder is selected from: autoimmune disorders of the nervous system, autoimmune disorders of the blood, autoimmune disorders of the blood vessels, autoimmune disorders of the skin, autoimmune disorders of the gastrointestinal system, autoimmune disorders of the endocrine glands, autoimmune disorders of multiple organs including connective tissue and musculoskeletal system diseases, and other immune system mediated diseases including graft-versus-host diseases and allergic disorders.

In some embodiments, the autoimmune disorders of the nervous system are selected from multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barré, and autoimmune uveitis.

In some embodiments, the autoimmune disorders of the blood are selected from autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia.

In some embodiments, the autoimmune disorders of the blood vessels are selected from temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener’s granulomatosis, and Behcet’s disease.

In some embodiments, the autoimmune disorders of the skin are selected from cutaneous lupus erythematosus, Steven-Johnson syndrome, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo.

In some embodiments, the autoimmune disorders of the gastrointestinal system are selected from Crohn’s disease, ulcerative colitis, chronic active hepatitis, idiopathic sprue, autoimmune inflammatory bowel disease, irritable bowel syndrome, alcoholic liver disease, nonalcoholic liver disease, nonalcoholic fatty liver, primary biliary cirrhosis, and autoimmune hepatitis.

In some embodiments, the autoimmune disorders of the endocrine glands are selected from Type 1 or immune-mediated diabetes mellitus, Grave’s disease, Hashimoto’s thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland.

In some embodiments, the autoimmune disorders of multiple organs are selected from rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies selected from ankylosing spondylitis, polychondritis, celiac disease, periodontitis, hyaline membrane disease, glomerular disease, endocrine opthalmopathy, Lupus nephritis, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, and Sjogren’s syndrome.

In some embodiments, the allergic disorders are selected from allergic rhinitis, sinusitis, rhinosinusitis, chronic or recurrent otitis media, ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma, and food allergies.

In some embodiments, the autoimmune disorder is a kidney disease selected from hyperoxaluria, chronic kidney disease, end stage renal disease and kidney stone disease; and wherein the hyperoxaluria is selected from primary hyperoxaluria type 1, primary hyperoxaluria type 2, primary hyperoxaluria type 3, and secondary hyperoxaluria.

In some embodiments, the method as described above comprises administering once daily, twice daily, or three times daily to a subject an effective amount of the compound as described above, or the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof, or the composition as described above.

Another objective of the present disclosure is to provide a use of a compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof, to manufacture a medicament in treating or preventing a disease associated with lactate dehydrogenase A activity.

A further objective of the present disclosure is to provide a compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or the pharmaceutically acceptable salt thereof, for use in treating or preventing a disease associated with lactate dehydrogenase A activity.

Detailed Description of the Present Disclosure

DEFINITIONS

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the claims.

Unless otherwise described, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase without being specifically defined should be understood by the plain meaning thereof rather than being regarded as uncertain or unclear. A brand name presented herein is intended to refer to a corresponding commercial product or the active component thereof.

As used herein, the term “a” “an” “the” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

The term “alkyl” refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups of 1-18, or 1-12, or 1-6, or 1-3 carbon atoms. Examples of the alkyl group include methyl, ethyl, 1-propyl or n-propyl ( “n-Pr” ) , 2-propyl or isopropyl ( “i-Pr” ) , 1-butyl or n-butyl ( “n-Bu” ) , 2-methyl-1-propyl or isobutyl ( “i-Bu” ) , 1-methylpropyl or s-butyl ( “s-Bu” ) , and 1, 1-dimethylethyl or t-butyl ( “t-Bu” ) . Other examples of the alkyl group include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl groups.

The term “alkenyl” refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C=C double bond and of 2-18, or 2-12, or 2-6 carbon atoms. Examples of the alkenyl group may be selected from ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1, 3-dienyl, 2-methylbuta-1, 3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1, 3-dienyl groups.

The term “alkynyl” refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C≡C triple bond and of 2-18, or 2-12, or 2-6 carbon atoms. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl (propargyl) , 1-butynyl, 2-butynyl, and 3-butynyl groups.

The term “cycloalkyl” refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, the cycloalkyl group may be of 3-12, or 3-8, or 3-6, or 3-4, or 5-6 carbon atoms. Even further for example, the cycloalkyl group may be a monocyclic group of 3-12, or 3-8, or 3-6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of the bicyclic cycloalkyl groups include those having 7-12 ring atoms arranged as a bicycle ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane. The ring may be saturated or have at least one double bond (i.e. partially unsaturated) , but is not fully conjugated, and is not aromatic, as aromatic is defined herein.

The term “aryl” herein refers to a group selected from: 5-and 6-membered carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

The term “aryloxy group” or “aryloxyl” refers to a univalent radical R-O-, or anion R-O-, where R is an aryl group.

The term “heteroaryloxy group” or “heteroaryloxyl” refers to a univalent radical R-O-, or anion R-O-, where R is a heteroaryl group.

The term “saturated, aromatic or partially unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms” or “containing heteroatom groups” , wherein those heteroatom (s) (group (s) ) are selected from N, O, S, NO, SO and SO₂ and are ring members, as used herein refers to monocyclic radicals, the monocyclic radicals being saturated, partially unsaturated or aromatic. The heterocyclic radical may be attached to the remainder of the molecule via a carbon ring member or via a nitrogen ring member.

Examples of 3-, 4-, 5-, 6-or 7-membered saturated heterocyclyl or heterocyclic rings include: oxiranyl, aziridinyl, azetidinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 1, 2, 4-oxadiazolidin-3-yl, 1, 2, 4-oxadiazolidin-5-yl, 1, 2, 4-thiadiazolidin-3-yl, 1, 2, 4-thiadiazolidin-5-yl, 1, 2, 4-triazolidin-3-yl, 1, 3, 4-oxadiazolidin-2-yl, 1, 3, 4-thiadiazolidin-2-yl, 1, 3, 4-triazolidin-2-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 1, 3-dioxan-5-yl, 1, 4-dioxan-2-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydropyridazinyl, 4-hexahy-dropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, 1, 3, 5-hexahydrotriazin-2-yl and 1, 2, 4-hexahydrotriazin-3-yl, 2-morpholinyl, 3-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl, 1, 1-dioxothiomorpholin-2-yl, 1, 1-dioxothiomorpholin-3-yl, hexahydroazepin-1-, -2-, -3-or-4-yl, hexahydrooxepinyl, hexahydro-1, 3-diazepinyl, hexahydro-1, 4-diazepinyl, hexahydro-1, 3-oxazepinyl, hexahydro-1, 4-oxazepinyl, hexahydro-1, 3-dioxepinyl, hexahydro-1, 4-dioxepinyl and the like.

Examples of 3-, 4-, 5-, 6-or 7-membered partially unsaturated heterocyclyl or heterocyclic rings include: 2, 3-dihydrofur-2-yl, 2, 3-dihydrofur-3-yl, 2, 4-dihydrofur-2-yl, 2, 4-dihydrofur-3-yl, 2, 3-dihydrothien-2-yl, 2, 3-dihydrothien-3-yl, 2, 4-dihydrothien-2-yl, 2, 4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4 isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2, 3-dihydropyrazol-1-yl, 2, 3-dihydropyrazol-2-yl, 2, 3-dihydropyrazol-3-yl, 2, 3 dihydropyrazol-4-yl, 2, 3-dihydropyrazol-5-yl, 3, 4-dihydropyrazol-1-yl, 3, 4-dihydropyrazol-3-yl, 3, 4-dihydropyrazol-4-yl, 3, 4-dihydropyrazol-5-yl, 4, 5-dihydropyrazol-1-yl, 4, 5-dihydropyrazol-3-yl, 4, 5-dihydropyrazol-4-yl, 4, 5-dihydropyrazol-5-yl, 2, 3-dihydrooxazol-2-yl, 2, 3-dihydrooxazol-3-yl, 2, 3-dihydrooxazol-4-yl, 2, 3-dihydrooxazol-5-yl, 3, 4-dihydrooxazol-2-yl, 3, 4-dihydrooxazol-3-yl, 3, 4-dihydrooxazol-4-yl, 3, 4-dihydrooxazol-5-yl, 3, 4-dihydrooxazol-2-yl, 3, 4-dihydrooxazol-3-yl, 3, 4-dihydrooxazol-4-yl, 2-, 3-, 4-, 5-or 6-di-or tetrahydropyridinyl, 3-di-or tetrahydropyridazinyl, 4-di-or tetrahydropyridazinyl, 2-di-or tetrahydropyrimidinyl, 4-di-or tetrahydropyrimidinyl, 5-di-or tetrahydropyrimidinyl, di-or tetrahydropyrazinyl, 1, 3, 5-di-or tetrahydrotriazin-2-yl, 1, 2, 4-di-or tetrahydrotriazin-3-yl, 2, 3, 4, 5-tetrahydro [1H] azepin-1-, -2-, -3-, -4-, -5-, -6-or -7-yl, 3, 4, 5, 6-tetrahydro [2H] azepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2, 3, 4, 7-tetrahydro [1H] azepin-1-, -2-, -3-, -4-, -5-, -6-or -7-yl, 2, 3, 6, 7-tetrahydro [1H] azepin-1-, -2-, -3-, -4-, -5-, -6-or -7-yl, tetrahydrooxepinyl, such as 2, 3, 4, 5-tetrahydro [1H] oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2, 3, 4, 7-tetrahydro [1H] oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2, 3, 6, 7-tetrahydro [1H] oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, tetrahydro-1, 3-diazepinyl, tetrahydro-1, 4-diazepinyl, tetrahydro-1, 3-oxazepinyl, tetrahydro-1, 4-oxazepinyl, tetrahydro-1, 3-dioxepinyl and tetrahydro-1, 4-dioxepinyl.

Examples of 5-or 6-membered aromatic heterocyclyl (heteroaryl) or heteroaromatic rings are: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazo-lyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazo-lyl, 2-imidazolyl, 4-imidazolyl, 1, 3, 4-triazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5-14 membered heteroaryl” ) , or a group derived therefrom. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl) . Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl” ) or substituted (a “substituted heteroaryl” ) with one or more substituents.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

C1-C6 is selected from C1, C2, C3, C4, C5, and C6; C3-6 is selected from C3, C4, C5, and C6.

Unless otherwise specified, the term “halo” or “halogen” itself or as a part of another substituent refers to a fluorine, chlorine, bromine or iodine. In addition, the term “haloalkyl” is intended to include monohaloalkyl and polyhaloalkyl. Examples of haloalkyl include but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term “Cn-Cm haloalkyl” as used herein (and also in Cn-Cm haloalkylsulfinyl and Cn-Cm haloalkylsulfonyl) refers to a straight-chain or branched alkyl group having n to m carbon atoms, e.g. 1 to 10 in particular 1 to 6 carbon atoms (as mentioned above) , where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example C1-C4 haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl, pentafluoroethyl and the like. The term C1-C10 haloalkyl in particular comprises C1-C2 fluoroalkyl, which is synonym with methyl or ethyl, wherein 1, 2, 3, 4 or 5 hydrogen atoms are substituted by fluorine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl and pentafluoromethyl.

The “alkoxy” represents an alkyl group as described above with a specific number of carbon atoms which is connected by an oxygen bridge. The C1-6 alkoxy includes C1, C2, C3, C4, C5 and C6 alkoxy. Examples of alkoxy include but not limited to: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentyloxy.

“Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygen single bond, including, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo [2.2.2] octyloxy.

“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, including, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo [2.2.2] octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.

“Cycloalkenyloxy” means a cycloalkenyl further consisting of a carbon-oxygen single bond, including, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo [2.2.2] octenyloxy.

The term “cycloalkylamino” as used herein, alone or in combination, represents a saturated monocyclic hydrocarbon group having an indicated number of carbon atoms linked through amino having a free valence bond from the nitrogen atom. Representative examples include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like.

As disclosed herein, a bond can be a covalent bond or an ionic bond. In some embodiments, a bond can be a saturated bond or an unsaturated bond. In some embodiments, a bond refers to a single bond. In some embodiments, a bond refers to a double bond. In other embodiments, a bond refers to a triple bond. The term “unsaturated bond” refers to a double or triple bond.

The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to a group which may be substituted or unsubstituted as defined herein.

The term “aliphatic group” refers to a straight-chain, branched-chain, or cyclic non-aromatic saturated or unsaturated hydrocarbon group and includes as alkyl groups, alkenyl groups, and alkynyl groups.

An “aryloxy” group refers to both an -O-aryl group and an -O-heteroaryl group, as defined herein.

A “cyano” group refers to a -CN group.

An “oxo” group refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.

Unless otherwise specified, the term “C1-C6 alkyl-C (O) -NH-” refers to a moiety containing an amide group connected to a C1-C6 alkyl, where the C1-C6 alkyl group is optionally substituted, and the substituent is each independently selected from an alkyl, a cycloalkyl, aryl, a heteroaryl (bonded through a ring carbon) , a heteroalkyl, and a heterocyclylalkyl. In some embodiments, the C1-C6 alkyl group may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain linking two groups in a molecule, which may be saturated or unsaturated (i.e., contains one or more double and/or triple bonds) , and have from one to twelve carbon atoms, preferably one to eight carbon atoms (C₁-C₈ alkylene) or one to six carbon atoms (C₁-C₆ alkylene) , e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule may be through one carbon, e.g., methylene, or any two carbons within the chain, e.g., -CH₂CH (CH₃) CH₂CH₂-. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted.

“Alkenylene” is an unsaturated alkylene, as defined herein, which comprises one or more carbon-carbon double bonds. Unless stated otherwise specifically in the specification, an alkenylene is optionally substituted.

“Alkynylene” is an unsaturated alkylene, as defined herein, which comprises one or more carbon-carbon triple bonds. Unless stated otherwise specifically in the specification, an alkynylene is optionally substituted.

Unless otherwise specified, the term “hetero” refers to a heteroatom or a heteroatom group (i.e. a group containing a heteroatom) , including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms, for example, including oxygen (O) , nitrogen (N) , sulfur (S) , silicon (Si) , germanium (Ge) , aluminum (Al) , boron (B) , -O-, -S-, =O, =S, -C (=O) O-, -C (=O) -, -C (=S) -, -S (=O) , -S (=O) ₂, and optionally substituted -C (=O) N (H) -, -N (H) -, -C (=NH) -, -S (=O) ₂N (H) -or -S (=O) N (H) -.

Unless otherwise specified, the “ring” refers to a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The so-called ring includes a single ring, a joint ring, a spiro ring, a fused ring or a bridged ring. A number of the atoms on the ring is usually defined as the member of the ring, for example, “5-to 7-membered ring” refers to a ring looped with 5 to 7 atoms. Unless otherwise specified, the ring optionally contains 1-3 of heteroatoms. Therefore, “5-to 7-membered ring” includes, for example, phenyl, pyridine and piperidinyl; on the other hand, the term “5-to 7-membered heterocycloalkyl” includes pyridyl and piperidinyl, but does not include phenyl. The term “ring” also includes a ring system containing at least one ring, wherein each of the “rings” is independently in line with the above definition.

Unless otherwise specified, the term “heterocyclic group” or “heterocyclyl” refers to a stable monocyclic, bicyclic or tricyclic group containing a heteroatom or heteroatom group, which can be saturated, partially unsaturated or unsaturated (aromatic) , and contains carbon atoms and 1, 2, 3 or 4 ring heteroatom (s) independently selected from the group consisting of N, O and S, wherein any of the above heterocycle can be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S (O) p) . The nitrogen atom can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent defined herein) . The heterocycle can be attached to a side group of any heteroatom or carbon atom to form a stable structure. If the formed compound is stable, the heterocyclic group described herein can be substituted on its carbon or nitrogen atom. The nitrogen atom in the heterocycle is optionally quaternized. As a preferred embodiment, when the total number of S and O atoms contained in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. As another preferred embodiment, the total number of S and O atoms in the heterocycle is no more than 1. As used herein, the term “aromatic heterocyclic group” or “heteroaryl” refers to a stable aromatic ring of a 5-, 6-, 7-membered monocyclic or bicyclic or 7-, 8-, 9-or 10-membered bicyclic heterocyclyl, which contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from the group consisting of N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent defined herein) . Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S (O) p) . It is worth noting that the total number of S and O atoms on the heteroaromatic ring is no more than 1. Bridge rings are also included in the definition of the heterocycle. When one or more than one atoms (i.e. C, O, N, or S) are connected to two nonadjacent carbon atoms or nitrogen atoms, a bridged ring is formed. The preferred bridge ring includes but is not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a monocyclic ring into a tricyclic ring. In the bridge ring, the substituent on the ring can also locate on the bridge.

Examples of heterocyclic group include but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoalkenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatino group, isobenzofuranyl, isoindolyl, isoindolinyl isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxyl indyl, pyrimidyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidyl, piperidinonyl, 4-oxopiperidinyl, piperonyl, pteridyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, oxazolopyridine, pyridoimidazole, pyridothiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolyl , quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazyl, isothiazolylthienyl, thienyl, thiophenoxazolyl, thiophenothiazolyl, thiophenoimidazolyl, triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl and xanthenyl. Fused and spiro cyclic groups are also included.

Unless otherwise specified, the term “C1-C6 haloalkoxy group” is a C1-C6 haloalkyl group, as defined above, attached via an oxygen atom. C1-C6 haloalkoxy group is, for example, OCH₂F, OCHF₂, OCF₃, OCH₂Cl, OCHCl₂, OCCl₃, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2, 2-difluoroethoxy, 2, 2-dichloro-2-fluoroethoxy, 2, 2, 2-trichloroethoxy, OC₂F₅, 2-fluoropropoxy, 3-fluoropropoxy, 2, 2-difluoropropoxy, 2, 3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2, 3-dichloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3, 3, 3-trifluoropropoxy, 3, 3, 3-trichloropropoxy, -OCH₂-C₂F₅, -OCF₂-C₂F₅, 1- (CH₂F) -2-fluoroethoxy, 1- (CH₂Cl) -2-chloroethoxy, 1- (CH₂Br) -2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, nonafluorobutoxy, 5-fluoropentoxy, 5-chloropentoxy, 5-brompentoxy, 5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy.

As used herein, “halogen” will be taken to mean fluorine, chlorine, bromine and iodine.

As used herein, the term “substituted” refers to any one or more hydrogen atoms on a specific atom being optionally replaced by a substituent, including a deuterium and a variant of hydrogen, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e. =O) , it means that two hydrogen atoms are replaced. A substitution of keto group will not occur on an aryl. The term “optionally substituted” means that it may be substituted or not be substituted, unless otherwise specified, the type and number of substituents can be arbitrary under the premise of being chemically feasible.

When any parameter (e.g. R) occurs more than once in the composition or structure of the compound, its definition at each occurrence is independent. Therefore, for example, if a group is substituted by 0-2 of R, the group may optionally be substituted by at most two Rs, and R has an independent option at each occurrence. In addition, a combination of substituents and/or their variants is allowed only if such a combination will lead to a stable compound.

The term "pharmaceutically acceptable" as used herein is directed to those compounds, materials, compositions and/or formulations which are within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues but without too much toxicity, irritation, allergic reactions or other problems or complications, and also commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable salt” refers to a salt of the compound disclosed herein, which is prepared from the compound with specific substituents disclosed herein and a relatively non-toxic acid or alkali. When the compound disclosed herein contains a relatively acidic functional group, an alkali-addition salt can be obtained by contacting the compound in a neutral form with a sufficient amount of alkali in a pure solution or suitable inert solvent. The pharmaceutically acceptable alkali-addition salt includes, for example, the salt of sodium, potassium, calcium, ammonium, organic ammine or magnesium or the like. When the compound disclosed herein contains a relatively alkaline functional group, an acid-addition salt can be obtained by contacting the compound in a neutral form with a sufficient amount of acid in a pure solution or suitable inert solvent. Examples of the pharmaceutically acceptable acid-addition salt include a salt of an inorganic acid, wherein the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydriodic acid, phosphorous acid; and a salt of an organic acid, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, phenylsulfonic acid, p-toluene sulfonic acid, citric acid, tartaric acid, methylsulfonic acid and the like; and also includes a salt of an amino acid (e.g. arginine etc. ) , and salts of organic acids such as glucuronic acid and the like (see Berge et al., “Pharmaceutical Salts, ” Journal of Pharmaceutical Science 66: 1-19 (1977) ) . Some specific compounds disclosed herein contain both alkaline and acidic functional groups and thereby may be transformed to any of the alkali-addition or acid-addition salt.

Further, the “pharmaceutically acceptable salt” used herein belongs to the derivatives of the compounds disclosed herein, wherein the compound disclosed herein is modified by salifying with an acid or an alkali. Examples of the pharmaceutically acceptable salt disclosed herein include but are not limited to: an inorganic acid or organic acid salt of an alkali such as amine, alkali metal or an organic salt of an acid radical such as carboxylic acid. Further, the pharmaceutically acceptable salts disclosed herein include conventional non-toxic salts or quaternary ammonium salts of the compounds disclosed herein, such as a salt formed by a non-toxic inorganic acid or organic acid. The conventional non-toxic salt includes but is not limited to those salts derived from an inorganic acid and an organic acid, the inorganic acid or organic acid is selected, for example, from 2-acetoxybenzoic acid, 2-isethionic acid, acetic acid, ascorbic acid, phenylsulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydriodate, hydroxyl, hydroxynaphthoic, isethionic acid, lactic acid, lactose, dodecanesulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonan, propionic acid, salicylic acid, stearic acid, folinic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulphuric acid, tannic acid, tartaric acid, and p-toluene sulfonic acid.

The pharmaceutically acceptable salt of the present disclosure can be prepared by a conventional chemical method using the compounds disclosed herein.

The compounds disclosed herein and/or the pharmaceutically acceptable salts thereof may be employed alone or in combination with at least one other therapeutic agent for treatment. The compound and/or a pharmaceutically acceptable salt thereof disclosed herein may be administered with the at least one other therapeutic agent in a single dosage form or as a separate dosage form. When administered as a separate dosage form, the at least one other therapeutic agent may be administered prior to, at the same time as, or following administration of the compound and/or a pharmaceutically acceptable salt thereof disclosed herein.

The composition comprising the compound disclosed herein and/or a pharmaceutically acceptable salt thereof can be administered in various known manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compositions disclosed herein may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art.

The compound disclosed herein and/or a pharmaceutically acceptable salt thereof can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragées, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions.

Liquid dosage forms for oral administration can further comprise at least one agent selected from coloring and flavoring agents to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene gycols can be examples of suitable carriers for parenteral solutions.

A pharmaceutically acceptable carrier disclosed herein is, for example, selected from carriers that are compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated. In some embodiments, solubilizing agents, such as cyclodextrins (which can form specific, more soluble complexes with the at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) , can be utilized as pharmaceutical excipients for delivery of the active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences, A. Osol, a standard reference text in the art.

Some compounds of the present disclosure may contain an asymmetric carbon atom (optical center) or double bond. The racemic isomers, diastereomers, geometric isomers and single isomers are all included within the scope of the present disclosure. As disclosed herein, the term “stereoisomers” includes enantiomers, diastereomers, racemic isomers, and geometric isomers.

As used herein, the term “effective amount” or “therapeutically effective amount” refers to a quantity of a compound disclosed herein or a composition comprising the compound that is sufficient to achieve desired effects without toxicity. For the oral formulation disclosed herein, “an effective amount” of the compound in the composition disclosed herein refers to the amount that is required to achieve desired effects in combination with another active substance, if any, in the composition. The determination of the therapeutically effective amount varies from person to person, and depends, for example, on the age and the general condition of a recipient. An appropriate therapeutically effective amount can be determined by a person skilled in the art according to conventional tests.

As used herein, the term “treat, ” “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another embodiment, “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) , physiologically (e.g., stabilization of a physical parameter) , or both. In yet another embodiment, “treat” , “treating” or “treatment” refers to delaying the development or progression of the disease or disorder.

As used herein, a subject is “in need of “atreatment if such subject would be expected to benefit biologically, medically or in quality of life from such treatment.

A disease associated with lactate dehydrogenase A activity disclosed herein includes a disease selected, for example, from autoimmune disorders, allergic disorders, inflammatory conditions, cancers, metabolic syndrome, and Syndrome X.

As used herein, the term “immune disorders” or “autoimmune disorders” include those diseases, syndrome, disorders or conditions that have an immune component and those that are substantially or entirely immune system-mediated. Autoimmune disorders are those wherein the animal’s (including humans) own immune system mistakenly attacks itself, thereby targeting the cells, tissues, and/or organs of the animal’s own body. Specific autoimmune disorders that may be ameliorated using the compounds and methods of this invention include without limitation, autoimmune disorders of the nervous system (e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barré, and autoimmune uveitis) , autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia) , autoimmune disorders of the blood vessels (e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener’s granulomatosis, and Behcet’s disease) , autoimmune disorders of the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo) , autoimmune disorders of the gastrointestinal system (e.g., Crohn’s disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis) , autoimmune disorders of the endocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus, Grave’s disease, Hashimoto’s thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland) ; and autoimmune disorders of multiple organs (including connective tissue and musculoskeletal system diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren’s syndrome) . In addition, other immune system mediated diseases, such as graft-versus-host disease and allergic disorders, are also included in the definition of immune disorders herein. Because a number of immune disorders are caused by inflammation, there is some overlap between disorders that are considered immune disorders and inflammatory disorders. For the purpose of this disclosure, in the case of such an overlapping disorder, it may be considered either an immune disorder or an inflammatory disorder.

As used herein, the term “allergic disorder” means a disease, condition or disorder associated with an allergic response against normally innocuous substances. These substances may be found in the environment (such as indoor air pollutants and aeroallergens) or they may be non-environmental (such as those causing dermatological or food allergies) . Allergens can enter the body through a number of routes, including by inhalation, ingestion, contact with the skin or injection (including by insect sting) . Many allergic disorders are linked to atopy, a predisposition to generate the allergic antibody IgE. Because IgE is able to sensitize 53the-cells anywhere in the body, atopic individuals often express disease in more than one organ. For the purpose of this disclosure, allergic disorders include any hypersensitivity that occurs upon re-exposure to the sensitizing allergen, which in turn causes the release of inflammatory mediators. Allergic disorders include without limitation, allergic rhinitis (e.g., hay fever) , sinusitis, rhinosinusitis, chronic or recurrent otitis media, ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma, and food allergies.

As used herein, the term “fibrosis” means the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process, in a pathological situation, as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue. Fibrosis may be the result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Scarring is confluent fibrosis that obliterates the architecture of the underlying organ or tissue. Different organs can be affected by fibrotic diseases, including: Pulmonary fibrosis (lungs) ; Idiopathic pulmonary fibrosis (where the cause is unknown) , Cystic fibrosis (caused by genetic mutation of CFTR gene [cystic fibrosis transmembrane conductance regulator] ) ; Cirrhosis (liver) ; Endomyocardial fibrosis (heart) ; Progressive kidney disease, Mediastinal fibrosis (soft tissue of the mediastinum) ; Myelofibrosis (bone marrow) , Retroperitoneal fibrosis (soft tissue of the retroperitoneum) ; Progressive massive fibrosis (lungs) ; a complication of coal workers’ pneumoconiosis; Nephrogenic systemic fibrosis (skin) , Crohn’s Disease (intestine) ; Keloid (skin) ; Old myocardial infarction (heart) ; Scleroderma/systemic sclerosis (skin, lungs) ; Arthrofibrosis (knee, shoulder, other joints) ; and some forms of adhesive capsulitis (shoulder) .

As used herein, “cancers” is not particularly limited, but in certain aspects, the cancer is characterized as hypoxic and/or highly glycolytic relative to normal tissue of the same type. Examples of cancer include cancers of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, or adrenals. More particularly, cancers include solid tumor, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi’s sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, retinoblastoma, a blood-borne tumor, acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acutenonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma. As used herein, cancer can also be a solid tumor, such as the leukemia, melanoma, liver cancer, pancreatic cancer, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, and renal cancer. In another embodiment, the cancer is liver cancer, pancreatic cancer, non-small cell lung cancer, breast cancer, or renal cancer.

Unless indicated otherwise, all references herein to the compounds disclosed herein include salts and solvates thereof, including stereoisomers, tautomers, and isotopically labeled versions thereof. For example, compounds of the present disclosure can be pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates.

The term “stereoisomers” refers to compounds that have identical chemical constitution but differ with regard to the arrangement of their atoms or groups in space. In particular, the term “enantiomers” refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. A pure enantiomer can be contaminated with up to 10%of the opposite enantiomer.

The terms “racemic” or “racemic mixture, ” as used herein, refer to a 1: 1 mixture of enantiomers of a particular compound. The term “diastereomers” , on the other hand, refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.

Where a compound of the present disclosure contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ( ‘tautomerism’ ) can occur. Examples of tautomerism include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Disclosed herein are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the present disclosure, including, for example, compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

The compounds of the present disclosure may be administered as prodrugs. Thus, certain derivatives of compounds of Formula I, which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound of Formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs. ” Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compound of Formula I with certain moieties known to those skilled in the art. See, e.g. “Pro-drugs as Novel Delivery Systems” , Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and “Bioreversible Carriers in Drug Design” , Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association) .

Salts of the present disclosure can be prepared according to methods known to those of skill in the art. Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate) , bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1, 4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1, 6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, 55 thenone 55 ph, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate) , palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The compound disclosed herein can be prepared through various synthetic methods, including the specific embodiments listed below and/or its combination with other chemical synthetic methods and equivalent alternatives known to a person skilled in the art.

The compounds disclosed herein are named manually or by softwareThe commercially available compounds are named according to the catalogs of the suppliers.

Examples

Example 1: Synthesis of Compound 546

Preparation of compound 546-4: 2-cyclopropylacetaldehyde

A solution of Oxalyl chloride (19.2 g, 151 mmol, 1.3 eq) in DCM (200 mL) was cooled to -60 ℃ and added DMSO (13.6 g, 174 mmol, 1.5 eq) dropwise under N₂ atmosphere. After addition, the mixture was stirred at -60 ℃ for 30 min, then another solution of 2-cyclopropylethan-1-ol (10.0 g, 116 mmol, 1.0 eq) in DCM (40 mL) was added to the mixture dropwise at –60 ℃. The mixture was maintained stirring for 1 h at the same temperature, then Et₃N (35.3 g, 348 mmol, 3.0 eq) was added dropwise. The reaction was stirred at rt for 1h. The mixture was diluted with DCM (100 mL) and washed with sat. NH₄Cl aq (100 mL × 5) , saturated sodium bicarbonate and finally with brine. The organic layer was dried over sodium sulfate and evaporated to dryness carefully afford the title product as a yellow oil (8.0 g, rude) , which was used directly in the next step without further purification.

¹HNMR (CDCl₃-d) δ: 9.77 (t, J = 2.2 Hz, 1H) , 2.31 –2.23 (m, 2H) , 1.04 –0.87 (m, 1H) , 0.63 –0.53 (m, 2H) , 0.19 –0.10 (m, 2H) .

Preparation of compound 546-6: 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide

Step 1: Preparation of compound 546-c: 4-cyano-2-fluorobenzenesulfonyl chloride

Bottle A: To the suspension of 4-amino-3-fluorobenzonitrile (20 g, 146.92 mmol, 1.0 eq) in 12 N HCl (200 mL) was added a solution of sodium nitrite (11.15 g, 161.61 mmol, 1.1 eq) in H₂O (200 mL) dropwise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour.

Bottle B: SOCl₂ (100 mL) was added dropwise to H₂O (200 mL) with the temperature was kept at 0 ℃. The resuting mixture was added chlorocopper (I) (4.36 g, 44.08 mmol, 0.3 eq) and stirred at RT for 1 hour.

The bottle B was added the reaction mixture in bottle A dropwise with the temperature was kept at 0 ℃. After addition, the resulting mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was diluted with EA (500 mL) and washed with brine (500 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/50 to 1/10) to afford the title product as a white solid (19 g, 59%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 7.84 (t, J = 7.4 Hz, 1H) , 7.78 (dd, J = 1.4, 9.6 Hz, 1H) , 7.65 (dd, J =1.4, 7.8 Hz, 1H) .

Step 2: Preparation of compound 546-d: 4-cyano-2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide

To the suspension of 4-cyano-2-fluorobenzenesulfonyl chloride (75 g, 341.51 mmol, 1.0 eq) and bis [ (4-methoxyphenyl) methyl] amine (87.88 g, 341.51 mmol, 1.0 eq) in DCM (1000 mL) was added DIEA (67.91 mL, 409.82 mmol, 1.2 eq) at 0 ℃. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with DCM (500 mL) and washed with brine (1000 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was triturated with a mixture solvent of EA (10 mL) in PE (90 mL) and filtered to afford a white solid (145 g, 96%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.09 (dd, J = 1.2, 10.2 Hz, 1H) , 7.92 –7.84 (m, 1H) , 7.84 –7.78 (m, 1H) , 7.06 –6.98 (m, 4H) , 6.83 –6.76 (m, 4H) , 4.34 (s, 4H) , 3.71 (s, 6H) .

Step 3: Preparation of compound 546-6: 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide

To the solution of 4-cyano-2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (135 g, 306.48 mmol, 1.0 eq) in MeOH (1350 mL) was added NH₄OH (30 mL) and Raney nickel (1.8 g, 30.65 mmol, 0.1 eq) . The reaction mixture was stirred at RT for 18 hours under H₂. The mixture was filtered, and the filter cake washed with MeOH. The filtrate was concentrated and purified by column chromatography through silica gel (eluting with EA/PE=1/1 to 1/0) to afford the title product as a white solid (120 g, 88%) . ¹HNMR (400 MHz, DMSO-d₆) δ = 7.76 (t, J = 7.8 Hz, 1H) , 7.42 (d, J = 11.8 Hz, 1H) , 7.33 (d, J = 8.0 Hz, 1H) , 6.96 (d, J = 8.6 Hz, 4H) , 6.79 (d, J = 8.6 Hz, 4H) , 4.25 (s, 4H) , 3.81 (s, 2H) , 3.71 (s, 6H) .

Preparation of compound 546: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Step 1: Preparation of compound 546-3: methyl (E) -6- (3- (3-iodophenyl) -3-oxoprop-1-en-1-yl) picolinate 4-Methylbenzenesulfonic acid hydrate (5.79 g, 30.4 mmol, 0.1 eq) was added to the solution of methyl 5-formylpyridine-3-carboxylate (50 g, 302.7 mmol, 1.0 eq) and 1- (3-bromophenyl) ethan-1-one (75 g, 304.8 mmol, 1.0 eq) in Toluene (500 mL) at rt. The mixture was stirred at 130 ℃ to remove water by Dean-Stark trap overnight. After the reaction completion, the mixture was concentrated under vacuum to afford crude product. The mixture was purified by silica gel column (eluent: 20% (v/v) EA in PE and 20% (v/v) EA in DCM) to afford the title product as a white solid (81 g, 67.51%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.40 (t, J = 1.5 Hz, 1H) , 8.38 –8.38 (m, 1H) , 8.28 (dd, J = 1.1, 7.5 Hz, 1H) , 8.14 –8.05 (m, 5H) , 7.74 (d, J = 15.6 Hz, 1H) , 7.41 (t, J = 7.8 Hz, 1H) , 3.93 (s, 3H) .

Step 2: Preparation of compound 546-5: methyl 6- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) picolinate

2-Cyclopropylacetaldehyde (126.69 g, 572.25 mmol, 5 eq) was added to the solution of methyl 5- [ (1E) -3- (3-iodophenyl) -3-oxoprop-1-enyl] pyridine-3-carboxylate (45 g, 114.45 mmol, 1.0 eq) , 3-ethyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium bromide (36.09 g, 143.07 mmol, 1.25 eq) and TEA (143 mL, 1030.05 mmol, 9 eq) in a mixture solvent of EtOH (120 mL) in dioxane (480 mL) at rt. The reaction mixture was stirred at 100 ℃ for 2 h. After the reaction completion, the mixture was concentrated under vacuum to afford crude product. The mixture was purified by silica gel column (eluent: 10%to 15% (v/v) EA in PE) to afford the title product as a yellow gum (53.7 g, 98.3%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.28 (t, J = 1.5 Hz, 1H) , 8.05 –7.92 (m, 4H) , 7.75 (dd, J = 1.1, 7.6 Hz, 1H) , 7.34 (t, J = 7.8 Hz, 1H) , 4.69 (dd, J = 4.9, 9.0 Hz, 1H) , 3.96 –3.83 (m, 4H) , 3.47 (dd, J = 4.9, 18.1 Hz, 1H) , 2.53 (br d, J = 6.9 Hz, 1H) , 2.42 –2.30 (m, 1H) , 0.94 –0.78 (m, 1H) , 0.48 –0.30 (m, 2H) , 0.09 –0.01 (m, 1H) , -0.05 --0.18 (m, 1H) .

Step 3: Preparation of compound 546-7: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate

Methyl 6- [5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopent-3-yl] pyridine-2-carboxylate (31 g, 64.95 mmol) was added to the solution of 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (30.31 g, 68.20 mmol, 1.0 eq) in AcOH (500 mL) at rt. The reaction mixture was stirred at 100 ℃ overnight. After the reaction completion, the mixture was concentrated under vacuum to afford crude product. The mixture was purified by silica gel column (eluent: 15%to 30% (v/v) EA in PE) to afford the title product as a yellow foam (41 g, 81.7%) .

MS (ESI, pos. ion) m/z: 886.1 [M+1] ⁺, Rt=1.357/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.98 –7.90 (m, 2H) , 7.84 –7.72 (m, 3H) , 7.67 (d, J = 7.9 Hz, 1H) , 7.39 (d, J = 8.0 Hz, 1H) , 7.17 (t, J = 7.8 Hz, 1H) , 6.99 –6.87 (m, 6H) , 6.84 –6.78 (m, 1H) , 6.78 –6.69 (m, 4H) , 5.43 (s, 2H) , 4.21 (s, 4H) , 3.88 (s, 3H) , 3.69 (s, 6H) , 3.23 (br d, J = 6.6 Hz, 2H) , 1.11 –0.98 (m, 1H) , 0.40 –0.24 (m, 4H) .

Step 4: Preparation of compound 546-8: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate

TFA (100 mL) was added to the solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (37 g, 41.77 mmol, 1.0 eq) in DCM (200 mL) . The reaction mixture was stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford crude product. The mixture was purified by silica gel column (eluent: 30%to 50% (v/v) EA in PE) to afford the title product as a yellow foam (26 g, 96.44%) . MS (ESI, pos. ion) m/z: 646.1 [M+1] ⁺, Rt=1.133/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.97 –7.89 (m, 2H) , 7.83 –7.77 (m, 1H) , 7.76 (t, J = 1.5 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.66 (d, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.37 (d, J = 7.9 Hz, 1H) , 7.17 (t, J = 7.8 Hz, 1H) , 6.95 –6.92 (m, 1H) , 6.89 (d, J = 11.1 Hz, 1H) , 6.78 (d, J = 8.3 Hz, 1H) , 5.41 (s, 2H) , 3.88 (s, 3H) , 3.19 (br d, J = 6.6 Hz, 2H) , 1.05 –0.91 (m, 1H) , 0.37 –0.19 (m, 4H) .

Step 5: Preparation of compound 546-9: methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Ethynylcyclobutane (0.58 mL, 6.20 mmol) was added to the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (2 g, 3.10 mmol, 1.0 eq) , CuI (120 mg, 0.62 mmol) , TEA (1.72 mL, 12.39 mmol) and palladium (2+) dichloridebis (triphenylphosphane) (430 mg, 0.62 mmol) in DMF (20 mL) at rt under N₂. The mixture was stirred at 40 ℃ overnight. After the reaction completion, the mixture was diluted with water (100 mL) , extracted with EA (50 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified with silica gel column (eluent: 30%to 40% (v/v) EA in PE) to afford the title product as a yellow solid (1.30 g, 70.20%) .

MS (ESI, pos. ion) m/z: 598.3 [M+1] ⁺, Rt=1.489/2min.

Step 6: Preparation of compound 546: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (1.3 g, 2.17 mmol, 1.0 eq) in a mixture solvent of EtOH (14 mL) in tetrahydrofuran (14 mL) was added a solution of lithium hydroxide (370 mg, 8.7 mmol, 4.0 eq) in water (2 mL) . The mixture was stirred at RT for 2 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by C-18 column (eluent: 50%to 80% (v/v) CH₃CN and H₂O with 0.1%FA) to afford the title product as a yellow solid (900 mg, 70.89%) .

MS (ESI, pos. ion) m/z: 584.2 [M+1] ⁺, Rt=1.092/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 12.94 (br s, 1H) , 7.94 –7.86 (m, 2H) , 7.78 (dd, J = 2.4, 6.3 Hz, 1H) , 7.71 (t, J = 7.8 Hz, 1H) , 7.60 (s, 2H) , 7.41 –7.26 (m, 4H) , 6.93 (s, 1H) , 6.88 (d, J = 11.0 Hz, 1H) , 6.81 –6.75 (m, 1H) , 5.41 (s, 2H) , 3.29 –3.24 (m, 1H) , 3.21 (br d, J = 6.9 Hz, 2H) , 2.35 –2.23 (m, 2H) , 2.18 –2.05 (m, 2H) , 2.01 –1.80 (m, 2H) , 0.99 –0.89 (m, 1H) , 0.32 –0.19 (m, 4H) .

Example 2: Synthesis of Compound 548

Step 1: Preparation of compound 548-2: methyl 2-vinylpyrimidine-4-carboxylate

To a solution of methyl 2-chloropyrimidine-4-carboxylate (4.50 g, 26.08 mmol, 1.0 eq) , trifluoro (vinyl) borate (6.99 g, 52.15 mmol, 2.0 eq) , K₂CO₃ (10.81 g, 78.23 mmol, 3.0 eq) in a mixture solution of H₂O (10 mL) and 1, 4-dioxane (40 mL) was added Pd (dppf) Cl₂ (1.91 g, 2.61 mmol, 0.1 eq) . The resulting mixture was stirred at 80 ℃ for 2 hours under N₂. After the reaction completion, the mixture was filtered and the filtrated washed with H₂O (50 mL) and extracted with EA (50 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (3.90 g, 91%) .

MS (ESI, pos. ion) m/z: 165.00 [M+1] ⁺, Rt= 0.617/2min.

Step 2: Preparation of compound 548-3: methyl 2-formylpyrimidine-4-carboxylate

A solution of methyl 2-vinylpyrimidine-4-carboxylate (3.90 g, 23.76 mmol, 1.0 eq) in DCM (20 mL) was stirred at -78 ℃ for 1.5 hours under O₃. Then the mixture was added dimethyl sulfide (4 mL) and stirred at RT for 1.5 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 8%MeOH in DCM ether as a gradient, to afford the title product as a yellow solid (3.40 g, 86%) .

MS (ESI, pos. ion) m/z: 166.95 [M+1] ⁺, Rt= 0.27/2min.

Step 3: Preparation of compound 548-4: methyl (E) -2- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of methyl 2-formylpyrimidine-4-carboxylate (1.50 g, 9.03 mmol, 1.0 eq) and K₃PO₄ (5.75 g, 27.09 mmol, 3.0 eq) in toluene (15 mL) was added 1- (3-bromophenyl) ethan-1-one (1.98 g, 9.93 mmol, 1.1 eq) . The mixture was stirred at 85 ℃ for 72 hours. After the reaction completion, the mixture was concentrated, filtered and the filtrate washed with H₂O (20 mL) , extracted with DCM (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 18%EtOAc in petroleum ether as a gradient to afford the title product as a white solid (480 mg, 15%) .

MS (ESI, pos. ion) m/z: 346.90/348.90 [M+H] ⁺, Rt=0.884/2min.

Step 4: Preparation of compound 548-5: methyl 2- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) pyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) pyrimidine-4-carboxylate (510 mg, 1.47 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (475 mg, 1.76 mmol, 1.2 eq) , TEA (1.83 mL, 13.22 mmol, 9.0 eq) in a mixture solution of EtOH (5 mL) and dioxane (20 mL) was added 2-cyclopropylacetaldehyde (2780 mg, 13.22 mmol, 9.0 eq) and stirred at 100 ℃ for 18 hours under N₂. After the reaction completion, the mixture was concentrated under vacuum, diluted with H₂O (30 mL) , extracted with EA (30 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (640 mg, 99%) .

MS (ESI, pos. ion) m/z: 431.1/433.1 [M+H] ⁺, Rt=1.01/2min.

Step 5: Preparation of compound 548-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 2- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) pyrimidine-4-carboxylate (600 mg, 1.39 mmol, 1.0 eq) in a mixture solution of EtOH (2 mL) in AcOH (8 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (928 mg, 2.09 mmol, 1.5 eq) and stirred at 110 ℃ for 18 hours. After the reaction completion, the mixture was concentrated under vacuum, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (670 mg, 57%) .

MS (ESI, pos. ion) m/z: 839.1/841.1 [M+H] ⁺, Rt=1.358/2min.

Step 6: Preparation of compound 548-7: methyl 2- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (670 mg, 0.80 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The mixture was stirred at RT for 48 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (460 mg, 96%) .

MS (ESI, pos. ion) m/z: 599.1/601.1 [M+H] ⁺, Rt=1.075/2min.

Step 7: Preparation of compound 548-8: methyl 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate To a solution of methyl 2- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (100 mg, 0.17 mmol, 1.0 eq) , 1, 4-diazabicyclo [2.2.2] octane (56 mg, 0.50 mmol, 3.0 eq) , Tri-tert-butylphosphine tetrafluoroborate (24 mg, 0.08 mmol, 0.5 eq) , Allylpalladium chloride dimer (12 mg, 0.03 mmol, 0.2 eq) in dioxane (10 mL) was added ethynylcyclobutane (40 mg, 0.50 mmol, 3.0 eq) . The mixture was stirred at RT for 18 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (55 mg, 55%) .

MS (ESI, pos. ion) m/z: 599.1 [M+1] ⁺, Rt=1.18/2min.

Step 8: Preparation of compound 548: 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (55 mg, 0.09 mmol, 1.0 eq) in a mixture solvent of methanol (1 mL) in tetrahydrofuran (2 mL) was added a solution of lithium hydroxide (15 mg, 0.36 mmol, 4.0 eq) in water (1 mL) . The mixture was stirred at RT for 16 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, extracted with EA (5 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (18 mg, 33%) .

MS (ESI, pos. ion) m/z: 585.2 [M+1] ⁺, Rt=1.08/2min.

¹HNMR (400 MHz, DMSO-d₆ ) δ 13.55 (br s, 1H) , 8.95 (d, J = 4.9 Hz, 1H) , 7.70 (t, J = 7.9 Hz, 1H) , 7.65 –7.57 (m, 3H) , 7.38 –7.26 (m, 4H) , 7.03 (s, 1H) , 6.88 (d, J = 11.1 Hz, 1H) , 6.76 (d, J = 7.9 Hz, 1H) , 5.42 (s, 2H) , 3.27 –3.19 (m, 3H) , 2.34 –2.24 (m, 2H) , 2.16 –2.06 (m, 2H) , 1.98 –1.83 (m, 2H) , 1.02 –0.93 (m, 1H) , 0.32 –0.23 (m, 4H) .

Example 3: Synthesis of compound 568

Step 1: Preparation of compound 568-1: methyl 5-formylnicotinate

To the solution of methyl 5- (hydroxymethyl) nicotinate (5 g, 29.91 mmol, 1.0 eq) in DCM (100 mL) was added MnO₂ (26.01 g, 299.11 mmol, 10 eq) . The reaction mixture was stirred at RT overnight. The reaction was filtered and concentrated to afford the title product as a yellow solid (4.9 g, 99%) .

MS (ESI, pos. ion) m/z: 165.95 [M+1] ⁺, Rt=0.508/2min.

Step 2: Preparation of compound 568-2: methyl (E) -5- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) nicotinate

To the solution of methyl 5-formylnicotinate (3.4 g, 20.59 mmol, 1.0 eq) and 1- (3-bromophenyl) ethan-1-one (3.03 mL, 22.65 mmol, 1.1 eq) in Toluene (50 mL) was added K₃PO₄ (6.55 g, 30.88 mmol, 1.5 eq) . The reaction mixture was stirred at 85℃ overnight. The reaction mixture was diluted with DCM (200 mL) . The organic layer washed with brine (200 mL) , dried over Na₂SO₄, filtered and concentrated. The residue in DCM (10 mL) was stirred for 30 min. The mixture was filtered to afford the title product as a white solid (2.4 g, 34%) .

MS (ESI, pos. ion) m/z: 345.8/347.8 [M+H] ⁺, Rt=1.208/2min.

Step 3: Preparation of compound 568-3: methyl 5- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) nicotinate

Under N₂, to the solution of methyl (E) -5- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) nicotinate (700 mg, 2.02 mmol, 1.0 eq) in a mixture solvent of dioxane in EtOH (20 mL, 4: 1) was added Et₃N (1842 mg, 18.20 mmol, 9.0 eq) and 3-benzyl-5- (2-hydroxyethyl) -4-methylthiazol-3-ium chloride (682 mg, 2.53 mmol, 1.2 eq) and cyclopropyl acetaldehyde (1530 mg, 18.20 mmol, 9.0 eq) . The reaction was stirred at 100 ℃overnight. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a grey solid (800 mg, 92%) .

MS (ESI, neg. ion) m/z: 428.1/430.1 [M-1] ⁺, Rt=1.033/2min.

Step 4: Preparation of compound 568-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (p-tolyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 5- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) nicotinate (500 mg, 1.16 mmol, 1.0 eq) in a mixture solvent of EtOH in CH₃COOH (10 mL, 4: 1) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (640 mg, 1.16 mmol, 1.0 eq) . The reaction mixture was stirred at 100 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then diluted with NaHCO₃ (10 mL) and extracted with EtOAc (30 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a grey solid (805 mg, 80%) .

MS (ESI, pos. ion) m/z: 837.9/839.8 [M+H] ⁺, Rt=1.333/2min.

Step 5: Preparation of compound 568-6: methyl 5- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinate

To a solution of methyl 5- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) nicotinate (110 mg, 0.13 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL) . The mixture was stirred at 25 ℃ for 48 h. The mixture was concentrated under vacuum and purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 70/30) to afford the title product as a yellow solid (70 mg, 90%) .

MS (ESI, pos. ion) m/z: 597.9/599.9 [M+H] ⁺, Rt=1.067/2min.

Step 6: Preparation of compound 568-7: methyl 5- (5- (3- (cyclopentylethynyl) phenyl) -2- (Cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinate

To a solution of methyl 5- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinate (70 mg, 0.12 mmol, 1.0 eq) , DABCO (65 mg, 0.58 mmol, 5.0 eq) , CuI (11 mg, 0.06 mmol, 0.5 eq) , Pd-162 (5 mg, 0.01 mmol, 0.1 eq) in dioxane (2 mL) was added ethynylcyclopentane (55 mg, 0.58 mmol, 5.0 eq) and stirred at RT for 18 hours under N₂. The reaction mixture was H₂O (30 mL) , extracted with EA (30 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 40%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (60 mg, 83%) .

MS (ESI, pos. ion) m/z: 612.4 [M+1] ⁺ , Rt=1.200/2min.

Step 7: Preparation of compound 568: 5- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinic acid

To the solution of methyl 5- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinate (60 mg, 0.10 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) in THF (2 mL) was added a solution of LiOH (15 mg, 0.39 mmol, 4.0 eq) in H₂O (1 mL) . The mixture was stirred at RT for 18 hours. The mixture was adjusted to pH=5～6 with 1M HCl, extracted with EA (10 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (20 mg, 41%) .

MS (ESI, pos. ion) m/z: 598.2 [M+1] ⁺ , Rt=1.067/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 13.45 (br s, 1H) , 8.93 (br s, 2H) , 8.33 (t, J = 2.1 Hz, 1H) , 7.72 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.37 –7.25 (m, 4H) , 6.91 (d, J = 11.4 Hz, 1H) , 6.79 (dd, J = 8.1, 1.6 Hz, 1H) , 6.66 (s, 1H) , 5.40 (s, 2H) , 2.88-2.79 (m, 1H) , 2.68 –2.62 (m, 2H) , 2.00 –1.91 (m, 2H) , 1.74 –1.64 (m, 2H) , 1.63 –1.52 (m, 4H) , 0.86 –0.79 (m, 1H) , 0.37 –0.29 (m, 2H) , 0.07 –0.01 (m, 2H) .

Example 4: Synthesis of compound 608

Step 1: Preparation of compound 608-2: methyl (E) -6- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of methyl 6-formylpicolinate (2.00 g, 12.11 mmol, 1.0 eq) and K₃PO₄ (7.71 g, 36.33 mmol, 3.0 eq) in toluene (20 mL) was added 1- (3-bromophenyl) ethan-1-one (2.65 g, 13.32 mmol, 1.1 eq) . The mixture was stirred at 85 ℃ for 18 hours. After the reaction completion, the mixture was concentrated, filtered and the filtrate was diluted with H₂O (40 mL) , extracted with DCM (40 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 18%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (632 mg, 15%) .

MS (ESI, pos. ion) m/z: 346.0/348.0 [M+H] ⁺ , Rt=0.967/2min.

Step 2: Preparation of compound 608-3: methyl 6- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate (510 mg, 1.47 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (475 mg, 1.76 mmol, 1.2 eq) , TEA (1.83 mL, 13.22 mmol, 9.0 eq) in a mixture solution of EtOH (5 mL) in dioxane (20 mL) was added 2-cyclopropylacetaldehyde (2780 mg, 13.22 mmol, 9.0 eq) and stirred at 100 ℃ for 18 hours under N₂. After the reaction completion, the mixture was concentrated under vacuum, diluted with H₂O (30 mL) , extracted with EA (30 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (600 mg, 94%) .

MS (ESI, pos. ion) m/z: 430.1/432.1 [M+H] ⁺, Rt=1.017/2min.

Step 3: Preparation of compound 608-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (220 mg, 0.51 mmol, 1.0 eq) in a mixture solvent of EtOH (1 mL) in AcOH (4 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (227 mg, 0.51 mmol, 1.0 eq) . The mixture was stirred at 110 ℃ for 18 hours. The reaction mixture was concentrated under vacuum, diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product was purified by column chromatography through silica gel, eluting with 0%to 18%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (340 mg, 79%) .

MS (ESI, pos. ion) m/z: 838.1/840.1 [M+H] ⁺ , Rt=1.375/2min.

Step 4: Preparation of compound 608-5: methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate (340 mg, 0.41 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The mixture was stirred at RT for 48 hours. The reaction mixture was concentrated under vacuum to afford the crude product was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (190 mg, 78%) .

MS (ESI, pos. ion) m/z: 598.1/600.1 [M+H] ⁺ , Rt=1.117/2min.

Step 5: Preparation of compound 608-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.20 mmol, 1.0 eq) , DABCO (112 mg, 1.00 mmol, 5.0 eq) , Tri-tert-butylphosphine tetrafluoroborate (29 mg, 0.10 mmol, 0.5 eq) , Allylpalladium chloride dimer (15 mg, 0.04 mmol, 0.2 eq) in dioxane (20 mL) was added 2-methylbut-3-yn-2-ol (140 mg, 2.01 mmol, 10.0 eq) . The mixture was stirred at RT for 18 hours under N₂. The mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product was purified by column chromatography through silica gel, eluting with 0%to 50%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (90 mg, 74%) .

MS (ESI, pos. ion) m/z: 602.3 [M+1] ⁺, Rt=1.033/2min.

Step 6: Preparation of compound 608: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) picolinate (90 mg, 0.15 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) in THF (2 mL) was added a solution of LiOH (25 mg, 0.60 mmol, 4.0 eq) in H₂O (1 mL) . The mixture was stirred at RT for 16 hours. The mixture was adjusted to pH=5～6 with 1M HCl, extracted with EA (10 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (35 mg, 40%) .

MS (ESI, pos. ion) m/z: 588.3 [M+1] ⁺, Rt=0.867/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.91 –7.82 (m, 2H) , 7.76 –7.68 (m, 2H) , 7.40-7.33 (m, 3H) , 7.32 –7.27 (m, 1H) , 6.91 (s, 1H) , 6.87 (d, J = 11.0 Hz, 1H) , 6.77 (d, J = 8.9 Hz, 1H) , 5.53-5.33 (m, 3H) , 3.21 (d, J = 6.7 Hz, 2H) , 1.45 (s, 6H) , 0.98 –0.89 (m, 1H) , 0.31 –0.19 (m, 4H) .

Example 5: Synthesis of compound 609

Step 1: Preparation of compound 609-2: methyl (E) -6- (3- (3-bromo-4-fluorophenyl) -3-oxoprop-1-en-1-yl) picolinate

To the solution of methyl 6-formylpyridine-2-carboxylate (1 g, 6.06 mmol, 1.0 eq) and 1- (5-bromo-3-fluorophenyl) ethan-1-one (1.58 g, 7.27 mmol, 1.2 eq) in toluene (30 mL) was added tripotassium phosphate (2.57 g, 12.11 mmol, 2.0 eq) . The reaction mixture was stirred at 80 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then the residue was diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 5%to 33%EtOAc in petroleum ether as a gradient) to afford the title product as a white solid (340 mg, 16.2%) .

MS (ESI, pos. ion) m/z: 364.0/366.0 [M+H] ⁺, Rt=0.983/2min.

Step 2: Preparation of compound 609-3: methyl 6- (1- (3-bromo-4-fluorophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl methyl (E) -6- (3- (3-bromo-4-fluorophenyl) -3-oxoprop-1-en-1-yl) picolinate (300 mg, 0.82 mmol, 1.0 eq) in a mixture solvent of dioxane (4 mL) in EtOH (1 mL) was added 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-iumchloride (278 mg, 1.03 mmol, 1.2 eq) and triethylamine (1 mL, 7.41 mmol, 9.0 eq) , then suspension was degassed under vacuum and purged with N₂ for 3 times. Then 2-cyclopropylacetaldehyde (624 mg, 7.41 mmol, 9.0 eq) was added to the mixture, and the resulting was stirred at 100℃ overnight. This mixture was concentrated under reduced vacuum, then the residue was diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 5%to 33%EtOAc in petroleum ether as a gradient) to afford the title product as a white solid (330 mg, 89.36%) .

MS (ESI, pos. ion) m/z: 448.1/450.1 [M+H] ⁺, Rt=1.142/2min.

Step 3: Preparation of compound 609-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (1- (3-bromo-4-fluorophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (280 mg, 0.62 mmol, 1.0 eq) in a mixture solvent of AcOH (2 mL) in EtOH (8 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (333 mg, 0.75 mmol, 1.2 eq) . The reaction mixture was stirred at 100 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then the residue was diluted with NaHCO₃ (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 5%to 33%EtOAc in petroleum ether as a gradient) to afford the title product as a white solid (480 mg, 89.70%) .

MS (ESI, pos. ion) m/z: 856.1/858.1 [M+H] ⁺, Rt=1.358/2min.

Step 4: Preparation of compound 609-5: methyl 6- (5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate (480 mg, 0.56 mmol, 1.0 eq) in DCM (6 mL) was added TFA (3 mL) . The reaction mixture was stirred at room temperature for 12 hours. This mixture was concentrated under reduced vacuum, then the residue was diluted with H₂O (30 mL) and extracted with DCM (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 5%to 33%EtOAc in petroleum ether as a gradient) to afford the title product as a yellow solid (220 mg, 63.70%) .

MS (ESI, pos. ion) m/z: 616.0/618.0 [M+H] ⁺, Rt=1.125/2min.

Step 5: Preparation of compound 609-6: methyl 6- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of methyl 6- (5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (150 mg, 0.24 mmol, 1.0 eq) and 2-methylbut-3-yn-2-ol (102 mg, 1.22 mmol, 5.0 eq) in dioxane (2 mL) was added DABCO (82 mg, 0.73 mmol, 3.0 eq) , CuI (9 mg, 0.05 mmol, 0.5 eq) and Pd-162 (10 mg, 0.02 mmol, 0.1 eq) . The reaction was stirred at room temperature for 12 hours. This mixture was concentrated under reduced vacuum, then the residue diluted with H₂O (20 mL) and extracted with EtOAc (20 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 5%to 33%EtOAc in petroleum ether as a gradient) to afford the title product as a white solid (140 mg, 92.85%) .

MS (ESI, pos. ion) m/z: 620.7 [M+1] ⁺, Rt=1.050/2min.

Step 6: Preparation of compound 609: 6- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (130 mg, 0.21 mmol, 1.0 eq) in a mixture (THF: MeOH: H₂O=4: 1: 1, 3 mL) was added lithium hydroxide (25 mg, 0.63 mmol, 3.0 eq) . The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum. The residue was adjusted to pH=6 with 2N HCl solution. The reaction mixture was extracted with EA (10 mL × 3) . The organic layer washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (83 mg, 65.63%) .

MS (ESI, pos. ion) m/z: 606.2 [M+1] +, Rt=0.883/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.92 (s, 1H) , 7.94-7.86 (m, 2H) , 7.77 (dd, J = 1.8, 6.8 Hz, 1H) , 7.70 (t, J = 7.9Hz, 1H) , 7.60 (s, 2H) , 7.43 (dd, J = 2.3, 6.9 Hz, 1H) , 7.41-7.35 (m, 1H) , 7.28 (t, J = 9.0 Hz, 1H) , 6.92 (s, 1H) , 6.88 (d, J = 11.1 Hz, 1H) , 6.77 (d, J = 8.1 Hz, 1H) , 5.52 (s, 1H) , 5.39 (s, 2H) , 3.21 (br d, J =6.8 Hz, 2H) , 1.46 (s, 6H) , 0.99-0.89 (m, 1H) , 0.31-0.19 (m, 4H) .

Example 6: Synthesis of compound 610

Step 1: Preparation of compound 610-2: methyl (E) -3- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) benzoate

To the solution of methyl 3-formylbenzoate (2 g, 12.18 mmol, 1.0 eq) and 1- (3-bromophenyl) ethan-1-one (2.44 mL, 18.27 mmol, 1.5 eq) in methanol (40 mL) was added sodium hydroxide (970 mg, 24.37 mmol, 2.0 eq) . The reaction mixture was stirred at room temperature for 18 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 1%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (1.8 g, 42.80%) .

MS (ESI, pos. ion) m/z: 344.8/346.8 [M+H] ⁺, Rt=1.208/2min.

Step 2: Preparation of compound 610-3: methyl 3- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) benzoate

Under N₂, to the solution of methyl (E) -3- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) benzoate (500 mg, 1.45 mmol, 1.0 eq ) in a mixture solvent of dioxane (8 mL) in EtOH (2 mL) was added TEA (1.81 mL, 13.03 mmol, 9.0 eq) and 3-benzyl-5- (2-hydroxyethyl) -4-methylthiazolium chloride (488 mg, 1.81 mmol, 1.2 eq) . Then the 2-cyclopropylacetaldehyde (610 mg, 7.25 mmol, 5.0 eq) was added to the mixture under N₂ atmosphere. The reaction was stirred at 100 ℃ for 18 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 10%to 80%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (300 mg, 48.24%) .

MS (ESI, pos. ion) m/z: 428.9/430.9 [M+1] ⁺, Rt=1.200/2min.

Step 3: Preparation of compound 610-4: methyl 3- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) benzoate

To the solution of methyl 3- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) benzoate (300 mg, 0.70 mmol, 1.0 eq) in a mixture solvent of EtOH (6 mL) in AcOH (2 mL) was added 4- (aminomethyl) -2-fluorobenzene-1-sulfonamide hydrochloride (421 mg, 1.75 mmol, 2.2 eq) and DIEA (226 mg, 1.75 mmol, 2.2 eq) . The reaction mixture was stirred at 100 ℃ for 18 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 1%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (169 mg, 40.36%) .

MS (ESI, pos. ion) m/z: 597.2/599.2 [M+H] ⁺, Rt=1.175/2min.

Step 4: Preparation of compound 610-5: methyl 3- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) benzoate

To a solution of methyl 3- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) benzoate (100 mg, 0.17 mmol, 1.0 eq) and 2-methylbut-3-yn-2-ol (65 μL, 0.67 mmol, 4.0 eq) in dioxane (10 mL) was added 1, 4-diazabicyclo [2.2.2] octane (56 mg, 0.50 mmol, 3.0 eq) , tetrafluoro-λ5-boranuide tris (2-methylprop-2-yl) phosphane (29. Mg, 0.10 mmol, 0.5 eq) and bis [chloropalladium (1+) ] bis(prop-2-en-1-ide) (18 mg, 0.05 mmol, 0.2 eq) . The mixture was exchanged with N₂ and stirred at 60 ℃for 18 hours. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL×2) , then the combined organic phases washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography through silica gel, eluting with 1%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (20 mg, 19.89%) .

MS (ESI, neg. ion) m/z: 599.2 [M-1] ⁺, Rt=1.083/2min.

Step 5: Preparation of compound 610: 3- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) benzoic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 3- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) benzoate (20 mg, 0.04 mmol, 1.0 eq) and THF (2 mL) . A solution of Lithium hydroxide monohydrate (6 mg, 0.16 mmol, 4.0 eq) in water (1 mL) was added, and the mixture was stirred at 25 ℃ for 18 hours. The mixture was acidified with 1 M aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (10 mL ×2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.1%HCOOH) to afford the title product as a yellow solid (3 mg, 17%) .

MS (ESI, neg. ion) m/z: 585.2 [M-1] ⁺, Rt=0.958/2min.

¹H NMR (400 MHz, DMSO-d₆) δ12.86 (br s, 1H) , 8.06 (s, 1H) , 7.82 (d, J = 7.8 Hz, 1H) , 7.76 –7.68 (m, 2H) , 7.60 (s, 2H) , 7.52 (t, J = 7.8 Hz, 1H) , 7.39 –7.33 (m, 3H) , 7.31 –7.26 (m, 1H) , 6.86 (d, J = 10.8 Hz, 1H) , 6.77 (d, J = 8.9 Hz, 1H) , 6.55 (s, 1H) , 5.44 (s, 1H) , 5.39 (s, 2H) , 2.63 (br d, J = 5.8 Hz, 2H) , 1.44 (s, 6H) , 0.88 –0.80 (m, 1H) , 0.35 –0.29 (m, 2H) , 0.07 –0.02 (m, 2H) .

Example 7: Synthesis of compound 612

Step 1: Preparation of compound 612-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 2- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (100 mg, 0.17 mmol, 1.0 eq) , 1, 4-diazabicyclo [2.2.2] octane (56 mg, 0.50 mmol, 3.0 eq) , CuI (16 mg, 0.08 mmol, 0.5 eq) , Pd-162 (13 mg, 0.03 mmol, 0.2 eq) in dioxane (10 mL) was added 2-methylbut-3-yn-2-ol (140 mg, 1.67 mmol, 10.0 eq) . The mixture was stirred at RT for 18 hours under N₂. The reaction mixture was diluted with H₂O (15 mL) and extracted with EA (15 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 50%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (70 mg, 69%) .

MS (ESI, neg. ion) m/z: 601.3 [M-1] ⁺ , Rt= 0.983/2min.

Step 2: Preparation of compound 612: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

To the solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (70 mg, 0.12 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) in THF (2 mL) was added a solution of LiOH (20 mg, 0.46 mmol, 4.0 eq) in H₂O (1 mL) . The mixture was stirred at RT for 16 hours. The mixture was adjusted to pH=5～6 with 1M HCl, extracted with EA (10 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (35 mg, 51%) .

MS (ESI, pos. ion) m/z: 589.3 [M+1] ⁺ , Rt=0.908/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 13.63 (br s, 1H) , 8.97 (d, J = 4.9 Hz, 1H) , 7.70 (t, J = 7.8 Hz, 1H) , 7.65 (d, J = 4.9 Hz, 1H) , 7.60 (s, 2H) , 7.39 –7.33 (m, 3H) , 7.33 –7.28 (m, 1H) , 7.04 (s, 1H) , 6.88 (br d, J = 11.1 Hz, 1H) , 6.76 (br d, J = 8.1 Hz, 1H) , 5.48-5.38 (m, 3H) , 3.22 (br d, J = 6.1 Hz, 2H) , 1.44 (s, 6H) , 1.02 –0.93 (m, 1H) , 0.33 –0.24 (m, 4H) .

Example 8: Synthesis of compound 616

Step 1: Preparation of compound 616-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (1000 mg, 1.67 mmol, 1.0 eq) in a mixture solvent of H₂O (9 mL) in dioxane (30 mL) was added K₂CO₃ (693 mg, 5.01 mmol, 3.0 eq) , Pd (dppf) Cl₂ (122 mg, 0.17 mmol, 0.1 eq) and (3-fluorophenyl) boronic acid (351 mg, 2.51 mmol, 1.5 eq) . The reaction mixture was stirred 60 ℃ for 2 hours under N₂ atmosphere. After completion, the reaction mixture was poured into water (40 mL) and extracted with EA (50 mL × 3) . The combined organic layer washed with brine, dried over Na₂SO₄, filtered, concentrated. The mixture was purified by column chromatography through silica gel (eluting with 0: 100 to 60: 40 petroleum ether: ethyl acetate) to afford the title compound (800 mg, 78 %yield) .

MS (ESI, pos. ion) m/z: 614.2 [M+1] ⁺, Rt=1.167/2min.

Step 2: Preparation of compound 616: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate (800 mg, 1.30 mmol, 1.0 eq) , THF (7 mL) and MeOH (7 mL) . A solution of 1 M aqueous LiOH (6 mL) was added, and the mixture was stirred at 25 ℃ overnight. The mixture was acidified with 1 M aqueous HCl solution until the pH was ～6 and extracted with ethyl acetate (20 mL × 3) . The organic layers were combined, washed with saturated aqueous NaHCO₃ solution and brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by reverse-phase column chromatography (using a C_l8 column, eluting with 90: 10 to 0: 100 H₂O: MeCN + 0.1%formic acid as a gradient) . Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (650 mg, 83 %yield) .

MS (ESI, pos. ion) m/z: 600.2 [M+1] , Rt=1.317/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.77 (br s, 1H) , 7.95 –7.87 (m, 2H) , 7.78 (dd, J = 2.1, 6.3 Hz, 1H) , 7.72 (t, J = 7.8 Hz, 1H) , 7.68 –7.62 (m, 2H) , 7.60 (s, 2H) , 7.55 –7.45 (m, 3H) , 7.42 –7.37 (m, 2H) , 7.20 (dt, J = 2.3, 8.6 Hz, 1H) , 6.99 (s, 1H) , 6.96 (d, J = 11.1 Hz, 1H) , 6.84 (d, J = 8.1 Hz, 1H) , 5.47 (s, 2H) , 3.23 (br d, J = 6.5 Hz, 2H) , 1.01-0.89 (m, 1H) , 0.32 –0.20 (m, 4H) .

Example 9: Synthesis of compound 617

Step 1: Preparation of compound 617-1: methyl 6- (2- (cyclopropylmethyl) -5- (3’, 6-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of methyl 6- (5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (50 mg, 0.08 mmol, 1.0 eq) and (3-fluorophenyl) boranediol (17 mg, 0.12 mmol 1.5 eq) in a mixture solvent of H₂O (0.5 mL) in dioxane (2 mL) was added potassium carbonate (38 mg, 0.32 mmol, 3.0 eq) and Pd (dppf) Cl₂ (6 mg, 0.01 mmol, 0.1 eq) . The reaction was stirred at 85 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then the residue was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a grey solid (40 mg, 78.08%) .

MS (ESI, pos. ion) m/z: 632.2 [M+1] ⁺, Rt=1.175/2min.

Step 2: Preparation of compound 617: 6- (2- (cyclopropylmethyl) -5- (3’, 6-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (2- (cyclopropylmethyl) -5- (3’, 6-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (40 mg, 0.06 mmol, 1.0 eq) in a mixture solvent of THF (1 mL) in MeOH (1 mL) was added a solution of lithium hydroxide (5 mg, 0.18 mmol, 3.0 eq) in H₂O (0.5 mL) . The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum. The residue was adjusted to pH=6 with 2N HCl solution. The reaction mixture was extracted with EA (10 mL × 3) . The organic layer washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (35 mg, 89.49%) .

MS (ESI, pos. ion) m/z: 618.2 [M+1] ⁺, Rt=1.050/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.90 (br s, 1H) , 7.94-7.85 (m, 2H) , 7.77 (dd, J = 1.3, 7.2 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.55-7.47 (m, 2H) , 7.44-7.22 (m, 5H) , 6.97-6.92 (m, 2H) , 6.82 (d, J = 8.8 Hz, 1H) , 5.44 (s, 2H) , 3.22 (br d, J = 6.6 Hz, 2H) , 0.99-0.90 (m, 1H) , 0.32-0.20 (m, 4H) .

Example 10: Synthesis of compound 622

Step 1: Preparation of compound 622-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate

A solution of methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (60 mg, 0.10 mmol, 1.0 eq) , (4- (2-hydroxypropan-2-yl) phenyl) boronic acid (27 mg, 0.15 mmol, 1.5 eq) , Pd (dppf) Cl₂ (6 mg, 0.01 mmol, 0.1 eq) and K₂CO₃ (34.64 mg, 0.25 mmol) in a mixture solvent of 1, 4-dioxane (2 mL) and water (0.5 mL) was degassed and purged with N₂. After stirred at 80 ℃for 3 hrs, the reaction mixture was poured into water (2 mL) and extracted with EtOAc (5 mL × 3) . The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residues were purified by flash chromatography through silica gel (eluting with EA/PE=0/100 to 100/0) to afford the title product as a white soild (45 mg, 0.07 mmol, 82%) .

MS (ESI, pos. ion) m/z: 654.3 [M+1] ⁺, Rt=1.092/2 min.

Step 2: Preparation of compound 622: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid

To a stirred solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate (45 mg, 0.07 mmol, 1.0 eq) in a mixture solvent of MeOH (0.4 mL) and H₂O (0.2 mL) was added lithium hydroxide (6.71 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred for 1.5 hrs. After removal of the solvents under reduced pressure, the residue was acidified (1N HCl) to pH < 4 and extracted with EtOAc (5 mL × 3) , the combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (23 mg, 52%) .

MS (ESI, pos. ion) m/z: 640.3 [M+1] ⁺, Rt=0.942/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.90 (br s, 1H) , 7.95 –7.88 (m, 2H) , 7.78 (dd, J = 6.2, 2.4 Hz, 1H) , 7.73 (t, J = 7.9 Hz, 1H) , 7.63 –7.57 (m, 4H) , 7.55 –7.43 (m, 5H) , 7.34 (d, J = 7.6 Hz, 1H) , 7.00 –6.94 (m, 2H) , 6.85 (d, J = 8.2 Hz, 1H) , 5.46 (s, 2H) , 5.03 (s, 1H) , 3.23 (br d, J = 6.4 Hz, 2H) , 1.44 (s, 6H) , 1.01 –0.91 (m, 1H) , 0.32 –0.21 (m, 4H) .

Example 11: Synthesis of compound 623

Step 1: Preparation of compound 623-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate

A mixture of methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (50 mg, 0.08 mmol, 1.0 eq) , 2- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl] propan-2-ol (26 mg, 0.10 mmol, 1.0 eq) , Pd (dppf) Cl₂ (6 mg, 0.01 mmol, 0.1 eq) and potassium carbonate (35 mg, 0.25 mmol, 2.5 eq) in a mixture solvent of 1, 4-dioxane (0.4 ml) and water (0.1 mL) was degassed and purged with N₂. After stirred at 80 ℃ for 3 hrs, the reaction mixture was poured into water (2 mL) and extracted with EtOAc (5 mL × 3) . The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residues were purified by prep-TLC (EA/PE=1: 1) to afford the title product as a white soild (48 mg, 0.07 mmol, 87%) .

MS (ESI, pos. ion) m/z: 654.3 [M+1] ⁺, Rt=1.100/2 min.

Step 2: Preparation of compound 623: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid

To a stirred solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate (48 mg, 0.07 mmol) in a mixture solvent of MeOH (0.4 mL) and H₂O (0.2 mL) was added lithium hydroxide (7 mg, 0.29 mmol, 3.0 eq) at room temperature. The resulting mixture was stirred for 1.5 hrs. After removal of the solvents under reduced pressure, the residue was acidified (1N HCl) to pH < 4 and extracted with EtOAc (5 mL × 3) , the combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid.

MS (ESI, pos. ion) m/z: 640.4 [M+1] ⁺, Rt=0.958/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.93 (br s, 1H) , 7.95 –7.88 (m, 2H) , 7.78 (dd, J = 6.1, 2.5 Hz, 1H) , 7.75 –7.69 (m, 2H) , 7.62 –7.57 (m, 4H) , 7.50 –7.43 (m, 2H) , 7.39 –7.31 (m, 3H) , 6.99 –6.94 (m, 2H) , 6.86 (d, J = 8.0 Hz, 1H) , 5.46 (s, 2H) , 5.06 (s, 1H) , 3.22 (br d, J = 6.6 Hz, 2H) , 1.45 (s, 6H) , 1.00 –0.89 (m, 1H) , 0.31 –0.20 (m, 4H) .

Example 12: Synthesis of compound 636

Step 1: Preparation of compound 636-1: methyl 6- (5- (3’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 167.09 μmol, 1 eq) was added to a mixture of water (0.5 mL) and THF (3 mL) , and followed by (3-cyanophenyl) boronic acid (36.83 mg, 250.63 μmol, 1.5 eq) , cesium carbonate (106.40 mg, 501.27 μmol, 3 eq) and Xphos Pd G₃ (14.14 mg, 16.71 μmol, 0.1 eq) in turn. The air in the system was replaced 3 times with nitrogen gas. The resulting mixture was stirred at 80 ℃ for 2 hours and diluted with water (5 mL) , and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with saturated NaCl aq (3 mL) , dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by chromatography through silica gel (eluting with PE/EtOAc (v/v) =3/1) to afford the title product as a yellow solid (105 mg, crude product) .

MS (ESI, pos. ion) m/z: 621.3 [M+1] ⁺.

Step 1: Preparation of compound 636: 6- (5- (3’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Methyl 6- (5- (3’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 161.11 μmol, 1 eq) was added to a mixture of methanol (2 mL) and THF (2 mL) , and LiOH (2 M, 4.00 mL) was added. The resulting mixture was stirred at 30 ℃ for 0.5 hour and diluted with 1 N HCl aq (3 mL) , and extracted with EtOAc (5 mL× 3) . The combined organic layers were washed with saturated NaCl aq (3 mL) , dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (column: Boston Prime C18 150× 30 mm× 5 um; mobile phase: [Water (FA) -MeCN] ; gradient: 40%-70%B over 9 min) to afford the title product as a yellow solid (34.72 mg, 35.5%yield) .

MS (ESI, pos. ion) m/z: 607.2 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d6) δ: 8.21 (s, 1H) , 7.94 –7.88 (m, 3H) , 7.83 (br d, J = 7.8 Hz, 1H) , 7.78 (dd, J = 1.1, 6.9 Hz, 1H) , 7.76 –7.72 (m, 1H) , 7.71 –7.66 (m, 2H) , 7.65 –7.58 (m, 3H) , 7.53 –7.47 (m, 1H) , 7.43 –7.39 (m, 1H) , 7.00 –6.98 (m, 1H) , 6.95 –6.90 (m, 1H) , 6.86 –6.81 (m, 1H) , 5.55 –5.42 (m, 2H) , 3.23 (br d, J = 6.4 Hz, 2H) , 1.04 –0.90 (m, 1H) , 0.35 –0.18 (m, 4H) .

Example 13: Synthesis of compound 637

Step 1: Preparation of compound 637-1: methyl 6- (5- (4’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoyl benzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 167.09 μmol, 1 eq) was added to a mixture of water (0.5 mL) and THF (3 mL) , and followed by (4-cyanophenyl) boronic acid (36.83 mg, 250.63 μmol, 1.5 eq) , K₃PO₄ (106.40 mg, 501.27 μmol, 3 eq) and Xphos Pd G₃ (14.14 mg, 16.71 μmol, 0.1 eq) in turn. The air in the system was replaced 3 times with nitrogen gas. The resulting mixture was stirred at 80 ℃ for 2 hours and diluted with water (5 mL) , and extracted with EA (5 mL × 3) . The combined organic layers were washed with saturated NaCl aq (3 mL) , dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by chromatography through silica gel (eluting with PE/EtOAc (v/v) =3/1) to afford the title product as a yellow solid (95 mg, 91.6%yield) .

MS (ESI, pos. ion) m/z: 621.3 [M+1] ⁺.

Step 2: Preparation of compound 637: 6- (5- (4’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Methyl 6- (5- (4’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (95 mg, 153.06 μmol, 1 eq) was added to a mixture of methanol (2 mL) and THF (2 mL) , and LiOH (2 M, 1.00 mL) was added. The resulting mixture was stirred at 30 ℃ for 0.5 hour and diluted with 1 N HCl aq (3 mL) , and extracted with EA (5 mL× 3) . The combined organic layers were washed with saturated NaCl aq (3 mL) , dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (column: Boston Prime C18 150× 30 mm× 5 um; mobile phase: [Water (FA) -MeCN] ; gradient: 40%-70%B over 9 min) to afford the title product as a yellow solid (40.99 mg, 44.1%yield) .

MS (ESI, pos. ion) m/z: 607.2 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.96 –7.86 (m, 4H) , 7.80 –7.74 (m, 3H) , 7.74 –7.67 (m, 2H) , 7.66 –7.63 (m, 3H) , 7.55 –7.49 (m, 1H) , 7.47 –7.43 (m, 1H) , 7.00 –6.94 (m, 2H) , 6.87 –6.83 (m, 1H) , 5.54 –5.39 (m, 2H) , 3.24 (br d, J = 6.5 Hz, 2H) , 1.02 –0.87 (m, 1H) , 0.37 –0.18 (m, 4H) .

Example 14: Synthesis of compound 646

Step 1: Preparation of compound 646-1: methyl 6- (2- (cyclopropylmethyl) -5- (3- ( (3, 3-difluorocyclobutyl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (150 mg, 0.25 mmol, 1.0 eq) , 3-ethynyl-1, 1-difluorocyclobutane (87 mg, 0.75 mmol, 3.0 eq) , DABCO (84 mg, 0.75 mmol, 3.0 eq) , CuI (5 mg, 0.03 mmol, 0.1 eq) , Pd-162 (50 mg, 0.13 mmol, 0.5 eq) and dioxane (6 mL) . The reaction mixture was degassed for 10 minutes and stirred at 25 ℃ for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography through silica gel (eluting with 100: 0 to 60: 40 petroleum ether: ethyl acetate) to afford the title compound (100 mg, 63 %yield) .

MS (ESI, pos. ion) m/z: 634.2 [M+1] ⁺, Rt=1.167/2min.

Step 2: Preparation of compound 646: 6- (2- (cyclopropylmethyl) -5- (3- ( (3, 3-difluorocyclobutyl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (2- (cyclopropylmethyl) -5- (3- ( (3, 3-difluorocyclobutyl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.16 mmol, 1.0 eq) , THF (2 mL) and MeOH (2 mL) . A solution of 1 M aqueous LiOH (1.0 mL, 4.5 eq) was added, and the mixture was stirred at 25 ℃ overnight. The mixture was acidified with 1 M aqueous HCl solution until the pH was ～6 and the mixture were extracted with ethyl acetate (10 mL × 3) . The organic layers were combined, washed with saturated aqueous NaHCO₃ solution and brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 70%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title compound (49 mg, 50%yield) .

MS (ESI, pos. ion) m/z: 620.2 [M+1] ⁺, Rt=1.042/2min.

¹HNMR (DMSO-d₆) δ 12.95 (br s, 1H) , 7.94 –7.86 (m, 2H) , 7.78 (dd, J = 2.0, 6.6 Hz, 1H) , 7.70 (t, J = 7.8 Hz, 1H) , 7.60 (s, 2H) , 7.42 (s, 1H) , 7.39 –7.31 (m, 3H) , 6.93 (s, 1H) , 6.88 (d, J = 11.0 Hz, 1H) , 6.78 (d, J = 8.4 Hz, 1H) , 5.41 (s, 2H) , 3.28 –3.18 (m, 3H) , 3.10 –2.96 (m, 2H) , 2.79 –2.63 (m, 2H) , 1.00 –0.89 (m, 1H) , 0.32 –0.20 (m, 4H) .

Example 15: Synthesis of compound 647

Step 1: Preparation of compound 647-1: methyl 6- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Ethynylcyclopentane (1.08 mL, 9.3 mmol, 2 eq) was added to the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (3 g, 4.65 mmol, 1.0 eq) , CuI (177 mg, 0.93 mmol, 0.2 eq) , TEA (2.58 mL, 18.59 mmol, 4 eq) and palladium (2+) dichloride bis (76thenone76phosphine) (652 mg, 0.93 mmol, 0.2 eq) in DMF (30 mL) at rt under N₂. The resulting was stirred at 40 ℃ for 18 h. After the reaction completion, the mixture was diluted with water (100 mL) , extracted with EA (50 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified with silica gel colume (eluent: 30%to 40% (v/v) EA in PE) to afford the title product as a yellow solid (2.3 g, 80.90%) .

MS (ESI, neg. ion) m/z: 610.1 [M-1] ⁺ , Rt=1.242/2min

¹HNMR (400 MHz, DMSO-d₆) δ = 7.96 –7.89 (m, 2H) , 7.83 –7.77 (m, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.60 (s, 2H) , 7.37 –7.26 (m, 4H) , 6.92 (s, 1H) , 6.88 (d, J = 11.1 Hz, 1H) , 6.77 (dd, J = 1.1, 8.2 Hz, 1H) , 5.41 (s, 2H) , 3.88 (s, 3H) , 3.19 (br d, J = 6.6 Hz, 2H) , 2.84 (quin, J = 7.6 Hz, 1H) , 1.98 –1.87 (m, 2H) , 1.77 –1.65 (m, 2H) , 1.64 –1.50 (m, 4H) , 1.06 –0.92 (m, 1H) , 0.37 –0.21 (m, 4H) .

Step 2: Preparation of compound 647: 6- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (2.3 g, 2.17 mmol, 1.0 eq) in a mixture solvent of EtOH (20 mL) in tetrahydrofuran (20 mL) was added a solution of lithium hydroxide (370 mg, 8.68 mmol, 4.0 eq) in water (5 mL) . The reaction mixture was stirred at RT for 2 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (50 mL) , extracted with EA (100 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by C-18 column (eluent: 55%to 80% (v/v) CH₃CN in H₂O with 0.1%FA) to afford the title product as a yellow solid (1.4 g, 62.3%) .

MS (ESI, pos. ion) m/z: 598.1 [M+1] ⁺, Rt=1.142/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.93 (br s, 1H) , 7.94 –7.87 (m, 2H) , 7.82 –7.75 (m, 1H) , 7.71 (t, J =7.9 Hz, 1H) , 7.60 (s, 2H) , 7.38 –7.26 (m, 4H) , 6.92 (s, 1H) , 6.89 (d, J = 11.0 Hz, 1H) , 6.78 (d, J = 8.3 Hz, 1H) , 5.40 (s, 2H) , 3.21 (br d, J = 6.5 Hz, 2H) , 2.89 –2.78 (m, 1H) , 2.01 –1.90 (m, 2H) , 1.78 –1.65 (m, 2H) , 1.63 –1.48 (m, 4H) , 1.00 –0.89 (m, 1H) , 0.31 –0.20 (m, 4H) .

Example 16: Synthesis of compound 648

Step 1: Preparation of compound 648-1: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (5-methylthiophen-2-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (700 mg, 1.17 mmol, 1.0 eq) and trimethyl [ (5-methylthiophen-2-yl) ethynyl] silane (682 mg, 3.51 mmol, 3.0 eq) in DMF (8 mL) was added K₂CO₃ (161 mg, 1.17 mmol, 1.0 eq) , TEA (0.49 mL, 3.51 mmol, 3.0 eq) , CuI (22 mg, 0.12 mmol, 0.1 eq) and Pd (PPh₃) ₂Cl₂ (82 mg, 0.12 mmol, 0.1 eq) . The mixture was stirred at 40 ℃ in an oil bath for 2 hours under N₂ atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. This mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL) . The organic layer washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. Column chromatography through silica gel (eluting with 5%to 33%EtOAc in petroleum ether as a gradient) to afford the title product as a solid (550 mg, 0.86 mmol, 73.50%) .

MS (ESI, neg. ion) m/z: 638.1 [M-1] ^-, Rt=1.250/2min.

Step 2: Preparation of compound 648: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (5-methylthiophen-2-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (5-methylthiophen-2-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinate (550 mg, 0.86 mmol, 1.0 eq) , methanol (5 mL) and H₂O (2 mL ) . Lithium hydroxide (108 mg, 2.58 mmol, 3.0 eq) was added, and the mixture was stirred at 25 ℃ for 2 h. The mixture was acidified with 1 M aqueous HCl solution until the pH was ～6 at 0 ℃. The resulting was extracted with EA (30 mL × 3) . The organic layer washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title compound (220 mg, 0.35 mmol, 40.90%) .

MS (ESI, pos. ion) m/z: 625.9 [M+1] ⁺, Rt=1.374/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.90 (br s, 1H) , 7.95 –7.88 (m, 2H) , 7.78 (dd, J = 2.6, 5.9 Hz, 1H) , 7.70 (t, J = 7.8Hz, 1H) , 7.60 (s, 2H) , 7.55 (d, J = 0.9 Hz, 1H) , 7.46 –7.38 (m, 3H) , 7.22 (d, J = 3.5 Hz, 1H) , 6.97 (s, 1H) , 6.89 (d, J = 11.0Hz, 1H) , 6.84 –6.76 (m, 2H) , 5.44 (s, 2H) , 3.22 (br d, J = 6.5 Hz, 2H) , 2.47 (s, 3H) , 1.01 –0.90 (m, 1H) , 0.32 –0.20 (m, 4H) .

Example 17: Synthesis of compound 649

Step 1: Preparation of compound 649-2: methyl (E) -6- (3- (3-bromo-4-methylphenyl) -3-oxoprop-1-en-1-yl) picolinate

To the solution of methyl 6-formylpicolinate (300 mg, 1.82 mmol, 1.0 eq) and 1- (3-bromo-4-methylphenyl) ethan-1-one (503 mg, 2.36 mmol , 1.3 eq) in toluene (20 mL) was added 4-methylbenzene-1-sulfonamide (259 mg, 1.51 mmol , 0.5 eq) . The reaction mixture was stirred at 140 ℃ for 18 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 30%EtOAc in petroleum ether) to afford the title product as a white solid (400 mg, 1.11 mmol, 61%) .

MS (ESI, pos. ion) m/z: 360.0/362.0 [M+1] ⁺, Rt=1.025/2min.

Step 2: Preparation of compound 649-3: methyl 6- (1- (3-bromo-4-methylphenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (3-bromo-4-methylphenyl) -3-oxoprop-1-en-1-yl) picolinate (400 mg, 1.11 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (375 mg, 1.40 mmol, 1.2 eq) , TEA (1011 mg, 9.99 mmol, 9.0 eq) in a mixture solution of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (467 mg, 5.55 mmol, 5.0 eq) . The resulting was stirred at 100 ℃ for 18 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel (eluting with 0%to 30%EtOAc in petroleum ether as a gradient) to afford the title product as a yellow oil (445 mg, 1.00 mol, 90%) .

MS (ESI, neg. ion) m/z: 444.2/442.2 [M-1] ^-, Rt=1.081/2min.

Step 3: Preparation of compound 649-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-4-methylphenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (3-bromo-4-methylphenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (445 mg, 1.0 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (578 mg, 1.3 mmol, 1.3 eq) in EtOH (4 mL) was added AcOH (16 mL) . The mixture was stirred at 100 ℃for 18 hours. After the reaction completion, the mixture was diluted with H₂O (30 mL) , extracted with EA (30 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel (eluting with 0%to 30%EtOAc in petroleum ether as a gradient) to afford the title product as a yellow solid (490 mg, 0.57 mol, 57%) .

MS (ESI, pos. ion) m/z: 852.2/854.2 [M+1] ⁺, Rt=1.339/2min.

Step 4: Preparation of compound 649-5: methyl 6- (5- (3-bromo-4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-4-methylphenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate (490 mg, 0.57 mmol, 1.0 eq) in DCM (9 mL) was added TFA (3 mL) . The resulting was stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a yellow solid (340 mg, 0.56 mol, 96%) .

MS (ESI, pos. ion) m/z: 612.2/614.2 [M+1] ⁺, Rt=1.138/2min.

Step 5: Preparation of compound 649-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro-6-methyl- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5- (3-bromo-4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.16 mmol, 1.0 eq) , (4-fluorophenyl) boronic acid (30 mg, 0.20 mmol, 1.3 eq) , K₂CO₃ (45 mg, 0.33 mmol, 2.0 eq) in a mixture solution of dioxane (10 mL) in H₂O (3 mL) was added Pd (dppf) Cl₂ (12 mg, 0.02 mmol, 0.1 eq) , and the mixture was stirred at 80 ℃ for 2 hours under N₂. After the reaction completion, the mixture washed with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a yellow solid (92 mg, 0.15 mol, 89%) .

MS (ESI, pos. ion) m/z: 628.2 [M+1] ⁺, Rt=1.200/2min.

Step 6: Preparation of compound 649: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro-6-methyl- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro-6-methyl- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate (92 mg, 0.15 mmol, 1.0 eq) in a mixture solution of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (25 mg, 0.59 mmol, 4.0 eq) in H₂O (2 mL) . The resulting was stirred at RT for 18 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, diluted with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (40 mg, 0.07 mol, 44%) .

MS (ESI, pos. ion) m/z: 614.3 [M+1] ⁺, Rt=1.037/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.88 (br s, 1H) , 7.93 –7.84 (m, 2H) , 7.76 (dd, J = 7.0, 1.6 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.62 (s, 2H) , 7.36 –7.29 (m, 3H) , 7.28 –7.20 (m, 3H) , 7.15 (d, J = 1.4 Hz, 1H) , 6.93 (d, J = 11.4 Hz, 1H) , 6.87 (s, 1H) , 6.82 (d, J = 8.0 Hz, 1H) , 5.41 (s, 2H) , 3.21 (br d, J = 6.6 Hz, 2H) , 2.22 (s, 3H) , 0.99 –0.89 (m, 1H) , 0.31 –0.19 (m, 4H) .

Example 18: Synthesis of compound 650

Preparation of compound 650-4: 4- (aminomethyl) -2-fluorobenzenesulfonamide

Step 1: Preparation of compound 650-a: 4-cyano-2-fluorobenzenesulfonamide

4-cyano-2-fluorobenzenesulfonyl chloride (5 g, 22.77 mmol, 1.0 eq) was added to Ammonia dioxane (200 mL) slowly, and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated to afford the crude product as a yellow solid (4.5 g, 98%) .

Step 2: Preparation of compound 650-4: 4- (aminomethyl) -2-fluorobenzenesulfonamide

To a solution of 4-cyano-2-fluorobenzenesulfonamide (4.5 g, 22.48 mmol, 1.0 eq) in MeOH (45 mL) was added NH₄OH (3 mL) and Raney nickel (130 mg, 2.25 mmol, 0.1 eq) . The reaction mixture was stirred at RT for 18 hours under H₂. The mixture was filtered and the filter cake washed with MeOH. The filtrate was concentrated to afford the crude product as a yellow oil (4.5 g, 98%) .

MS (ESI, pos. ion) m/z: 205.1 [M+1] ⁺, Rt=0.15/2 min.

Preparation of compound 650: 6- (2- (cyclopropylmethyl) -5- (4’-fluoro-2-methyl- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Step 1: Preparation of compound 650-2: methyl (E) -6- (3- (3-bromo-2-methylphenyl) -3-oxoprop-1-en-1-yl) picolinate

To the solution of methyl 6-formylpyridine-2-carboxylate (500 mg, 3.03 mmol, 1.0 eq) and 1- (3-bromo-2-methylphenyl) ethan-1-one (709.59 mg, 3.33 mmol, 1.1 eq) in toluene (10 mL) was added PTSA (287.95 mg, 1.51 mmol) . The reaction mixture was stirred at 140 ℃ for 2 hours with dean-Stark trap. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (30 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a grey solid (800 mg, 73.36%) .

MS (ESI, pos. ion) m/z: 360.0/326.0 [M+H] ⁺, Rt=1.008/2min.

Step 2: Preparation of compound 650-3: methyl 6- (1- (3-bromo-2-methylphenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

Under N₂, to the solution of methyl (E) -6- (3- (3-bromo-2-methylphenyl) -3-oxoprop-1-en-1-yl) picolinate (500 mg, 1.39 mmol, 1.0 eq) in a mixture solvent of dioxane (8 mL) in EtOH (2 mL) was added 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-iumchloride (469 mg, 1.74 mmol, 1.2 eq) and TEA (1.65 mL, 12.51 mmol, 9.0 eq) . Then the 2-cyclopropylacetaldehyde (584 mg, 6.94 mmol, 5.0 eq) was added to the reaction mixture. The resulting was stirred at 100 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a grey solid (290 mg, 47.02%) .

MS (ESI, pos. ion) m/z: 444.2/446.2 [M+H] ⁺, Rt=1.075/2min.

Step 3: Preparation of compound 650-5: methyl 6- (5- (3-bromo-2-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (1- (3-bromo-2-methylphenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (270 mg, 0.61 mmol) in a mixture solvent of AcOH (1 mL) in EtOH (4 mL) was added 4- (aminomethyl) -2-fluorobenzenesulfonamide (124 mg, 0.61 mmol, 1.0 eq) . The reaction mixture was stirred at 100 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then diluted with NaHCO₃ (10 mL) and extracted with EtOAc (20 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a grey solid (230 mg, 63.65%) .

MS (ESI, pos. ion) m/z: 612.1/614.1 [M+H] ⁺, Rt=1.158/2min.

Step 4: Preparation of compound 650-6: methyl 6- (2- (cyclopropylmethyl) -5- (4’-fluoro-2-methyl- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5- (3-bromo-2-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.19 mmol, 1.0 eq) in a mixture solvent of H₂O (1 mL) in dioxane (4 mL) was added K₂CO₃ (81 mg, 0.59 mmol, 3.0 eq) , Pd (dppf) Cl₂ (15 mg, 0.02 mmol, 0.1 eq) and (4-fluorophenyl) boronic acid (40 mg, 0.28 mmol, 1.5 eq) . The reaction mixture was stirred 85 ℃for 2 hours under N₂ atmosphere. After completion, the reaction mixture was poured into water (10 mL) and extracted with EA (10 mL × 3) . The combined organic layer washed with brine, dried over Na₂SO₄, filtered, concentrated. The mixture was purified by column chromatography through silica gel (eluting with 0: 100 to 60: 40 petroleum ether: ethyl acetate) to afford the title compound (115 mg, 95.65%) .

MS (ESI, pos. ion) m/z: 628.3 [M+1] ⁺, Rt=1.200/2min.

Step 5: Preparation of compound 650: 6- (2- (cyclopropylmethyl) -5- (4’-fluoro-2-methyl- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (2- (cyclopropylmethyl) -5- (4’-fluoro-2-methyl- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (115 mg, 0.18 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) in MeOH (2 mL) was added a solution of hydroxy lithium hydrate (22 mg, 0.54 mmol, 3.0 eq) in H₂O (0.5 mL) . The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum. The reaction mixture was adjusted to pH=6 with 2N HCl solution. The reaction mixture was extracted with EA (10 mL × 3) . The organic layer washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (66 mg, 58.77%) .

MS (ESI, pos. ion) m/z: 614.2 [M+1] ⁺ , Rt=1.050/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.88 (br s, 1H) , 7.91-7.86 (m, 1H) , 7.82 (dd, J = 8.2, 1.2 Hz, 1H) , 7.76 (dd, J = 7.5, 1.1 Hz, 1H) , 7.67 (t, J=7.9 Hz, 1H) , 7.59 (s, 2H) , 7.40-7.34 (m, 2H) , 7.29-7.16 (m, 5H) , 6.81-6.74 (m, 2H) , 6.70 (s, 1H) , 5.16 (br s, 2H) , 2.53-2.51 (m, 2H) , 1.95 (s, 3H) , 1.00-0.92 (m, 1H) , 0.28-0.23 (m, 4H) .

Example 19: Synthesis of compound 651

Step 1: Preparation of compound 651-2: methyl (E) -6- (3- (3-bromo-2-fluorophenyl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of 1- (3-bromo-2-fluorophenyl) ethan-1-one (1.97 g, 9.09 mmol, 1.5 eq) , 4-methylbenzene-1-sulfonamide (520 mg, 3.03 mmol, 0.5 eq) in Toluene (15 mL) was added methyl 6-formylpicolinate (1.00 g, 6.06 mmol, 1.0 eq) and stirred at 140 ℃ remove water by Dean-Stark trap. After the reaction completion, the mixture was diluted with H₂O (40 mL) , extracted with DCM (40 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (570 mg, 26%) .

MS (ESI, pos. ion) m/z: 364.0/366.0 [M+H] ⁺ , Rt=0.525/2min

Step 2: Preparation of compound 651-3: methyl 6- (1- (3-bromo-2-fluorophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (3-bromo-2-fluorophenyl) -3-oxoprop-1-en-1-yl) picolinate (200 mg, 0.55 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (177 mg, 0.66 mmol, 1.2 eq) , TEA (500 mg, 4.94 mmol, 9.0 eq) in a mixture solvent of dioxane (8 mL) and EtOH (2 mL) was added 2-cyclopropylacetaldehyde (416 mg, 4.94 mmol, 9.0 eq) , and the mixture was stirred at 100 ℃ for 18 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (190 mg, 77%) .

MS (ESI, pos. ion) m/z: 448.1/450.1 [M+H] ⁺, Rt=1.033/2min.

Step 3: Preparation of compound 651-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-2-fluorophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (3-bromo-2-fluorophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (150 mg, 0.33 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (178 mg, 0.40 mmol, 1.2 eq) in EtOH (15 mL) was added AcOH (4 mL) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction completion, the mixture was diluted with H₂O (30 mL) , extracted with EA (30 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (190 mg, 66%) .

MS (ESI, pos. ion) m/z: 856.1/858.1 [M+H] ⁺, Rt=1.358/2min.

Step 4: Preparation of compound 651-5: methyl 6- (5- (3-bromo-2-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-2-fluorophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate (190 mg, 0.22 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) and stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (100 mg, 73%) .

MS (ESI, pos. ion) m/z: 616.1/618.1 [M+H] ⁺, Rt=1.108/2min.

Step 5: Preparation of compound 651-6: methyl 6- (2- (cyclopropylmethyl) -5- (2, 4’-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5- (3-bromo-2-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.16 mmol, 1.0 eq) , (4-fluorophenyl) boronic acid (45 mg, 0.32 mmol, 2.0 eq) , K₂CO₃ (67 mg, 0.49 mmol, 3.0 eq) in a mixure solvent of dioxane (10 mL) in H₂O (2 mL) was added Pd (dppf) Cl₂ (12 mg, 0.02 mmol, 0.1 eq) . The mixture was stirred at 80 ℃ for 2 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product as a yellow solid (190 mg) .

MS (ESI, pos. ion) m/z: 632.2 [M+1] ⁺, Rt=1.158/2min.

Step 6: Preparation of compound 651: 6- (2- (cyclopropylmethyl) -5- (2, 4’-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -5- (2, 4’-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (190 mg, 0.30 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) in THF (2 mL) was added a mixed solution of LiOH (35 mg, 1.20 mmol, 4.0 eq) in H₂O (1 mL) . The mixture was stirred at RT for 16 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, washed with H₂O (5 mL) , extracted with EA (5 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (59 mg, 31%) .

MS (ESI, pos. ion) m/z: 618.2 [M+1] ⁺, Rt=1.025/2min.

¹HNMR (400 MHz, DMSO-d₆ ) δ δ 12.93 (br s, 1H) , 7.95 –7.88 (m, 1H) , 7.85 (dd, J = 8.1, 1.2 Hz, 1H) , 7.78 (dd, J = 0.9, 7.4 Hz, 1H) , 7.66 (t, J = 7.9 Hz, 1H) , 7.61 –7.54 (m, 4H) , 7.48 (dt, J = 1.8, 7.5 Hz, 1H) , 7.37 (dt, J = 1.7, 7.2 Hz, 1H) , 7.34 –7.26 (m, 3H) , 6.88 (s, 1H) , 6.82 (d, J = 11.1 Hz, 1H) , 6.77 (d, J = 8.1 Hz, 1H) , 5.31 (s, 2H) , 3.25 (br d, J = 6.6 Hz, 2H) , 0.99-0.89 (m, 1H) , 0.31 –0.20 (m, 4H) .

Example 20: Synthesis of compound 652

Step 1: Preparation of compound 652-2: methyl 6- (5- (4’-carbamoyl- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (80 mg, 0.13 mmol, 1.0 eq) and (4-carbamoylphenyl) boronic acid (29 mg, 0.17 mmol, 1.3 eq) in a mixture solvent of dioxane (4 mL) in H₂O (1 mL) was added Pd (dppf) Cl₂ (8 mg, 0.01 mmol, 0.1 eq) and K₂CO₃ (37 mg, 0.27 mmol, 2.0 eq) . The reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 70%EtOAc in petroleum ether) to afford the title product as a yellow solid (60 mg, 0.09 mmol, 70.28 %) .

MS (ESI, neg. ion) m/z: 637.3 [M-1] ^-, Rt=0.917/2min.

Step 2: Preparation of compound 652: 6- (5- (4’-carbamoyl- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (5- (4’-carbamoyl- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (60 mg, 0.09 mmol, 1.0 eq) , THF (1 mL) and MeOH (3 mL) . A solution of LiOH (15 mg, 0.37 mmol, 4.0 eq) in H₂O (1 mL) was added, and the mixture was stirred at 25 ℃ for 18 hours. The mixture was acidified with 1 N aqueous HCl solution until the pH～6 at 0 ℃ and extracted with EA (20 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 70%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (31.65 mg, 0.05 mmol, 53.9%) .

MS (ESI, pos. ion) m/z: 625.2 [M+1] ⁺, Rt=0.833/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.92 (br s, 1H) , 7.99 (br s, 1H) , 7.96 –7.89 (m, 4H) , 7.78 (dd, J = 2.6, 6.0 Hz, 1H) , 7.75 –7.69 (m, 4H) , 7.67 (dt, J = 7.7, 1.4 Hz, 1H) , 7.61 (s, 2H) , 7.49 (t, J = 7.8 Hz, 1H) , 7.44 –7.36 (m, 2H) , 6.99 (s, 1H) , 6.95 (dd, J = 11.1, 1.6 Hz, 1H) , 6.85 (d, J = 9.0 Hz, 1H) , 5.47 (s, 2H) , 3.23 (br d, J = 6.4 Hz, 2H) , 1.00 –0.91 (m, 1H) , 0.33 –0.21 (m, 4H) .

Example 21: Synthesis of compound 653

Preparation of compound 653-2: 2-bromo-4- (trifluoromethyl) oxazole

To a stirred solution of t-BuONO (3661 mg, 35.51 mmol, 2.5 eq) and cupric dibromide (3525 mg, 15.78 mmol, 1.2 eq) in acetonitrile (20 mL) was added 4- (trifluoromethyl) -1, 3-oxazol-2-amine (2000 mg, 13.15 mmol, 1.0 eq) portion wise at 0 ℃. After stirred at room temperature overnight, the reaction mixture was poured into 10%aq HCl (15 mL) and extracted with DCM (30 mL × 3) , the organic layer washed with brine, dried over Na₂SO₄, and carefully evaporated in vacuo (bath temperature should not exceed 23 ℃) . The crude product concentrated in 2 mL of DCM was used directly without purification.

Preparation of compound 653: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid

Step 1: Preparation of compound 653-1: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate

A mixture of methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.20 mmol, 1.0 eq) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (102 mg, 0.40 mmol, 2.0 eq) , Pd (dppf) Cl₂ (15 mg, 0.02 mmol, 0.1 eq) and potassium acetate (59 mg, 0.60 mmol, 3.0 eq) in 1, 4-dioxane (2 mL) was degassed and purged with N₂, then the mixture was stirred at 80 ℃ overnight and used directly in next step.

MS (ESI, pos. ion) m/z: 645.9 [M+1] ⁺, Rt=1.158/2 min.

Step 2: Preparation of compound 653-3: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate

To the reaction mixture of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate (129.1 mg, 0.20 mmol, 1.0 eq) in 2 ml of 1, 4-dioxane, Pd (dppf) Cl₂ (15 mg, 0.02 mmol, 0.1 eq) , potassium carbonate (83 mg, 0.60 mmol, 3.0 eq) , 2-bromo-4- (trifluoromethyl) oxazole (0.15 mL) and water (0.5 mL) added, the resulting mixture was degassed and purged with N₂, the resulting mixture was stirred at 80 ℃ for 3 hrs. The reaction mixture was poured onto water (3 mL) and extracted with EtOAc (5 mL × 3) , the combined organic layer was dried over Na₂SO₄. After removal of the solvent, the crude product was purified by Prep-TLC (PE/EA = 2: 1) to afford the desired product as an orange oil (110 mg, 0.17 mmol, 84 %) .

MS (ESI, pos. ion) m/z: 655.0 [M+1] ⁺, Rt=1.117/2 min.

Step 3: Preparation of compound 653: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid

To a stirred solution of ethyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate (110 mg, 0.17 mmol, 1.0 eq) in a mixture solvent of methanol (1 mL) and water (1 mL) in tetrahydrofuran (1 mL) was added lithium hydroxide (16 mg, 0.67 mmol, 4.0 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 hrs. After removal of the solvents and volatiles, the residue was acidified with HCl (1 N) aqueous solution (pH was about 4 to 5) , then extracted with EtOAc (5 mL × 3) , the combined organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the desired product as a yellow solid (19 mg, 0.03 mmol, 17%) .

MS (ESI, pos. ion) m/z: 641.0 [M+1] ⁺, Rt=1.107/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.92 (br s, 1H) , 8.99 (d, J = 1.6 Hz, 1H) , 7.97 –7.88 (m, 4H) , 7.82 –7.76 (m, 1H) , 7.71 (t, J = 7.8 Hz, 1H) , 7.65 –7.55 (m, 4H) , 7.02 (s, 1H) , 6.91 (d, J = 11.0 Hz, 1H) , 6.80 (d, J = 8.6 Hz, 1H) , 5.46 (s, 2H) , 3.25 (br d, J = 6.6 Hz, 2H) , 1.03 –0.93 (m, 1H) , 0.33 –0.21 (m, 4H) .

Example 22: Synthesis of compound 654

Step 1: Preparation of compound 654-2: 4-cyano-2-methylbenzenesulfonyl chloride

Bottle A: To the suspension of 4-amino-3-methylbenzene-1-carbonitrile (5.00 g, 37.83 mmol, 1.0 eq) in 12 N HCl (10 mL) was added a sodium nitrite (2.87 g, 41.61 mmol, 1.1 eq) in H₂O (10 mL) portion wise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour.

Bottle B: SOCl₂ (10 mL) was added to the H₂O (20 mL) portion wise with the temperature was kept at 0 ℃. The resuting mixture was added chlorocopper (I) (1.12 g, 11.35 mmol, 0.3 eq) . The reaction mixture was stirred at RT for 1 hour.

The bottle B was added the reaction mixture in bottle A portion wise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was extracted with EA (20 mL) . The organic layer washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/50 to 1/10) to afford the title product as a white solid (3.8 g, 17.62 mmol, 46.58%) .

¹HNMR (400 MHz, DMSO-d₆) δ 7.86 (d, J = 8.0 Hz, 1H) , 7.64 –7.58 (m, 2H) , 2.56 (s, 3H) .

Step 2: Preparation of compound 654-3: 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2-methylbenzenesulfonamide

To the suspension of 4-cyano-2-methylbenzenesulfonyl chloride (3.00 g, 13.91 mmol, 1.0 eq) and bis [ (4-methoxyphenyl) methyl] amine (3.58 g, 13.91 mmol, 1.0 eq) in DCM (30 mL) was added DIEA (2.16 g, 16.69 mmol, 1.2 eq) at 0 ℃. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with DCM (30 mL) and washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by trituration with a mixture solvent of EA (5 mL) in PE (50 mL) . The solid was collected after filtering as a white solid (2.5 g, 5.73 mmol, 41.17%) .

¹HNMR (400 MHz, DMSO-d₆) δ 7.96 (s, 1H) , 7.91 –7.87 (m, 1H) , 7.85 –7.79 (m, 1H) , 7.01-6.96 (m, 4H) , 6.85 -6.80 (m, 4H) , 4.27 (s, 4H) , 3.74 –3.71 (m, 6H) , 2.54 (s, 3H) .

Step 3: Preparation of compound 654-4: 4- (aminomethyl) -N, N-bis [ (4-methoxyphenyl) methyl] -2-methylbenzenesulfonamide

To the solution of 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2-methylbenzenesulfonamide (2 g, 4.58 mmol, 1.0 eq) in MeOH (20 mL) was added NH₄OH (5 mL) and nickel (0) (0.10 g, 0.46 mmol, 0.1 eq) . The reaction mixture was stirred at RT for 18 hours under H₂. The mixture was filtered, and the filter cake washed with MeOH. The filtrate was concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/1 to 1/1) to afford the title product as a white solid (1.2 g, 2.72 mmol, 59.45%) .

MS (ESI, pos. ion) m/z: 441.0 [M+1] ⁺, Rt=0.667/2min.

Step 4: Preparation of compound 654-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-methylbenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) picolinate (500 mg, 1.05 mmol, 1.0 eq) in AcOH (5 mL) was added 4- (aminomethyl) -N, N-bis [ (4-methoxyphenyl) methyl] -2-methylbenzenesulfonamide (553 mg, 1.26 mmol, 1.2 eq) . The mixture was heated to 80 ℃ in an oil bath for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. This mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL) . The organic layer washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a solid (520 mg, 0.59 mmol, 56.29%) .

MS (ESI, pos. ion) m/z: 881.9 [M+1] ⁺, Rt=1.392/2min.

Step 5: Preparation of compound 654-6: methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-methylbenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (480 mg, 0.54 mmol, 1.0 eq) in DCM (10 mL) was added 2, 2, 2-trifluoroacetaldehyde (3 mL) . The mixture was stirred at RT for 48 h. After completion, the reaction was concentrated to afford the title product as a yellow solid (280 mg, 0.44 mmol, 80.18%) , which was used directly in the next step without further purification.

MS (ESI, pos. ion) m/z: 641.9 [M+1] ⁺, Rt=1.420/2min.

Step 6: Preparation of compound 654-7: methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (250 mg, 0.39 mmol, 1.0 eq) in DMF (8 mL) was added TEA (0.16 mL, 1.17 mmol, 3.0 eq) , Pd (PPh₃) ₂Cl₂ (27 mg, 0.04 mmol, 0.1 eq) and CuI (7 mg, 0.04 mmol, 0.1 eq) . The mixture was stirred at 40 ℃ in an oil bath for 2 hours under N₂. The reaction mixture was cooled to room temperature and diluted with water (50 mL) , and then extracted with EtOAc (2 × 20 mL) . The combined organic layer washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a solid (180 mg, 0.30 mmol, 77.79%) .

MS (ESI, pos. ion) m/z: 594.1 [M+1] ⁺, Rt=1.217/2min.

Step 7: Preparation of compound 654: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.17 mmol, 1.0 eq) , methanol (5 mL) and H₂O (1 mL) . Lithium hydroxide (21 mg, 0.51 mmol, 3.0 eq) was added, and the mixture was stirred at 25 ℃ for 16 h. The mixture was acidified with 1 M aqueous HCl solution until the pH was ～6 at 0 ℃, and the mixture was extracted with ethyl acetate (10 mL × 3) . The organic layers were combined, washed with saturated aqueous NaHCO₃ solution and brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 30%to 60% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title compound (30 mg, 0.05 mmol, 30.73%) .

MS (ESI, pos. ion) m/z: 580.0 [M+1] ⁺, Rt=1.492/2min.

¹HNMR (400 MHz, METHANOL-d₄) δ 7.99 –7.91 (m, 2H) , 7.86 (d, J = 8.3 Hz, 2H) , 7.32 (s, 1H) , 7.28 –7.22 (m, 3H) , 6.95 (s, 1H) , 6.87 –6.82 (m, 1H) , 6.75 (s, 1H) , 5.36 (s, 2H) , 3.23 (t, J = 8.3 Hz, 1H) , 3.17 –3.12 (m, 2H) , 2.59 (s, 3H) , 2.38 -2.28 (m, 2H) , 2.22 –2.11 (m, 2H) , 2.04 –1.89 (m, 2H) , 0.99 –0.90 (m, 1H) , 0.37 –0.29 (m, 2H) , 0.18-0.11 (m, 2H) .

Example 23: Synthesis of compound 655

Step 1: Preparation of compound 655-2: 4-cyano-2- [ (trifluoromethyl) oxy] benzene sulfonyl chloride

Bottle A: To the suspension of 4-amino-3- [ (trifluoromethyl) oxy] benzene-1-carbonitrile (2.00 g, 9.89 mmol, 1.0 eq) in 12N HCl (20 mL) was added a sodium nitrite (1.10 g, 15.94 mmol, 1.50 eq) in H₂O (20 mL) portion wise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour.

Bottle B: SOCl₂ (10 mL) was added to the H₂O (20 mL) portion wise with the temperature was kept at 0 ℃. The resuting mixture was added chlorocopper (I) (0.43 g, 4.34 mmol, 0.4 eq) and stirred at RT for 1 hour. Bottle B was added the reaction mixture in bottle A portion wise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was extracted with EA (20 mL) . The organic layer washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/50 to 1/10) to afford the title product as an oil (2.4 g, 8.40 mmol, 84.93%) .

Step 2: Preparation of compound 655-3: 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2- [ (trifluoromethyl) oxy] benzenesulfonamide

To the suspension of 4-cyano-2- [ (trifluoromethyl) oxy] benzene sulfonyl chloride (1.9 g, 6.65 mmol, 1.0 eq) and bis [ (4-methoxyphenyl) methyl] amine (1.88 g, 7.32 mmol, 1. q eq) in DCM (17 mL) was added DIEA (1.03 g, 7.98 mmol, 1.2 eq) at 0 ℃. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with DCM (15 mL) . The organic layer washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by trituration with a mixture solvent of EA (5 mL) in PE (50 mL) . The white solid was collected after filtering (1.89 g, 3.73 mmol, 56.09%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.15 (s, 1H) , 7.96 (s, 2H) , 7.02 (d, J = 8.6 Hz, 4H) , 6.83 –6.77 (m, 5H) , 4.34 (s, 4H) , 3.72 (s, 6H) .

Step 3: Preparation of compound 655-4: 4-cyano-2- [ (trifluoromethyl) oxy] benzene-1-sulfonamide

To the solution of 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2- [ (trifluoromethyl) oxy] benzenesulfonamide (1.8 g, 3.55 mmol, 1.0 eq) in MeOH (20 mL) was added NH₄OH (5 mL) and nickel (0) (0.18 g, 0.52 mmol, 0.1 eq) . The reaction mixture was stirred at RT for 18 hours under H₂. The mixture was filtered, and the filter cake washed with MeOH. The filtrate was concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/1 to 1/0) to afford the title product as a solid (1.8 g, 3.64 mmol, 71.41%) .

MS (ESI, pos. ion) m/z: 511.2 [M+1] ⁺, Rt=0.669/2min.

Step 4: Preparation of compound 655-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- (trifluoromethoxy) benzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) picolinate (300 mg, 0.63 mmol, 1.0 eq) and 4- (aminomethyl) -N, N-bis (4-methoxybenzyl) -2- (trifluoromethoxy) benzenesulfonamide (417 mg, 0.81 mmol, 1.3 eq) in EtOH (4 mL) was added AcOH (16 mL) . The mixture was stirred at 100 ℃for 18 hours. After the reaction completion, the mixture was diluted with H₂O (30 mL) , extracted with EA (30 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (304 mg, 0.32 mmol, 50.8%) .

MS (ESI, pos. ion) m/z: 952.0 [M+1] ⁺, Rt=1.375/2min.

Step 5: Preparation of compound 655-6: methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- (trifluoromethoxy) benzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (304 mg, 0.32 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The resulting was stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (170 mg, 0.24 mmol, 74.8%) .

MS (ESI, pos. ion) m/z: 712.0 [M+1] ⁺, Rt=1.158/2min.

Step 6: Preparation of compound 655-7: methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinate (110 mg, 0.15 mmol, 1.0 eq) , CuI (7 mg, 0.03 mmol, 0.2 eq) , Pd (PPh₃) ₂Cl₂ (22 mg, 0.03 mmol, 0.2 eq) and TEA (47 mg, 0.46 mmol, 3.0 eq) in DMF (5 mL) was added ethynylcyclobutane (38 mg, 0.46 mmol, 3.0 eq) under N₂ atmosphere. The resulting was stirred at 40 ℃ for 18 hours under N₂. After the reaction completion, the mixture washed with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (97 mg, 0.14 mmol, 94.5%) .

MS (ESI, pos. ion) m/z: 664.5 [M+1] ⁺, Rt=1.233/2min.

Step 7: Preparation of compound 655: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinate (97 mg, 0.14 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) in THF (2 mL) was added a solution of LiOH (23 mg, 0.58 mmol, 4.0 eq) in H₂O (1 mL) . The resulting was stirred at RT for 16 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, washed with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (51.8 mg, 0.08 mmol, 54.5%) .

MS (ESI, pos. ion) m/z: 650.2 [M+1] ⁺ , Rt=1.127/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.93 (br s, 1H) , 7.93 –7.86 (m, 2H) , 7.82 (d, J = 8.2 Hz, 1H) , 7.78 (dd, J = 1.8, 6.8 Hz, 1H) , 7.56 (s, 2H) , 7.38 –7.26 (m, 4H) , 7.00 (d, J = 8.4 Hz, 1H) , 6.92 (s, 2H) , 5.46 (s, 2H) , 3.30 –3.20 (m, 3H) , 2.35 –2.24 (m, 2H) , 2.16 –2.04 (m, 2H) , 2.00 –1.81 (m, 2H) , 0.97 –0.88 (m, 1H) , 0.31 –0.18 (m, 4H) .

Example 24: Synthesis of compound 656

Step 1: Preparation of compound 656-2: 4-cyano-2-methylbenzenesulfonyl chloride

Bottle A: To the suspension of 4-amino-3- (trifluoromethyl) benzene-1-carbonitrile (2.00 g, 10.74 mmol, 1.0 eq) in 12 N HCl (20 mL) was added a sodium nitrite (1.10 g, 15.94 mmol, 1.50 eq) in H₂O (20 mL) portion wise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour.

Bottle B: SOCl₂ (10 mL) was added to the H₂O (20 mL) portion wise with the temperature was kept at 0 ℃. The resuting mixture was added chlorocopper (I) (0.43 g, 4.34 mmol, 0.4 eq) . The reaction mixture was stirred at RT for 1 hour.

The bottle B was added the reaction mixture in bottle A portion wise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was extracted with EA (20 mL) . The organic layer washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/50 to 1/10) to afford the title product as a solid (1.7 g, 58.68%) .

¹HNMR (400 MHz, DMSO-d₆) δ 8.25 –8.18 (m, 2H) , 8.10 (dd, J = 1.5, 8.1 Hz, 1H) .

Step 2: Preparation of compound 656-3: 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2- (trifluoromethyl) benzenesulfonamide

To the suspension of 4-cyano-2- (trifluoromethyl) benzenesulfonyl chloride (1.70 g, 6.31 mmol, 1.0 eq) and bis[ (4-methoxyphenyl) methyl] amine (1.62 g, 6.31 mmol, 1.0 eq) in DCM (17 mL) was added DIEA (0.98 g, 7.57 mmol, 1.2 eq) at 0 ℃. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with DCM (15 mL) , washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was trituration with a mixture solvent of EA (5 mL) in PE (50 mL) . The solid was collected after filtering as a white solid (2.5 g, 5.10 mmol, 80.84%) .

¹H NMR (400 MHz, DMSO-d₆₎ δ 8.55 (d, J = 1.1 Hz, 1H) , 8.23 (dd, J = 1.6, 8.2 Hz, 1H) , 7.98 (d, J = 8.3 Hz, 1H) , 7.05-7.00 (m, 4H) , 6.85 –6.79 (m, 4H) , 4.38 (s, 4H) , 3.72 (s, 6H) .

Step 3: Preparation of compound 656-4: 4- (aminomethyl) -N, N-bis [ (4-methoxyphenyl) methyl] -2- (trifluoromethyl) benzenesulfonamide

To the solution of 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2- (trifluoromethyl) benzenesulfonamide (2.5 g, 5.10 mmol, 1.0 eq) in MeOH (20 mL) was added NH₄OH (5 mL) and nickel (0) (0.11 g, 0.51 mmol, 0.1 eq) . The reaction mixture was stirred at RT for 18 hours under H₂. The mixture was filtered and the filter cake washed with MeOH. The filtrate was concentrated and purified by column chromatography through silica gel (eluting with EA/PE=0/1 to 1/1) to afford the title product as a solid (1.8 g, 3.64 mmol, 71.41%) .

MS (ESI, pos. ion) m/z: 495.2 [M+1] ⁺, Rt=0.675/2min.

Step 4: Preparation of compound 656-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- (trifluoromethyl) benzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) picolinate (0.41 g, 0.87 mmol, 1.0 eq) in AcOH (8 mL) was added 4- (aminomethyl) -N, N-bis [ (4-methoxyphenyl) methyl] -2- (trifluoromethyl) benzenesulfonamide (0.51 g, 1.04 mmol, 1.2 eq) . The mixture was stirred at 80 ℃ in an oil bath for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. This mixture was diluted with water (20 mL) , and then extracted with EtOAc (2 × 10 mL) . The organic layer washed with brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=0/1 to 1/3) to afford the title product as a solid (0.4 g, 0.43 mmol, 49.28%) .

MS (ESI, pos. ion) m/z: 936.1 [M+1] ⁺, Rt=1.317/2min.

Step 5: Preparation of compound 656-6: methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- (trifluoromethyl) benzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (200 mg, 0.21 mmol, 1.0 eq) in DCM (10 mL) was added 2, 2, 2-trifluoroacetaldehyde (3 mL) . The mixture was stirred at RT for 48 h. After completion, the reaction was concentrated to afford the title product as a yellow solid (132 mg, 88.05%) , which was used directly in the next step without further purification.

MS (ESI, pos. ion) m/z: 696.1 [M+1] ⁺, Rt=1.150/2min.

Step 6: Preparation of compound 656-7: methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.17 mmol, 1.0 eq) in DMF (8 mL) was added TEA (0.6 mL, 0.51 mmol, 3.0 eq) , Pd (PPh₃) ₂Cl₂ (14 mg, 0.02 mmol, 0.1 eq) and CuI (4 mg, 0.02 mmol, 0.1 eq) . The mixture was stirred at 40 ℃ in an oil bath for 2 hours under N₂. This mixture was diluted with water (50 mL) , and then extracted with EtOAc (2 × 20 mL) . The combined organic layer washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a solid (75 mg, 0.12 mmol, 67.11%) .

MS (ESI, pos. ion) m/z: 648.3 [M+1] ⁺, Rt=1.233/2min.

Step 7: Preparation of compound 656: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinatein (65 mg, 0.10 mmol, 1.0 eq) , methanol (5 mL) and H₂O (1 mL) . Lithium hydroxide (7 mg, 0.30 mmol, 3.0 eq) was added, and the mixture was stirred at 25 ℃ for 16 h. The mixture was acidified with 1 M aqueous HCl solution until the pH was ～6 at 0 ℃, and the mixture was extracted with ethyl acetate (10 mL × 3) . The organic layers were combined, washed with saturated aqueous NaHCO₃ solution and brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford to afford the title compound (30 mg, 0.05 mmol, 50%) .

MS (ESI, pos. ion) m/z: 634.2 [M+1] ⁺, Rt=1.162/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.89 (br s, 1H) , 8.04 (d, J = 8.3 Hz, 1H) , 7.93 –7.86 (m, 2H) , 7.77 (dd, J = 1.9, 6.6 Hz, 1H) , 7.64 (s, 2H) , 7.46 (d, J = 1.8 Hz, 1H) , 7.37 –7.26 (m, 4H) , 7.19 (d, J = 8.3 Hz, 1H) , 6.93 (s, 1H) , 5.50 (s, 2H) , 3.28 -3.22 (m, 3H) , 2.31 –2.24 (m, 2H) , 2.15 –2.04 (m, 2H) , 2.00 –1.83 (m, 2H) , 0.95 –0.84 (m, 1H) , 0.30 –0.17 (m, 4H) .

Example 25: Synthesis of compound 657

Step 1: Preparation of compound 657-1: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (2’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (80 mg, 0.12 mmol, 1.0 eq) , (2-fluorophenyl) boronic acid (37 mg, 0.25 mmol, 2.0 eq) , K₂CO₃ (51 mg, 0.37 mmol, 3.0 eq) in a mixture solvent of H₂O (1 mL) in dioxane (4 mL) was added Pd (dppf) Cl₂ (9 mg, 0.01 mmol, 0.1 eq) . The mixture was stirred at 80 ℃ for 2 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product as a yellow solid (128 mg, 99%) .

MS (ESI, neg. ion) m/z: 612.2 [M-1] ⁺ , Rt=1.167/2min

Step 2: Preparation of compound 657 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (2’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (2’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate (128 mg, 0.21 mmol, 0.1 eq) in a mixture solution of MeOH (1 mL) in THF (2 mL) was added a solution LiOH (35 mg, 0.83 mmol, 4.0 eq) in H₂O (1 mL) . The mixture was stirred at RT for 18 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, washed with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (31 mg, 25%) .

MS (ESI, pos. ion) m/z: 600.2 [M+1] ⁺, Rt=1.025/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.93 (br s, 1H) , 7.94 –7.86 (m, 2H) , 7.78 (dd, J = 1.9, 6.6 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.60 (s, 2H) , 7.52 (s, 1H) , 7.50 –7.38 (m, 5H) , 7.33 –7.26 (m, 2H) , 6.96 –6.90 (m, 2H) , 6.83 (d, J = 8.1 Hz, 1H) , 5.46 (s, 2H) , 3.22 (br d, J = 6.4 Hz, 2H) , 1.00 –0.91 (m, 1H) , 0.32 –0.20 (m, 4H) .

Example 26: Synthesis of compound 658

Step 1: Preparation of compound 658-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (93thenone-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (80 mg, 0.12 mmol, 1.0 eq) and 2- (tributylstannyl) pyridine (0.05 mL, 0.16 mmol, 1.3 eq) in dioxane (2 mL) was added palladium (0) tetrakis (93thenone93phosphine) (4 mg, 0.03 mmol, 0.2 e) . The reaction was stirred at 100 ℃ for 18 hours. This mixture was quenched with saturated aqueous solution of potassium fluoride (10 mL) and extracted with EtOAc (10 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (30 mg, 40.57%) .

MS (ESI, pos. ion) m/z: 597.3 [M+1] ⁺, Rt=1.000/2min.

Step 2: Preparation of compound 658: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (93thenone-2-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (93 thenone-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate (30 mg, 0.05 mmol, 1.0 eq) in a mixture solvent of THF (1 mL) in MeOH (1 mL) was added a solution of hydroxy lithium hydrate (6 mg, 0.15 mmol, 3.0 eq ) in H₂O (0.3 mL) . The reaction mixture was concentrated under vacuum. The reaction mixture was adjusted to pH=6 with 2N HCl solution. The reaction mixture was extracted with EA (10 mL × 3) . The organic layer washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (16 mg, 56.47%) .

MS (ESI, pos. ion) m/z: 583.2 [M+1] ⁺ , Rt=0.808/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.89 (br s, 1H) , 8.66-8.61 (m, 1H) , 8.05-7.99 (m, 2H) , 7.94-7.76 (m, 5H) , 7.73 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.51 (t, J = 7.6 Hz, 1H) , 7.45 (dt, J = 7.7, 1.5 Hz, 1H) , 7.35 (ddd, J = 1.8, 4.9, 6.7 Hz, 1H) , 6.98-6.92 (m, 2H) , 6.85 (d, J = 8.1 Hz, 1H) , 5.46 (s, 2H) , 3.24 (br d, J = 6.5 Hz, 2H) , 1.03-0.92 (m, 1H) , 0.33-0.21 (m, 4H) .

Example 27: Synthesis of compound 659

Step 1: Preparation of compound 659-1: methyl 6- (5- (3- (cyclobutylethynyl) -4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of methyl 6- (5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (190 mg, 0.31 mmol, 1.0 eq) and ethynylcyclobutane (74 mg, 0.92 mmol, 3.0 eq) in dioxane (3 mL) was added CuI (12 mg, 0.06 mmol, 0.2 eq) , DABCO (104 mg, 0.92 mmol, 3.0 eq) and Pd-162 (12 mg, 0.03 mmol, 0.1) . The reaction was stirred at room temperature for 18 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a grey solid (150 mg, 79.05%) .

MS (ESI, pos. ion) m/z: 616.3 [M+1] ⁺, Rt=1.208/2min.

Step 2: Preparation of compound 659: 6- (5- (3- (cyclobutylethynyl) -4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (5- (3- (cyclobutylethynyl) -4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (150 mg, 0.24 mmol, 1.0 eq) in a mixture solvent of THF (3 mL) in MeOH (3 mL) was added a solution of hydroxy lithium hydrate (20 mg, 0.49 mmol, 2.0 eq ) in H₂O (1 mL) . The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum. The reaction mixture was adjusted to pH=6 with 2N HCl solution. The reaction mixture was extracted with EA (10 mL × 3) . The organic layer washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (87.19 mg, 58.13%) .

MS (ESI, pos. ion) m/z: 602.2 [M+1] ⁺ , Rt=1.092/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.91 (br s, 1H) , 7.94-7.85 (m, 2H) , 7.77 (dd, J=1.4, 7.1 Hz, 1H) , 7.70 (t, J=7.8 Hz, 1H) , 7.60 (s, 2H) , 7.44 (dd, J=2.2, 6.9 Hz, 1H) , 7.38-7.32 (m, 1H) , 7.26 (t, J = 9.0 Hz, 1H) , 6.92 –6.85 (m, 2H) , 6.77 (d, J=7.9 Hz, 1H) , 5.38 (s, 2H) , 3.30-3.25 (m, 1H) , 3.21 (br d, J=6.5 Hz, 2H) , 2.36-2.26 (m, 2H) , 2.18-2.07 (m, 2H) , 2.01-1.81 (m, 2H) , 0.98-0.89 (m, 1H) , 0.31-0.19 (m, 4H) .

Example 28: Synthesis of compound 660

Step 1: Preparation of compound 660-2: methyl 6- (5- (4’-chloro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (110 mg, 0.17 mmol, 1.0 eq) and (4-chlorophenyl) boronic acid (35 mg, 0.22 mmol, 1.3 eq) in a mixture solvent of dioxane (4 mL) in H₂O (1 mL) was added Pd (dppf) Cl₂ (13 mg, 0.02 mmol, 0.1 eq) and K₂CO₃ (47 mg, 0.34 mmol, 2.0 eq) . The reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether, to afford the title product as a yellow solid (102 mg, 0.16 mmol, 94.99 %) .

MS (ESI, pos. ion) m/z: 630.2 [M+1] ⁺, Rt=1.217/2min.

Step 2: Preparation of compound 660: 6- (5- (4’-chloro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (5- (4’-chloro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (102 mg, 0.16 mmol, 1.0 eq) , THF (1 mL) and MeOH (3 mL) . A solution of LiOH (27 mg, 0.65 mmol, 4.0 eq) in H₂O (1 mL) was added, and the mixture was stirred at 25 ℃ for 18 hours. The mixture was acidified with 1 N aqueous HCl solution until the pH～6 at 0 ℃ and extracted with EA (20 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 70%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (60.00 mg, 0.10 mmol, 60.16%) .

MS (ESI, pos. ion) m/z: 616.2 [M+1] ⁺, Rt=1.083/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.95 (br s, 1H) , 7.95 –7.87 (m, 2H) , 7.78 (dd, J = 6.6, 2.0 Hz, 1H) , 7.74 (t, J = 7.9 Hz, 1H) , 7.65 –7.56 (m, 6H) , 7.52 –7.45 (m, 3H) , 7.39 (d, J = 7.8 Hz, 1H) , 7.00 –6.95 (m, 2H) , 6.86 (d, J = 8.6 Hz, 1H) , 5.46 (s, 2H) , 3.24 (br d, J = 6.6 Hz, 2H) , 1.01 –0.90 (m, 1H) , 0.33 –0.22 (m, 4H) .

Example 29: Synthesis of compound 661

Step 1: Preparation of compound 661-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (1-methyl-1H-imidazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinate

A mixture of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.15 mmol, 1.0 eq) , 1-methyl-4- (tributylstannyl) -1H-imidazole (69 mg, 0.18 mmol, 1.2 eq) , Pd (Ph₃P) ₄ (18 mg, 0.01 mmol, 0.1 eq) in 1, 4-dioxane (2.5 mL) was degassed and purged with N₂, then the mixture was stirred at 90 ℃ overnight. The reaction mixture was quenched with a saturated solution of KF (2 mL) , the resulting mixture was stirred for 1 h, then extracted with EtOAc (5 mL × 3) , the combined organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification of the crude product by prep-TLC (EA/PE=1: 1) afforded the desired product as an orange solid (75 mg, 0.12 mmol, 80%) .

MS (ESI, pos. ion) m/z: 600.2 [M+1] ⁺, Rt=0.708/2 min.

Step 2: Preparation of compound 661: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (1-methyl-1H-imidazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid

To a stirred solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (1-methyl-1H-imidazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinate (75 mg, 0.12 mmol) in a mixture solvent of MeOH (1 mL) and H₂O (1 mL) was added lithium hydroxide (24 mg, 0.50 mmol, 4.0 eq) at room temperature. The resulting mixture was stirred for 1 h. After removal of the solvent under reduced pressure, the residue was acidified with HCl (1 N) aqueous solution (pH was about 4 to 5) , then extracted with EtOAc (5 mL × 3) , the combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification of the crude product by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afforded a yellow solid (59 mg, 0.10 mmol, 80%) .

MS (ESI, pos. ion) m/z: 586.2 [M+1] ⁺, Rt=0.575/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.84 (br s, 1H) , 7.94 –7.87 (m, 2H) , 7.78 (dd, J = 2.4, 6.0 Hz, 1H) , 7.74 –7.68 (m, 2H) , 7.67 (d, J = 7.8 Hz, 1H) , 7.62 (s, 1H) , 7.60 (s, 2H) , 7.48 (s, 1H) , 7.34 (t, J = 7.6 Hz, 1H) , 7.17 (d, J = 7.6 Hz, 1H) , 6.92 –6.87 (m, 2H) , 6.82 (d, J = 8.2 Hz, 1H) , 5.43 (s, 2H) , 3.67 (s, 3H) , 3.22 (br d, J = 6.4 Hz, 2H) , 1.01 –0.91 (m, 1H) , 0.32 –0.21 (m, 4H) .

Example 30: Synthesis of compound 662

Step 1: Preparation of compound 662-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (thiazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinate

A mixture of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.15 mmol, 1.0 eq) , 4- (tributylstannyl) thiazole (70 mg, 0.18 mmol, 1.2 eq) , Pd (Ph₃P) ₄ (18 mg, 0.01 mmol, 0.1 eq) in 1, 4-dioxane (2.5 mL) was degassed and purged with N₂, then the mixture was stirred at 90 ℃ overnight. The reaction mixture was quenched with a saturated solution of KF (2 mL) , the resulting mixture was stirred for 1 h, then extracted with EtOAc (5 mL × 3) , the combined organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification of the crude product by prep-TLC (EA/PE=1: 1) afforded the desired product as an orange soild (49 mg, 0.08 mmol, 55%) .

MS (ESI, pos. ion) m/z: 603.2 [M+1] ⁺, Rt=1.380/2 min.

Step 2: Preparation of compound 662: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (thiazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid

To a stirred solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (thiazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinate (49 mg, 0.08 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) and H₂O (1 mL) was added lithium hydroxide (8 mg, 0.32 mmol, 4.0 eq) at room temperature. The resulting mixture was stirred for 1 h. After removal of the solvent under reduced pressure, the residue was acidified with HCl (1 N) aqueous solution (pH was about 4 to 5) , then extracted with EtOAc (5 mL × 3) , the combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification of the crude product by Prep-HPLC afforded a yellow solid (38 mg, 0.06 mmol, 79%) .

MS (ESI, pos. ion) m/z: 589.2 [M+1] ⁺, Rt=0.892/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.88 (br s, 1H) , 9.18 (d, J = 2.0 Hz, 1H) , 8.17 (d, J = 2.0 Hz, 1H) , 8.02 (s, 1H) , 7.96 –7.87 (m, 3H) , 7.81 –7.75 (m, 1H) , 7.70 (t, J = 8.0 Hz, 1H) , 7.59 (s, 2H) , 7.46 (t, J = 7.8 Hz, 1H) , 7.34 (d, J = 7.8 Hz, 1H) , 6.94 (s, 1H) , 6.90 (d, J = 11.2 Hz, 1H) , 6.82 (d, J = 8.2 Hz, 1H) , 5.45 (s, 2H) , 3.24 (br d, J = 6.8 Hz, 2H) , 1.02 –0.91 (m, 1H) , 0.34 –0.21 (m, 4H) .

Example 31: Synthesis of compound 663

Step 1: Preparation of compound 663-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 2- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (100 mg, 0.17 mmol, 1.0 eq) , (3-fluorophenyl) boronic acid (47 mg, 0.34 mmol, 2.0 eq) , K₂CO₃ (70 mg, 0.51 mmol, 3.0 eq) in a mixture solvent of H₂O (1 mL) in dioxane (4 mL) was added Pd (dppf) Cl₂ (12 mg, 0.02 mmol, 0.1 eq) . The mixture was stirred at 80 ℃ for 2 hours under N₂. The reaction mixture was diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product as a yellow solid (170 mg) .

MS (ESI, pos. ion) m/z: 615.2 [M+1] ⁺, Rt= 1.175/2min.

Step 2: Preparation of compound 663: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

To the solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (170 mg, 0.28 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) in THF (2 mL) was added a solution of LiOH (46 mg, 1.11 mmol, 4.0 eq) in H₂O (1 mL) . The mixture was stirred at RT for 18 hours. The mixture was adjusted to pH=5～6 with 1M HCl, extracted with EA (10 mL × 3) . The combined organic phase washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (57 mg, 34%) .

MS (ESI, pos. ion) m/z: 601.2 [M+1] ⁺, Rt=1.050/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.60 (br s, 1H) , 8.97 (d, J = 4.9 Hz, 1H) , 7.72 (t, J = 7.9 Hz, 1H) , 7.67 –7.63 (m, 3H) , 7.61 (s, 2H) , 7.53 (dt, J = 10.5, 2.2 Hz, 1H) , 7.51 –7.44 (m, 2H) , 7.42 –7.36 (m, 2H) , 7.19 (td, J = 8.4, 2.6 Hz, 1H) , 7.11 (s, 1H) , 6.95 (d, J = 11.0 Hz, 1H) , 6.83 (d, J = 9.0 Hz, 1H) , 5.48 (s, 2H) , 3.24 (br d, J = 6.5 Hz, 2H) , 1.04 –0.95 (m, 1H) , 0.34 –0.26 (m, 4H) .

Example 32: Synthesis of compound 664

Step 1: Preparation of compound 664-2: methyl (E) -6- (3- (4-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate

To the solution of methyl 6-formylpicolinate (500 mg, 3.03 mmol, 1.0 eq) and 1- (4-bromophenyl) ethan-1-one (903 mg, 4.54 mmol , 1.5 eq) in toluene (20 mL) was added 4-methylbenzene-1-sulfonamide (259 mg, 1.51 mmol , 0.5 eq) . The reaction mixture was stirred at 140℃ for 18 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether, to afford the title product as a white solid (470 mg, 1.36 mmol, 45%) .

MS (ESI, pos. ion) m/z: 346.0/348.0 [M+1] ⁺, Rt=0.969/2min.

Step 2: Preparation of compound 664-3: methyl 6- (1- (4-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (4-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate (470 mg, 1.36 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (458 mg, 1.70 mmol, 1.2 eq) , TEA (1236 mg, 12.22 mmol, 9.0 eq) in a mixture solvent of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (571 mg, 6.79 mmol, 5.0 eq) . The resulting was stirred at 100 ℃ for 18 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (435 mg, 1.01 mol, 74%) .

MS (ESI, pos. ion) m/z: 430.1/432.1 [M+1] ⁺, Rt=1.019/2min.

Step 3: Preparation of compound 664-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (4-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (435 mg, 1.01 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (584 mg, 1.3 mmol, 1.3 eq) in EtOH (4 mL) was added AcOH (16 mL) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction completion, the mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (550 mg, 0.66 mol, 65%) .

MS (ESI, pos. ion) m/z: 838.1/840.1 [M+1] ⁺, Rt=1.298/2min.

Step 4: Preparation of compound 664-5: methyl 6- (5- (4-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (4-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate (550 mg, 0.66 mmol, 1.0 eq) in DCM (9 mL) was added TFA (3 mL) . The resulting was stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (364 mg, 0.61 mol, 92%) .

MS (ESI, pos. ion) m/z: 598.1/600.1 [M+1] ⁺, Rt=1.094/2min.

Step 5: Preparation of compound 664-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro- [1, 1’-biphenyl] -4-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5- (4-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.17 mmol, 1.0 eq) , (4-fluorophenyl) boronic acid (30 mg, 0.22 mmol, 1.3 eq) , K₂CO₃ (46 mg, 0.33 mmol, 2.0 eq) in a mixture solvent of dioxane (10 mL) in H₂O (3 mL) was added Pd (dppf) Cl₂ (12 mg, 0.02 mmol, 0.1 eq) . The mixture was stirred at 80 ℃ for 2 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (80 mg, 0.13 mol, 78%) .

MS (ESI, pos. ion) m/z: 614.3 [M+1] ⁺, Rt=1.12/2min.

Step 6: Preparation of compound 664: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro- [1, 1’-biphenyl] -4-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro- [1, 1’-biphenyl] -4-yl) -1H-pyrrol-3-yl) picolinate (80 mg, 0.13 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (22 mg, 0.52 mmol, 4.0 eq) in H₂O (2 mL) . The resulting was stirred at RT for 18 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, diluted with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (39 mg, 0.07 mol, 50%) .

MS (ESI, pos. ion) m/z: 600.2 [M+1] ⁺ , Rt=1.016/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.95 (br s, 1H) , 7.95 –7.87 (m, 2H) , 7.79 (dd, J = 1.6, 6.8 Hz, 1H) , 7.76 –7.70 (m, 3H) , 7.68 (d, J = 8.2 Hz, 2H) , 7.62 (s, 2H) , 7.49 –7.44 (m, 2H) , 7.32 –7.25 (m, 2H) , 6.94 –6.89 (m, 2H) , 6.85 (d, J = 8.2 Hz, 1H) , 5.46 (s, 2H) , 3.21 (br d, J = 6.4 Hz, 2H) , 1.00-0.90 (m, 1H) , 0.31 –0.21 (m, 4H) .

Example 33: Synthesis of compound 666

Step 1: Preparation of compound 666-2: 1- [1- (4-fluorophenyl) pyrazol-3-yl] ethenone

To a degassed solution of 1- (1H-pyrazol-3-yl) 100thenone (3 g, 27.24 mmol, 1 eq) in dry DCM (100 mL) was added (4-fluorophenyl) boronic acid (5.72 g, 40.87 mmol, 1.5 eq) , Cu (Oac) ₂ (9.90 g, 54.49 mmol, 2 eq) and TEA (13.78 g, 136.22 mmol, 18.96 mL, 5 eq) . The mixture was stirred at 25 ℃ for 16 hours. The reaction mixture was filtered and the filtrate was diluted with H₂O 100 mL and extracted with DCM (50 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 30%EtOAc in petroleum ether as a gradient) to afford the title product as a white solid (370 mg, 6.65%) .

¹HNMR (400 MHz, DMSO-d₆) δ 8.61 (d, J = 2.5 Hz, 1H) , 8.00 –7.94 (m, 2H) , 7.46 –7.38 (m, 2H) , 6.97 (d, J = 2.6 Hz, 1H) , 2.57 (s, 3H) .

Step 2: Preparation of compound 666-3: methyl 6- [ (E) -3- [1- (4-fluorophenyl) pyrazol-3-yl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate

To a solution of 1- [1- (4-fluorophenyl) pyrazol-3-yl] 100thenone (350 mg, 1.71 mmol, 1 eq) in Tol. (20 mL) was added K₃PO₄ (1.09 g, 5.14 mmol, 3 eq) , methyl 6-formylpyridine-2-carboxylate (424.59 mg, 2.57 mmol, 1.5 eq) . The mixture was stirred at 80 ℃ for 16 hours. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (10 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (543 mg, 90.17%) .

MS (ESI, pos. ion) m/z: 352.1 [M+H] ⁺, Rt=0.964/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.71 –8.64 (m, 1H) , 8.28 –8.21 (m, 1H) , 8.15 –8.08 (m, 3H) , 8.06 –7.99 (m, 2H) , 7.89 (d, J = 15.8 Hz, 1H) , 7.50 –7.43 (m, 2H) , 7.18 –7.14 (m, 1H) , 3.94 (s, 3H) .

Step 3: Preparation of compound 666-4: methyl 6- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) pyrazol-3-yl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate

To a solution of methyl 6- [ (E) -3- [1- (4-fluorophenyl) pyrazol-3-yl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate (543 mg, 1.55 mmol, 1 eq) in dioxane (24 mL) and EtOH (6 mL) was added TEA (1.4 g, 13.91 mmol, 1.94 mL, 9 eq) , 2-cyclopropylacetaldehyde (1 g, 12.36 mmol, 8 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol chloride (521.22 mg, 1.93 mmol, 1.25 eq) and purged with N₂ for 3 times. The mixture was stirred at 100 ℃ for 16 hours. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a brown oil (440 mg, 65%) .

MS (ESI, pos. ion) m/z: 436.2 [M+H] ⁺, Rt=1.010 min/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.68 –8.57 (m, 1H) , 8.04 –7.91 (m, 4H) , 7.80 –7.69 (m, 1H) , 7.46 –7.37 (m, 2H) , 7.31 –7.25 (m, 1H) , 7.23 –7.09 (m, 1H) , 6.97 (d, J = 2.5 Hz, 1H) , 4.76 –4.71 (m, 1H) , 3.88 –3.84 (m, 3H) , 3.48 –3.38 (m, 2H) , 2.35 –2.24 (m, 2H) , 0.92 –0.78 (m, 1H) , 0.44 –0.34 (m, 2H) , 0.08 --0.17 (m, 2H) .

Step 4: Preparation of compound 666-5: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) pyrazol-3-yl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate (100 mg, 229.65 μmol, 1 eq) in AcOH (3 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (122.50 mg, 275.58 μmol, 1.2 eq) . The mixture was stirred at 80 ℃ for 16 hours. The mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a brown solid (90 mg, 46%) .

MS (ESI, pos. ion) m/z: 844.2 [M+H] +, Rt=1.239/1.5 min.

Step 5: Preparation of compound 666-6: methyl 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] pyrrol-3-yl] pyridine-2-carboxylate (90.00 mg, 106.64 μmol, 1 eq) in dry DCM (3 mL) was added TFA (490.38 mg, 4.30 mmol, 319.46 μL, 40.33 eq) . The mixture was stirred at 25 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel (eluting with 0%to 40%EtOAc in petroleum ether as a gradient) to afford the title product as a brown solid (53 mg, 82%) .

MS (ESI, pos. ion) m/z: 604.3 [M+H] +, Rt=1.076/1.5 min.

Step 6: Preparation of compound 666: 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a 40 mL round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (53 mg, 87.80 μmol, 1 eq) , THF (1 mL) and MeOH (3 mL) . A solution of LiOH (21.03 mg, 0.87 mmol, 10.0 eq) in H₂O (0.5 mL) was added and the mixture was stirred at 25 ℃ for 16 hours. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EtOAc (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by prep-HPLC (column: Boston Prime C18 150× 30mm× 5um; mobile phase: [Water (FA) -MeCN] ; gradient: 42%-72%B over 8 min) to afford the title product as a yellow solid (22 mg, 40%) .

MS (ESI, pos. ion) m/z: 590.2 [M+1] ⁺, Rt=0.981/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.45 (d, J = 2.6 Hz, 1H) , 7.97 –7.87 (m, 2H) , 7.82 –7.77 (m, 1H) , 7.74 –7.67 (m, 3H) , 7.59 (br s, 2H) , 7.34 –7.26 (m, 3H) , 7.01 –6.92 (m, 2H) , 6.85 (d, J = 2.5 Hz, 1H) , 5.94 (br s, 2H) , 3.30 (d, J = 6.5 Hz, 2H) , 0.98 –0.87 (m, 1H) , 0.33 –0.20 (m, 4H) .

Example 34: Synthesis of compound 667

Preparation of compound 667-1: 1- [1- (4-fluorophenyl) -3-piperidyl] 102thenone

Step 1: Preparation of compound 667-b: methyl 1- (4-fluorophenyl) piperidine-3-carboxylate

To a solution of methyl piperidine-3-carboxylate (10 g, 69.84 mmol, 1 eq) in dioxane (200 mL) was added 1-fluoro-4-iodo-benzene (18.61 g, 83.81 mmol, 9.67 mL, 1.2 eq) , Cs₂CO₃ (45.51 g, 139.68 mmol, 2 eq) and RuPhos Pd G3 (2.92 g, 3.49 mmol, 0.05 eq) and purged with N₂ for 3 times, and then the mixture was stirred at 80 ℃ for 16 hours under N₂ atmosphere. The reaction mixture was filtered and the filtrate was diluted with H₂O 200 mL and extracted with EtOAc (100 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 20%EtOAc in petroleum ether as a gradient) to afford the title product as a colorless oil (4.1 g, 24.74%) .

¹HNMR (400 MHz, DMSO-d₆) δ 7.08 –7.00 (m, 2H) , 6.98 –6.91 (m, 2H) , 3.69 –3.60 (m, 3H) , 3.51 (dd, J = 3.5, 12.1 Hz, 1H) , 3.33 –3.26 (m, 1H) , 2.99 –2.87 (m, 1H) , 2.82 –2.71 (m, 1H) , 2.71 –2.61 (m, 1H) , 1.94 –1.84 (m, 1H) , 1.80 –1.66 (m, 1H) , 1.66 –1.54 (m, 2H) .

Step 2: Preparation of compound 667-c: 1- (4-fluorophenyl) piperidine-3-carboxylic acid

Into a 250 mL round bottom flask equipped with a magnetic stir bar was added methyl 1- (4-fluorophenyl) piperidine-3-carboxylate (4.1 g, 17.28 mmol, 1 eq) , THF (20 mL) and MeOH (40 mL) . A solution of LiOH (2.76 g, 69.12 mmol, 4.0 eq) in H₂O (20 mL) was added and the mixture was stirred at 25 ℃ for 16 hours. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃and extracted with EtOAc (50 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a brown solid (2.56 g, 66.36%) .

MS (ESI, pos. ion) m/z: 224.1 [M+H] ⁺, Rt=0.688/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.46 –12.21 (m, 1H) , 7.08 –7.00 (m, 2H) , 6.98 –6.89 (m, 2H) , 3.56 –3.46 (m, 1H) , 2.96 –2.84 (m, 1H) , 2.79 –2.66 (m, 1H) , 2.59 –2.51 (m, 2H) , 1.92 –1.81 (m, 1H) , 1.78 –1.67 (m, 1H) , 1.62 –1.47 (m, 2H) .

Step 3: Preparation of compound 667-d: 1- (4-fluorophenyl) -N-methoxy-N-methyl-piperidine-3-carboxamide

To a solution of 1- (4-fluorophenyl) piperidine-3-carboxylic acid (2.46 g, 11.02 mmol, 1 eq) in dioxane (50 mL) was added DIEA (4.27 g, 33.06 mmol, 5.76 mL, 3 eq) , N-methoxymethanamine hydrochloride (2.15 g, 22.04 mmol, 2 eq) and T₄P (9.53 g, 13.22 mmol, 50%purity, 1.2 eq) . The mixture was stirred at 100 ℃for 16 hours. The reaction mixture was diluted with H₂O 50 mL and extracted with EtOAc (30 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 20%EtOAc in petroleum ether as a gradient) to afford the title product as a brown oil (1.78 g, 60.66%) .

¹HNMR (400 MHz, DMSO-d₆) δ 7.07 –6.99 (m, 2H) , 6.97 –6.90 (m, 2H) , 3.70 (s, 3H) , 3.67 –3.57 (m, 2H) , 3.11 (s, 3H) , 3.00 –2.88 (m, 1H) , 2.73 –2.61 (m, 2H) , 1.87 –1.77 (m, 1H) , 1.75 –1.66 (m, 1H) , 1.65 –1.45 (m, 2H) .

Step 4: Preparation of compound 667-1: 1- [1- (4-fluorophenyl) -3-piperidyl] ethenone

To a solution of 1- (4-fluorophenyl) -N-methoxy-N-methyl-piperidine-3-carboxamide (1.78 g, 6.68 mmol, 1 eq) in THF (50 mL) was added MeMgBr (3 M, 6.68 mL, 3 eq) by dropwise at -78 ℃ for 10 mins, and then the mixture was stirred at 25 ℃ for 4 hours. The reaction mixture was quenched by addition NH₄Cl (aq. 30 mL) and extracted with EtOAc (30 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a colorless oil (1.39 g, 93.99%) .

MS (ESI, pos. ion) m/z: 222.1 [M+H] ⁺, Rt=0.717/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.07 –7.00 (m, 2H) , 7.00 –6.93 (m, 2H) , 3.66 –3.55 (m, 1H) , 3.46 –3.38 (m, 1H) , 2.79 –2.59 (m, 3H) , 2.21 (s, 3H) , 2.00 –1.87 (m, 1H) , 1.79 –1.67 (m, 1H) , 1.65 –1.48 (m, 1H) , 1.47 –1.35 (m, 1H) .

Preparation of compound 667: 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Step 1: Preparation of compound 667-2: methyl 6- [ (E) -3- [1- (4-fluorophenyl) -3-piperidyl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate

To a solution of 1- [1- (4-fluorophenyl) -3-piperidyl] ethenone (1.35 g, 6.10 mmol, 1 eq) in Tol. (30 mL) was added K₃PO₄ (3.89 g, 18.30 mmol, 3 eq) , methyl 6-formylpyridine-2-carboxylate (1.51 g, 9.15 mmol, 1.5 eq) . The mixture was stirred at 80 ℃ for 16 hours. The mixture was diluted with H₂O (50 mL) and extracted with EtOAc (30 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a brown solid (1.4 g, 62.29%) .

MS (ESI, pos. ion) m/z: 369.2 [M+H] ⁺, Rt=0.848/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.11 –8.03 (m, 3H) , 7.68 (d, J = 15.9 Hz, 1H) , 7.39 (d, J = 16.0 Hz, 1H) , 7.08 –6.95 (m, 4H) , 3.91 (s, 3H) , 3.73 –3.64 (m, 1H) , 3.55 –3.48 (m, 1H) , 3.23 –3.14 (m, 1H) , 2.81 (dd, J = 10.2, 12.2 Hz, 1H) , 2.67 (dt, J = 2.9, 11.6 Hz, 1H) , 2.02 (br d, J = 3.1 Hz, 1H) , 1.83 –1.63 (m, 2H) , 1.53 –1.40 (m, 1H) .

Step 2: Preparation of compound 667-3: methyl 6- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -3-piperidyl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate

To a solution of methyl 6- [ (E) -3- [1- (4-fluorophenyl) -3-piperidyl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate (1.4 g, 3.80 mmol, 1 eq) in dioxane (24 mL) and EtOH (6 mL) was added TEA (3.46 g, 34.20 mmol, 4.76 mL, 9 eq) , 2-cyclopropylacetaldehyde (2.56 g, 30.40 mmol, 8 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol chloride (1.28 g, 4.75 mmol, 1.25 eq) and purged with N₂ for 3 times. The mixture was stirred at 100 ℃ for 16 hours. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a brown oil (1.3 g, 75.6%) .

MS (ESI, pos. ion) m/z: 453.2 [M+H] ⁺, Rt=0.902/1.5 min.

Step 3: Preparation of compound 667-4: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -3-piperidyl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate (300 mg, 662.96 μmol, 1 eq) in AcOH (3 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (324.17 mg, 729.25 μmol, 1.1 eq) . The mixture was stirred at 80 ℃ for 16 hours. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown solid (220 mg, 38.54%) .

MS (ESI, pos. ion) m/z: 861.5 [M+H] +, Rt=1.129/1.5 min.

Step 4: Preparation of compound 667-5: methyl 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate (220 mg, 255.52 μmol, 1 eq) in dry DCM (3 mL) was added TFA (1.17 g, 10.30 mmol, 765.43 μL, 40.33 eq) . The mixture was stirred at 25 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel, eluting with 0%to 40%EtOAc in petroleum ether as a gradient, to afford the title product as a brown solid (126 mg, 79.44%) .

MS (ESI, pos. ion) m/z: 621.5 [M+H] +, Rt=0.970/1.5 min.

Step 5: Preparation of compound 667: 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a 40 mL round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (126 mg, 202.99 μmol, 1 eq) , THF (1 mL) and MeOH (3 mL) . A solution of LiOH (48.62 mg, 2.03 mmol, 10.0 eq) in H₂O (1 mL) was added and the mixture was stirred at 25 ℃ for 16 hours. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EtOAc (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by prep-HPLC (column: Boston Prime C18 150× 30mm× 5um; mobile phase: [Water (FA) -MeCN] ; gradient: 32%-62%B over 8 min) to afford the title product as a yellow solid (54.27 mg, 44.07%) .

MS (ESI, pos. ion) m/z: 607.4 [M+1] ⁺, Rt=0.730/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.86 (t, J = 7.8 Hz, 1H) , 7.81 –7.71 (m, 3H) , 7.68 (br s, 2H) , 7.00 –6.92 (m, 3H) , 6.85 –6.80 (m, 1H) , 6.66 (dd, J = 4.6, 9.1 Hz, 2H) , 6.62 (s, 1H) , 5.41 (s, 2H) , 3.58-3.53 (m, 1H) , 3.24-3.10 (m, 2H) , 2.78 –2.55 (m, 4H) , 1.93 –1.81 (m, 1H) , 1.76 –1.68 (m, 1H) , 1.63 –1.49 (m, 2H) , 0.90 –0.78 (m, 1H) , 0.29 –0.16 (m, 4H) .

Example 35: Synthesis of compound 668

Step 1: Preparation of compound 668-2: methyl 4-formylpicolinate

To the solution of methyl 4- (hydroxymethyl) pyridine-2-carboxylate (1.00 g, 5.98 mmol, 1.0 eq) in DCM (20 mL) was added DMP (3.81 g, 8.97 mmol, 1.5 eq) . The reaction mixture was stirred at room temperature for 12 hours. After the reaction completion, the mixture was diluted with H₂O (30 mL) and extracted with DCM (100 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (700 mg, 70.85%) .

MS (ESI, pos. ion) m/z: 166.2 [M+1] ⁺, Rt=0.22/2min.

Step 2: Preparation of compound 668-3: methyl (E) -4- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate To the solution of methyl 4-formylpicolinate (500 mg, 3.03 mmol, 1.0) and 1- (3-bromophenyl) ethan-1-one (663 mg, 3.33 mmol, 1.1 eq) in toluene (15 mL) was added PTSA (288 mg, 1.51 mmol, 0.5 eq) . The reaction mixture was stirred at 140 ℃ with Dean-Stark trap for 2 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (250 mg, 23.85%) .

MS (ESI, pos. ion) m/z: 345.8/347.8 [M+H] ⁺, Rt=0.967/2min.

Step 3: Preparation of compound 668-4: methyl 4- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

Under N₂, to the solution of methyl (E) -4- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate (190 mg, 0.55 mmol, 1.0 eq) , TEA (0.65 mL, 4.94 mmol, 9.0 eq) and 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (177 mg, 0.66 mmol, 1.2 eq) in a mixture solvent of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (231 mg, 2.75 mmol, 5.0 eq) . The reaction was stirred at 100 ℃ for 12 hours. After the reaction completion, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (135 mg, 57.16%) .

MS (ESI, pos. ion) m/z: 429.9/431.9 [M+H] ⁺, Rt=0.97/2min.

Step 4: Preparation of compound 668-5: methyl 4- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 4- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (135 mg, 0.31 mmol, 1.0 eq) in a mixture solvent of EtOH (1 mL) in AcOH (4 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (209 mg, 0.47 mmol, 1.5 eq) . The reaction mixture was stirred at 100 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with EtOAc (50 mL × 2) . The organic layers were combined, washed with brine and NaHCO₃, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (135 mg, 60.80%) .

MS (ESI, pos. ion) m/z: 838.0/840.0 [M+H] ⁺, Rt=1.317/2min.

Step 5: Preparation of compound 668-6: methyl 4- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 4- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate (150 mg, 0.18 mmol, 1.0 eq) in DCM (4 mL) was added TFA (2 mL) . The reaction mixture was stirred at room temperature for 12 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (30 mL) and extracted with DCM (50 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (100 mg, 93.43%) .

MS (ESI, pos. ion) m/z: 597.9/599.9 [M+H] ⁺, Rt=0.992/2min.

Step 6: Preparation of compound 668-7: methyl 4- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of methyl 4- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (90 mg, 0.15 mmol, 1.0 eq) and ethynylcyclobutane (60 mg, 0.75 mmol, 5.0 eq) in dioxane (2 mL) was added DABCO (51 mg, 0.45 mmol, 3.0 eq) , CuI (6 mg, 0.03 mmol, 0.2 eq) and Pd-162 (6 mg, 0.02 mmol, 0.1 eq) . The reaction was stirred at 40 ℃ for 12 hours. After the reaction completion, the mixture was diluted with H₂O (20 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (60 mg, 50.07%) .

MS (ESI, pos. ion) m/z: 598.1 [M+1] ⁺, Rt=1.102/2min.

Step 7: Preparation of compound 668: 4- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 4- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (60 mg, 0.08 mmol, 1.0 eq) in mixture solvent of THF (2 mL) in MeOH (0.5 mL) was added a solution of lithium hydroxide (5 mg, 0.23 mmol, 3.0 eq) in H₂O (0.5 mL) . The reaction mixture was stirred at room temperature for 12 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, diluted with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (7 mg, 17.14%) .

MS (ESI, pos. ion) m/z: 584.0 [M+1] ⁺ , Rt=0.917/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.65 (d, J = 5.1 Hz, 1H) , 8.19 (s, 1H) , 7.76 (dd, J = 1.5, 5.1 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.39 (s, 1H) , 7.37 –7.28 (m, 3H) , 6.90 (d, J = 11.1 Hz, 1H) , 6.79-6.74 (m, 2H) , 5.40 (s, 2H) , 3.28-3.21 (m, 1H) , 2.75 (br d, J = 5.6 Hz, 2H) , 2.32-2.23 (m, 2H) , 2.17-2.05 (m, 2H) , 2.01 –1.82 (m, 2H) , 0.92-0.83 (m, 1H) , 0.39-0.32 (m, 2H) , 0.13 –0.07 (m, 2H) .

Example 36: Synthesis of compound 671

Step 1: Preparation of compound 671-1: methyl 6- (5- (3- (cyclobutylethynyl) -4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5- (3-bromo-4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.19 mmol, 1.0 eq) in dioxane (5 mL) was added Pd-162 (8 mg, 0.02 mmol, 0.1 eq) , 1, 4-diazabicyclo [2.2.2] octane (66 mg, 0.59 mmol, 3.0 eq) , CuI (8 mg, 0.04 mmol, 0.2 eq) and ethynylcyclobutane (47 mg, 0.58 mmol, 3.0 eq) portion wise with the temperature was kept at RT to get a yellow suspension. The reaction mixture was stirred at RT for 18 hours. The reaction mixture was filtered and diluted with H₂O (10 mL) extracted with EA (10 mL × 3) . The combined organic layer washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (97 mg, 0.15 mmol, 80%yield) .

MS (ESI, neg. ion) m/z: 610.2 [M-1] ⁺, Rt=1.245/2min.

Step 2: Preparation of compound 671: 6- (5- (3- (cyclobutylethynyl) -4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (5- (3- (cyclobutylethynyl) -4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (97 mg, 0.16 mmol, 1.0 eq) in a mixture solvent of MeOH (1 mL) in THF (2 mL) added a solution of LiOH (27 mg, 0.63 mmol, 4.0 eq) in H₂O (1 mL) . The mixture was stirred at RT for 18 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, washed with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (27 mg, 0.05 mol, 28%) .

MS (ESI, pos. ion) m/z: 598.2 [M+1] ⁺ , Rt=1.142/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.87 br s, 1H) , 7.93 –7.85 (m, 2H) , 7.77 (dd, J = 1.8, 6.8 Hz, 1H) , 7.71 (t, J = 7.8 Hz, 1H) , 7.60 (br s, 2H) , 7.33 (d, J = 1.6 Hz, 1H) , 7.26 (d, J = 8.0 Hz, 1H) , 7.22 (dd, J = 7.9, 1.9 Hz, 1H) , 6.91 –6.84 (m, 2H) , 6.78 (d, J = 8.2 Hz, 1H) , 5.39 (s, 2H) , 3.40-3.25 (m, 1H) , 3.20 (br d, J = 6.6 Hz, 2H) , 2.37 –2.27 (m, 1H) , 2.40 –2.25 (m, 4H) , 2.17 –2.06 (m, 2H) , 2.00 –1.84 (m, 2H) , 0.99 –0.89 (m, 1H) , 0.31 –0.19 (m, 4H) .

Example 37: Synthesis of compound 682

Step 1: Preparation of compound 682-1: methyl 6- (5- (4’-chloro-3’-fluoro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.15 mmol, 1.0 eq) and (4-chloro-3-fluorophenyl) boranediol (41 mg, 0.23 mmol, 1.5 eq) in a mixture solvent of H₂O (0.5 mL) in dioxane (2 mL) was added potassium carbonate (64 mg, 0.46 mmol, 3.0 eq) and Pd (dppf) Cl₂ (11 mg, 0.02 mmol, 0.1 eq) . The reaction was stirred at 80 ℃ for 2 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (20 mL) and extracted with EtOAc (20 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (80 mg, 79.68%) .

MS (ESI, pos. ion) m/z: 648.0 [M+1] ⁺, Rt=1.208/2min.

Step 2: Preparation of compound 682: 6- (5- (4’-chloro-3’-fluoro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (5- (4’-chloro-3’-fluoro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (80 mg, 0.12 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) in MeOH (0.5 mL) was added a solution of lithium hydroxide hydrate (16 mg, 0.38 mmol, 3.0 eq) in H₂O (0.5 mL) . The reaction mixture was stirred at room temperature for 12 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, diluted with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (35 mg, 43.92%) .

MS (ESI, pos. ion) m/z: 634.0 [M+1] ⁺ , Rt=1.075/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.93 (s, 1H) , 7.95-7.87 (m, 2H) , 7.78 (td, J = 2.1, 8.8 Hz, 2H) , 7.74-7.59 (m, 6H) , 7.51-7.38 (m, 3H) , 6.99 (s, 1H) , 6.94 (d, J = 11.3 Hz, 1H) , 6.83 (d, J = 9.0 Hz, 1H) , 5.46 (s, 2H) , 3.23 (br d, J = 6.6 Hz, 2H) , 1.01-0.91 (m, 1H) , 0.33 -0.21 (m, 4H) .

Example 38: Synthesis of compound 683

Step 1: Preparation of compound 683-1: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (3 g, 4.65 mmol, 1.0 eq) in a mixture solvent of THF (20 mL) in MeOH (5 mL) was added a solution of lithium hydroxide hydrate (0.59 g, 13.94 mmol, 3.0 eq) in H₂O (5 mL) . The reaction mixture was stirred at room temperature for 12 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the title product as a yellow solid (2.66 g, 90.78%) .

MS (ESI, pos. ion) m/z: 631.9 [M+1] ⁺, Rt=0.983/2min.

Step 2: Preparation of compound 683: 6- (5- (4’-cyclopentyl- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

Under N₂, to the solution of 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinic acid (100 mg, 0.16 mmol, 1.0 eq) and (4-cyclopentylphenyl) boranediol (45 mg, 0.24 mmol, 1.5 eq) in a mixture solvent of H₂O (0.5 mL) in dioxane (2 mL) was added k₂CO₃ (66 mg, 0.48 mmol, 3.0 eq) and Pd (dppf) Cl₂ (12 mg, 0.02 mmol, 0.1 eq) . The reaction was stirred at 80 ℃ for 2 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (30 mg, 40.57%) .

MS (ESI, pos. ion) m/z: 650.1 [M+1] ⁺, Rt=1.233/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.93-7.85 (m, 2H) , 7.79-7.71 (m, 2H) , 7.66-7.52 (m, 3H) , 7.48-7.41 (m, 3H) , 7.36-7.28 (m, 3H) , 6.99 (d, J = 11.0 Hz, 1H) , 6.94 (s, 1H) , 6.85 (d, J = 8.3 Hz, 1H) , 5.45 (s, 2H) , 3.23 (br d, J = 6.4 Hz, 2H) , 3.05-2.94 (m, 1H) , 2.07-1.97 (m, 2H) , 1.86-1.73 (m, 2H) , 1.72-1.62 (m, 2H) , 1.60-1.49 (m, 2H) , 1.01 –0.90 (m, 1H) , 0.32-0.20 (m, 4H) .

Example 39: Synthesis of compound 688

Step 1: Preparation of compound 688-1: methyl 6- (5- (3- (cyclohexylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (100 mg, 0.15 mmol, 1.0 eq) and ethynylcyclohexane (50 mg, 0.46 mmol, 3.0 eq) in N, N-dimethylmethanamide (2 mL) was added CuI (6 mg, 0.03 mmol, 0.2 eq) , TEA (0.05 mL, 0.46 mmol, 3.0 eq) and Pd (pph₃) ₂Cl₂ (11 mg, 0.02 mmol, 0.1 eq) . The reaction was stirred at 40 ℃ for 2 hours. This mixture was diluted with H₂O (30 mL) and extracted with EtOAc (20 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 5%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (90 mg, 92.84%) .

MS (ESI, pos. ion) m/z: 626.1 [M+1] ⁺, Rt=1.275/2min.

Step 2: Preparation of compound 688: 6- (5- (3- (cyclohexylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (5- (3- (cyclohexylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (90 mg, 0.14 mmol) in n a mixture solvent of THF (2 mL) in MeOH (0.5 mL) was added a solution of lithium hydroxide hydrate (18 mg, 0.43 mmol, 3.0 eq) in H₂O (0.5 mL) . The reaction mixture was stirred at room temperature for 12 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, diluted with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (23 mg, 26.13%) .

MS (ESI, pos. ion) m/z: 612.1 [M+1] ⁺ , Rt=1.192/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.90 (br s, 1H) , 7.94-7.87 (m, 2H) , 7.81-7.75 (m, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.59 (s, 2H) , 7.37-7.30 (m, 3H) , 7.30-7.26 (m, 1H) , 6.93 (s, 1H) , 6.89 (br d, J = 10.8 Hz, 1H) , 6.79 (d, J = 8.0 Hz, 1H) , 5.40 (s, 2H) , 3.20 (br d, J = 6.4 Hz, 2H) , 2.65-2.57 (m, 1H) , 1.85-1.75 (m, 2H) , 1.71-1.61 (m, 2H) , 1.53-1.40 (m, 3H) , 1.38-1.28 (m, 3H) , 1.00-0.89 (m, 1H) , 0.31-0.20 (m, 4H) .

Example 40: Synthesis of compound 695

Step 1: Preparation of compound 695-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4-methyloxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate

Under N₂, to the solution of 2-bromo-4-methyl-1, 3-oxazole (50 mg, 0.31 mmol, 1.0 eq) and methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate (292 mg, 0.46 mmol, 1.5 eq) in a mixture solvent of dioxane (4 mL) in H₂O (1 mL) was added K₂CO₃ (128 mg, 0.93 mmol, 3.0 eq) and Pd (dppf) Cl₂ (23 mg, 0.03 mmol, 0.1 eq) . The reaction mixture was stirred at 80 ℃ for 12 hours. This mixture was concentrated under reduced vacuum, then diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 20%to 80%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (120 mg, 64.72%) .

MS (ESI, neg. ion) m/z: 599.0 [M-1] ^-, Rt=1.058/2min.

Step 2: Preparation of compound 695: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4-methyloxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid

To the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4-methyloxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.20 mmol, 1.0 eq) in a mixture solvent of methanol (0.5 mL) in tetrahydrofuran (2 mL) was added a solution of lithium hydroxide (24 mg, 0.60 mmol, 3.0 eq) in water (0.5 mL) The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum. The reaction mixture was adjusted to pH=6 with 2N HCl solution. The reaction mixture was extracted with EA (10 mL × 3) . The organic layer washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (94 mg, 79.89%) .

MS (ESI, pos. ion) m/z: 587.0 [M+1] ⁺, Rt=0.958/2min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.94 (br s, 1H) , 7.95-7.90 (m, 2H) , 7.89-7.83 (m, 3H) , 7.82-7.76 (m, 1H) , 7.71 (t, J = 7.8 Hz, 1H) , 7.60 (s, 2H) , 7.56-7.49 (m, 2H) , 6.99 (s, 1H) , 6.92 (d, J = 11.1 Hz, 1H) , 6.80 (d, J = 8.1 Hz, 1H) , 5.45 (s, 2H) , 3.25 (br d, J = 6.6 Hz, 2H) , 2.15 (s, 3H) , 1.04-0.92 (m, 1H) , 0.34-0.20 (m, 4H) .

Example 41: Synthesis of compound 696

Step 1: Preparation of compound 696-1: methyl 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

A mixture of methyl 6- (5- (3-bromo-2-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (200 mg, 0.32 mmol, 1.0 eq) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (165 mg, 0.65 mmol, 2.0 eq) , Pd (dppf) Cl₂ (24 mg, 0.03 mmol, 0.1 eq) and potassium acetate (96 mg, 0.97 mmol, 3.0 eq) in 1, 4-dioxane (3 mL) was degassed and purged with N₂, and then the mixture was stirred at 80 ℃ overnight. The reaction mixture was used directly in next step.

MS (ESI, pos. ion) m/z: 664.1 [M+1] ⁺, Rt= 1.150/2 min.

Step 2: Preparation of compound 696-2: methyl 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

The reaction mixture of methyl 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (212.2 mg, 0.32, 1 eq) was added Pd (dppf) Cl₂ (24 mg, 0.03 mmol, 0.1 eq) , potassium carbonate (134 mg, 0.97 mmol, 3.0 eq) , 2-bromo-4- (trifluoromethyl) -1, 3-oxazole (84 mg, 0.39 mmol, 1.2 eq) and water (0.5 mL) . The resulting mixture was degassed and purged with N₂, then stirred at 80 ℃ for 3 hrs. The reaction mixture was poured into water (3 mL) and extracted with EtOAc (5 mL × 3) ; the combined organic phases were dried over Na₂SO₄. After removal of the solvent, the crude product was purified by flash chromatography (silica, PE/EA =100: 0 to 55: 45) to afford the desired product as an orange oil (197 mg, 0.29 mmol, 90%) .

MS (ESI, pos. ion) m/z: 673.0 [M+1] ⁺, Rt= 1.108/2 min.

Step 3: Preparation of compound 696: 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To a stirred solution of methyl 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (197 mg, 0.29 mmol, 1.0 eq) in a mixture solvent of methanol (1 mL) in water (1 mL) was added lithium hydroxide (28 mg, 1.17 mmol, 4.0 eq) at room temperature. The resulting mixture was stirred at same temperature for 3 hrs. The solvents and volatiles were evaporated under reduced pressure, the residue was acidified with HCl (1 N) aqueous solution (pH was about 4 to 5) , then extracted with EtOAc (5 mL × 3) , the combined organic phases were dried over Na₂SO₄, then filtered and concentrated under reduced pressure. Purification of the crude product by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) afforded the desired product as a yellow powder (56 mg, 0.05 mmol, 29%) .

MS (ESI, pos. ion) m/z: 659.0 [M+1] ⁺, Rt= 1.042/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ 9.13 –9.10 (m, 1H) , 8.07 –8.01 (m, 1H) , 7.95 –7.85 (m, 2H) , 7.79 (dd, J = 1.2, 7.2 Hz, 1H) , 7.69 –7.54 (m, 4H) , 7.39 (t, J = 7.8 Hz, 1H) , 6.95 (s, 1H) , 6.84 –6.70 (m, 2H) , 5.32 (s, 2H) , 3.25 (br d, J = 6.6 Hz, 2H) , 1.01 –0.91 (m, 1H) , 0.31 –0.21 (m, 4H) .

Example 42: Synthesis of compound 720 and 721

¹HNMR (400 MHz, DMSO-d₆) δ 7.08 -7.00 (m, 2H) , 6.98 -6.91 (m, 2H) , 3.69 -3.60 (m, 3H) , 3.51 (dd, J = 3.5, 12.1 Hz, 1H) , 3.33 -3.26 (m, 1H) , 2.99 -2.87 (m, 1H) , 2.82 -2.71 (m, 1H) , 2.71 -2.61 (m, 1H) , 1.94 -1.84 (m, 1H) , 1.80 -1.66 (m, 1H) , 1.66 -1.54 (m, 2H) .

MS (ESI, pos. ion) m/z: 224.1 [M+H] ⁺, Rt=0.688/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 12.46 -12.21 (m, 1H) , 7.08 -7.00 (m, 2H) , 6.98 -6.89 (m, 2H) , 3.56 -3.46 (m, 1H) , 2.96 -2.84 (m, 1H) , 2.79 -2.66 (m, 1H) , 2.59 -2.51 (m, 2H) , 1.92 -1.81 (m, 1H) , 1.78 -1.67 (m, 1H) , 1.62 -1.47 (m, 2H) .

¹HNMR (400 MHz, DMSO-d₆) δ 7.07 -6.99 (m, 2H) , 6.97 -6.90 (m, 2H) , 3.70 (s, 3H) , 3.67 -3.57 (m, 2H) , 3.11 (s, 3H) , 3.00 -2.88 (m, 1H) , 2.73 -2.61 (m, 2H) , 1.87 -1.77 (m, 1H) , 1.75 -1.66 (m, 1H) , 1.65 -1.45 (m, 2H) .

MS (ESI, pos. ion) m/z: 222.1 [M+H] ⁺, Rt=0.717/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.07 -7.00 (m, 2H) , 7.00 -6.93 (m, 2H) , 3.66 -3.55 (m, 1H) , 3.46 -3.38 (m, 1H) , 2.79 -2.59 (m, 3H) , 2.21 (s, 3H) , 2.00 -1.87 (m, 1H) , 1.79 -1.67 (m, 1H) , 1.65 -1.48 (m, 1H) , 1.47 -1.35 (m, 1H) .

Step 5: Preparation of compound 667-2: methyl 6- [ (E) -3- [1- (4-fluorophenyl) -3-piperidyl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate

To a solution of 1- [1- (4-fluorophenyl) -3-piperidyl] ethanone (1.35 g, 6.10 mmol, 1 eq) in Tol. (30 mL) was added K₃PO₄ (3.89 g, 18.30 mmol, 3 eq) , methyl 6-formylpyridine-2-carboxylate (1.51 g, 9.15 mmol, 1.5 eq) . The mixture was stirred at 80 ℃ for 16 hours. The mixture was diluted with H₂O (50 mL) and extracted with EtOAc (30 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a brown solid (1.4 g, 62.29%) .

MS (ESI, pos. ion) m/z: 369.2 [M+H] ⁺, Rt=0.848/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.11 -8.03 (m, 3H) , 7.68 (d, J = 15.9 Hz, 1H) , 7.39 (d, J = 16.0 Hz, 1H) , 7.08 -6.95 (m, 4H) , 3.91 (s, 3H) , 3.73 -3.64 (m, 1H) , 3.55 -3.48 (m, 1H) , 3.23 –3.14 (m, 1H) , 2.81 (dd, J = 10.2, 12.2 Hz, 1H) , 2.67 (dt, J = 2.9, 11.6 Hz, 1H) , 2.02 (br d, J = 3.1 Hz, 1H) , 1.83 -1.63 (m, 2H) , 1.53 -1.40 (m, 1H) .

Step 6: Preparation of compound 667-3: methyl 6- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -3-piperidyl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate

To a solution of methyl 6- [ (E) -3- [1- (4-fluorophenyl) -3-piperidyl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate (1.4 g, 3.80 mmol, 1 eq) in dioxane (24 mL) and EtOH (6 mL) was added TEA (3.46 g, 34.20 mmol, 4.76 mL, 9 eq) , 2-cyclopropylacetaldehyde (2.56 g, 30.40 mmol, 8 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (1.28 g, 4.75 mmol, 1.25 eq) and purged with N₂ for 3 times. The mixture was stirred at 100 ℃ for 16 hours. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 0%to 25%EtOAc in petroleum ether as a gradient) to afford the title product as a brown oil (1.3 g, 75.6%) .

MS (ESI, pos. ion) m/z: 453.2 [M+H] ⁺, Rt=0.902/1.5 min.

Step 7: Preparation of compound 667-4: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate

MS (ESI, pos. ion) m/z: 861.5 [M+H] +, Rt=1.129/1.5 min.

Step 8: Preparation of compound 667-5: methyl 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

MS (ESI, pos. ion) m/z: 621.5 [M+H] +, Rt=0.970/1.5 min.

Preparation of compound 720: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [rac- (3S) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Step 1: Preparation of compound 720-1: methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [rac- (3S) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate

Compound 667-5 (180 mg) was further separated by SFC (column: DAICEL CHIRALPAK AD (250mm×30mm, 10um) ; mobile phase: [CO₂-EtOH (0.1%NH3H2O) ] ; B%: 50%, isocratic elution mode) to afford the title product as a brown solid (70 mg, 32.80%) .

Step 2: Preparation of compound 720: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [rac- (3S) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a 40 mL round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [rac- (3S) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate (70.00 mg, 112.77 μmol, 1 eq) , THF (1 mL) and MeOH (3 mL) . A solution of LiOH (27.01 mg, 1.13 mmol, 10.0 eq) in H₂O (0.5 mL) was added and the mixture was stirred at 25 ℃ for 16 hours. The mixture was acidified with 1 N aqueous HCl solution until the pH = ～6 at 0 ℃ and extracted with EtOAc (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by prep-HPLC (column: Boston Prime C18 150× 30mm× 5um; mobile phase: [Wate r (FA) -MeCN] ; gradient: 36%-66%B over 8 min) to afford the title product as a yellow solid (28.64 mg, 41.86%) .

MS (ESI, pos. ion) m/z: 607.2 [M+1] ⁺, Rt=0.866/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.86 (t, J = 7.8 Hz, 1H) , 7.81 –7.71 (m, 3H) , 7.68 (br s, 2H) , 7.00 –6.92 (m, 3H) , 6.84 –6.80 (m, 1H) , 6.66 (dd, J = 4.6, 9.1 Hz, 2H) , 6.63 (s, 1H) , 5.41 (s, 2H) , 3.58-3.40 (m, 1H) , 3.28-3.10 (m, 2H) , 2.78 –2.55 (m, 4H) , 1.92 –1.82 (m, 1H) , 1.76 –1.68 (m, 1H) , 1.63 –1.49 (m, 2H) , 0.89 –0.79 (m, 1H) , 0.29 –0.16 (m, 4H) .

Preparation of compound 721: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5-[rac- (3R) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Step 1: Preparation of compound 721-1: methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [rac- (3R) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate

Compound 667-5 (180 mg) was further separated by SFC (column: DAICEL CHIRALPAK AD (250mm×30mm, 10um) ; mobile phase: [CO₂-EtOH (0.1%NH3H2O) ] ; B%: 50%, isocratic elution mode) , to afford the title product as a brown solid (67 mg, 31.40%) .

Step 2: Preparation of compound 721: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [rac- (3R) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a 40 mL round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [rac- (3R) -1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate (67.00 mg, 107.94 μmol, 1 eq) , THF (1 mL) and MeOH (3 mL) . A solution of LiOH (25.85 mg, 1.08 mmol, 10.0 eq) in H₂O (0.5 mL) was added and the mixture was stirred at 25 ℃ for 16 hours. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EtOAc (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by prep-HPLC (column: Boston Prime C18 150× 30mm× 5um; mobile phase: [Water (FA) -MeCN] ; gradient: 36%-66%B over 8 min) to afford the title product as a yellow solid (19.34 mg, 29.53%) .

MS (ESI, pos. ion) m/z: 607.2 [M+1] ⁺, Rt=0.865/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.86 (t, J = 7.8 Hz, 1H) , 7.81 –7.71 (m, 3H) , 7.68 (br s, 2H) , 7.00 –6.92 (m, 3H) , 6.85 –6.80 (m, 1H) , 6.66 (dd, J = 4.6, 9.1 Hz, 2H) , 6.63 (s, 1H) , 5.41 (s, 2H) , 3.59-3.40 (m, 1H) , 3.28-3.10 (m, 2H) , 2.78 –2.55 (m, 4H) , 1.92 –1.82 (m, 1H) , 1.76 –1.67 (m, 1H) , 1.63 –1.49 (m, 2H) , 0.90 –0.79 (m, 1H) , 0.30 –0.15 (m, 4H) .

Example 43: Synthesis of compound 633

Step 1: Preparation of compound 633-1: methyl 6- [2- (cyclopropylmethyl) -5- [3- (3, 4-difluorophenyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (100 mg, 167.09 μmol, 1 eq) in THF (3 mL) and H₂O (0.8 mL) was added (3, 4-difluorophenyl) boronic acid (52.77 mg, 334.18 μmol, 2 eq) , K₃PO₄ (106.40 mg, 501.27 μmol, 3 eq) and Xphos Pd G3 (14.14 mg, 16.71 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with H₂O (5 mL) and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (100 mg, 64.75%) .

MS (ESI, pos. ion) m/z: 632.1 [M+H] ⁺, Rt=1.107/1.5 min.

Step 2: Preparation of compound 633: 6- [2- (cyclopropylmethyl) -5- [3- (3, 4-difluorophenyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -5- [3- (3, 4-difluorophenyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (100 mg, 158.31 μmol, 1 eq) in THF (1 mL) and MeOH (3 mL) . A solution of LiOH (37.92 mg, 1.58 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150×30mm×5um; mobile phase: [Water (FA) -MeCN] ; gradient: 45%-75%B over 9 min) to afford the title product as a white solid (45.72 mg, 46.76%) .

MS (ESI, pos. ion) m/z: 618.1 [M+1] ⁺, Rt=1.051/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.96 –7.87 (m, 2H) , 7.82 –7.75 (m, 2H) , 7.74 –7.69 (m, 1H) , 7.65 –7.59 (m, 4H) , 7.51 –7.44 (m, 2H) , 7.43 –7.35 (m, 2H) , 6.99 –6.97 (m, 1H) , 6.97 –6.92 (m, 1H) , 6.86 –6.82 (m, 1H) , 5.50 –5.44 (m, 2H) , 3.23 (br d, J = 6.5 Hz, 2H) , 1.02 –0.89 (m, 1H) , 0.31 –0.22 (m, 4H) .

Example 44: Synthesis of compound 634

Step 1: Preparation of compound 634-1: methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [4- (trifluoromethyl) phenyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (100 mg, 167.09 μmol, 1 eq) in THF (3 mL) and H₂O (0.8 mL) was added [4- (trifluoromethyl) phenyl] boronic acid (63.47 mg, 334.18 μmol, 2 eq) , K₃PO₄ (106.40 mg, 501.27 μmol, 3 eq) and Xphos Pd G3 (14.14 mg, 16.71 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with H₂O (5 mL) and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (110 mg, 99.19%) .

MS (ESI, pos. ion) m/z: 664.1 [M+H] ⁺, Rt=1.133/1.5 min.

Step 2: Preparation of compound 634: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [4- (trifluoromethyl) phenyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [4- (trifluoromethyl) phenyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylate (110 mg, 165.74 μmol, 1 eq) in THF (1 mL) and MeOH (3 mL) . A solution of LiOH (39.70 mg, 1.66 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150×30mm×5um; mobile phase: [Water (FA) -MeCN] ; gradient: 50%-80%B over 9 min) to afford the title product as a white solid (45.72 mg, 46.76%) .

MS (ESI, pos. ion) m/z: 650.1 [M+H] ⁺, Rt=1.083/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.95 –7.86 (m, 2H) , 7.82 –7.76 (m, 5H) , 7.76 –7.71 (m, 1H) , 7.69 –7.61 (m, 4H) , 7.55 –7.49 (m, 1H) , 7.47 –7.41 (m, 1H) , 7.00 –6.94 (m, 2H) , 6.87 –6.83 (m, 1H) , 5.46 (s, 2H) , 3.25 (br d, J = 6.5 Hz, 2H) , 1.03 –0.87 (m, 1H) , 0.33 –0.21 (m, 4H) .

Example 45: Synthesis of compound 670

Step 1: Preparation of compound 670-1: methyl 6- [5- [3- (2-cyclopropylethynyl) phenyl] -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (115 mg, 192.15 μmol, 1 eq) in DMF (3 mL) was added TEA (58.33 mg, 576.46 μmol, 80.24 μL, 3 eq) , ethynylcyclopropane (38.10 mg, 576.46 μmol, 47.81 μL, 3 eq) and Pd (PPh₃) ₂Cl₂ (13.49 mg, 19.22 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 70 ℃for 16 hr. The mixture was diluted with H₂O (5 mL) and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (55 mg, 49.04%) .

MS (ESI, pos. ion) m/z: 584.1 [M+H] ⁺, Rt=1.095/1.5 min.

Step 2: Preparation of compound 670: 6- [5- [3- (2-cyclopropylethynyl) phenyl] -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [5- [3- (2-cyclopropylethynyl) phenyl] -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (55 mg, 94.23 μmol, 1 eq) in THF (1 mL) and MeOH (3 mL) . A solution of LiOH (22.51 mg, 0.942 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL ×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150×30mm×5um; mobile phase: [Water (FA) -MeCN] ; gradient: 45%-75%B over 8 min) to afford the title product as a white solid (5.29 mg, 9.86%) .

MS (ESI, pos. ion) m/z: 570.1 [M+H] ⁺, Rt=1.031/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.95 –7.85 (m, 2H) , 7.77 (dd, J = 1.5, 6.8 Hz, 1H) , 7.74 –7.67 (m, 1H) , 7.66 –7.54 (m, 2H) , 7.38 –7.25 (m, 4H) , 6.94 –6.84 (m, 2H) , 6.78 –6.74 (m, 1H) , 5.45 –5.35 (m, 2H) , 3.20 (br d, J = 6.8 Hz, 2H) , 1.58 –1.47 (m, 1H) , 0.98 –0.91 (m, 1H) , 0.91 –0.84 (m, 2H) , 0.76 –0.68 (m, 2H) , 0.30 –0.18 (m, 4H) .

Example 46: Synthesis of compound 679

Step 1: Preparation of compound 679-2: 1- [1- (3-fluorophenyl) pyrazol-3-yl] ethanone

To a solution of 1- (1H-pyrazol-3-yl) 119thenone (3 g, 27.24 mmol, 1 eq) in DCM (100 mL) was added TEA (8.27 g, 81.73 mmol, 11.38 mL, 3 eq) , (3-fluorophenyl) boronic acid (5.72 g, 40.87 mmol, 1.5 eq) and Cu(Oac) ₂ (9.90 g, 54.49 mmol, 2 eq) . The mixture was stirred at 25 ℃ for 16 hr. The mixture was filtered and the filter was diluted with brine (100 mL) and extracted with EtOAc (30 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 15/85) to afford the title product as a colorless oil (285 mg, 5.12%) .

MS (ESI, pos. ion) m/z: 205.1 [M+H] ⁺, Rt=0.911/1.5 min.

Step 2: Preparation of compound 679-3: methyl 6- [ (E) -3- [1- (3-fluorophenyl) pyrazol-3-yl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate

To a solution of 1- [1- (3-fluorophenyl) pyrazol-3-yl] 119thenone (285 mg, 1.40 mmol, 1 eq) in Tol. (20 mL) was added K₃PO₄ (888.79 mg, 4.19 mmol, 3 eq) and methyl 6-formylpyridine-2-carboxylate (345.74 mg, 2.09 mmol, 1.5 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (10 mL) and extracted with EtOAc (5 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 20/80) to afford the title product as a brown solid (310 mg, 63.22%) .

¹HNMR (400 MHz, DMSO-d₆) δ 8.82 –8.75 (m, 1H) , 8.33 –8.24 (m, 1H) , 8.18 –8.06 (m, 3H) , 7.96 –7.86 (m, 3H) , 7.70 –7.61 (m, 1H) , 7.34 –7.26 (m, 1H) , 7.20 –7.14 (m, 1H) , 3.98 –3.89 (m, 3H) .

Step 3: Preparation of compound 679-4: methyl 6- [3-cyclopropyl-1- [2- [1- (3-fluorophenyl) pyrazol-3-yl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate

A mixture of methyl 6- [ (E) -3- [1- (3-fluorophenyl) pyrazol-3-yl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate (310 mg, 882.36 μmol, 1 eq) in dioxane (20 mL) and EtOH (5 mL) was added TEA (803.57 mg, 7.94 mmol, 1.11 mL, 9 eq) , 2-cyclopropylacetaldehyde (742.21 mg, 8.82 mmol, 10 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol chloride (297.56 mg, 1.10 mmol, 1.25 eq) then suspension was degassed under vacuum and purged with N₂ for 3 times. The mixture was stirred at 100 ℃ for 16 hr. The mixture was diluted with brine (10 mL) and extracted with EtOAc (5 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown oil (350 mg, 91.09%) .

MS (ESI, pos. ion) m/z: 436.2 [M+H] ⁺. Rt=1.013/1.5 min.

Step 4: Preparation of compound 679-5: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) pyrazol-3-yl] pyrrol-3-yl] pyridine-2-carboxylate

A mixture of methyl 6- [3-cyclopropyl-1- [2- [1- (3-fluorophenyl) pyrazol-3-yl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate (350 mg, 803.77 μmol, 1 eq) in AcOH (20 mL) was 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (393.02 mg, 884.15 μmol, 1.1 eq) . The mixture was stirred at 80 ℃ for 16 hrs. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (280 mg, 41.28%) .

MS (ESI, pos. ion) m/z: 844.4 [M+H] ⁺. Rt=1.237/1.5 min.

Step 5: Preparation of compound 679-6: methyl 6- [2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) pyrazol-3-yl] pyrrol-3-yl] pyridine-2-carboxylate (280 mg, 331.78 μmol, 1 eq) in DCM (3 mL) was added TFA (1.53 g, 13.38 mmol, 993.89 μL, 40.33 eq) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (120 mg, 59.92%) .

MS (ESI, pos. ion) m/z: 604.2 [M+H] ⁺. Rt=1.066/1.5 min.

Step 6: Preparation of compound 679: 6- [2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (120 mg, 198.79 μmol, 1 eq) in THF (1 mL) and MeOH (3 mL) . A solution of LiOH (47.61 mg, 1.99 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150×30mm×5um; mobile phase: [Water (FA) -MeCN] ; gradient: 43%-73%B over 8 min) to afford the title product as a yellow solid (49.75 mg, 42.44%) .

MS (ESI, pos. ion) m/z: 590.1 [M+H] ⁺, Rt=0.990/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.57 –8.52 (m, 1H) , 7.98 –7.87 (m, 2H) , 7.80 (dd, J = 1.0, 7.4 Hz, 1H) , 7.73 –7.68 (m, 1H) , 7.61 –7.45 (m, 5H) , 7.34 –7.31 (m, 1H) , 7.13 –7.05 (m, 1H) , 6.99 (d, J = 11.2 Hz, 1H) , 6.94 (d, J = 8.4 Hz, 1H) , 6.91 –6.87 (m, 1H) , 6.05 –5.85 (m, 2H) , 3.32 (br s, 2H) , 0.98 –0.87 (m, 1H) , 0.32 –0.21 (m, 4H) .

Example 47: Synthesis of compound 680

Step 1: Preparation of compound 680-2: 1- [2- (4-fluorophenyl) pyrazol-3-yl] ethanone

To a solution of 1- (1H-pyrazol-3-yl) ethanone (2 g, 18.16 mmol, 1 eq) in Pyridine (30 mL) was added (4-fluorophenyl) boronic acid (3.05 g, 21.80 mmol, 1.2 eq) , Cu (OAc) ₂ (4.95 g, 27.24 mmol, 1.5 eq) and 4A MS (1.5 g, 1.00 eq) . The mixture was stirred at 40 ℃ for 16 hr. The mixture was filtered and the filter was diluted with brine (100 mL) and extracted with EtOAc (30 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 30/70) to afford the title product as a colorless oil (380 mg, 10.25%) .

¹HNMR (400 MHz, DMSO-d₆) δ 7.82 –7.78 (m, 1H) , 7.47 –7.42 (m, 2H) , 7.33 –7.27 (m, 3H) , 2.51 (s, 3H) .

Step 2: Preparation of compound 680-3: methyl 6- [ (E) -3- [2- (4-fluorophenyl) pyrazol-3-yl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate

To a solution of 1- [2- (4-fluorophenyl) pyrazol-3-yl] ethanone (380 mg, 1.86 mmol, 1 eq) in Tol. (20 mL) was added K₃PO₄ (1.19 g, 5.58 mmol, 3 eq) and methyl 6-formylpyridine-2-carboxylate (460.98 mg, 2.79 mmol, 1.5 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (10 mL) and extracted with EtOAc (5 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 20/80) to afford the title product as a brown solid (200 mg, 30.59%) .

¹HNMR (400 MHz, DMSO-d₆) δ 8.21 –8.17 (m, 1H) , 8.15 –8.06 (m, 2H) , 7.91 (d, J = 2.0 Hz, 1H) , 7.89 –7.83 (m, 1H) , 7.72 –7.64 (m, 1H) , 7.56 –7.47 (m, 3H) , 7.36 –7.28 (m, 2H) , 3.95 –3.90 (m, 3H) .

Step 3: Preparation of compound 680-4: methyl 6- [3-cyclopropyl-1- [2- [2- (4-fluorophenyl) pyrazol-3-yl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate

A mixture of methyl 6- [ (E) -3- [2- (4-fluorophenyl) pyrazol-3-yl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate (200 mg, 569.26 μmol, 1 eq) in dioxane (20 mL) and EtOH (5 mL) was added TEA (518.43 mg, 5.12 mmol, 713.12 μL, 9 eq) , 2-cyclopropylacetaldehyde (478.84 mg, 5.69 mmol, 10 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol chloride (191.98 mg, 711.58 μmol, 1.25 eq) then suspension was degassed under vacuum and purged with N₂ for 3 times. The mixture was stirred at 100 ℃ for 16 hr. The mixture was diluted with brine (10 mL) and extracted with EtOAc (5 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown oil (220 mg, 88.75%) .

MS (ESI, pos. ion) m/z: 436.2 [M+H] ⁺. Rt=0.972/1.5 min.

Step 4: Preparation of compound 680-5: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [2- (4-fluorophenyl) pyrazol-3-yl] pyrrol-3-yl] pyridine-2-carboxylate

A mixture of methyl 6- [3-cyclopropyl-1- [2- [2- (4-fluorophenyl) pyrazol-3-yl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate (220 mg, 505.23 μmol, 1 eq) in AcOH (3 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (269.50 mg, 606.27 μmol, 1.2 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (256 mg, 60.04%) .

MS (ESI, pos. ion) m/z: 844.4 [M+H] ⁺. Rt=1.237/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.96 –7.90 (m, 1H) , 7.85 –7.77 (m, 2H) , 7.76 –7.67 (m, 2H) , 7.32 –7.25 (m, 2H) , 7.24 –7.16 (m, 2H) , 6.95 –6.88 (m, 5H) , 6.81 –6.69 (m, 6H) , 6.55 –6.51 (m, 1H) , 5.11 –4.96 (m, 2H) , 4.20 (s, 4H) , 3.91 –3.85 (m, 3H) , 3.69 (s, 6H) , 3.23 –3.13 (m, 2H) , 1.02 –0.84 (m, 1H) , 0.31 –0.21 (m, 4H) .

Step 5: Preparation of compound 680-6: methyl 6- [2- (cyclopropylmethyl) -5- [2- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [2- (4-fluorophenyl) pyrazol-3-yl] pyrrol-3-yl] pyridine-2-carboxylate (256 mg, 303.34 μmol, 1 eq) in DCM (3 mL) was added TFA (1.39 g, 12.23 mmol, 908.70 μL, 40.33 eq) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (130 mg, 71.00%) .

MS (ESI, pos. ion) m/z: 604.2 [M+H] ⁺, Rt=1.078/1.5 min.

Step 6: Preparation of compound 680: 6- [2- (cyclopropylmethyl) -5- [2- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -5- [2- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (130.00 mg, 215.36 μmol, 1 eq) in THF (1 mL) and MeOH (3 mL) . A solution of LiOH (51.58 mg, 2.15 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150×30mm×5um; mobile phase: [water (FA) -ACN] ; gradient: 40%-60%B over 11 min) to afford the title product as a yellow solid (50.4 mg, 39.69%) .

MS (ESI, pos. ion) m/z: 590.1 [M+H] ⁺, Rt=0.927/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.06 –7.00 (m, 1H) , 6.91 (dd, J = 2.8, 7.6 Hz, 2H) , 6.88 –6.84 (m, 1H) , 6.82 –6.75 (m, 3H) , 6.42 –6.32 (m, 4H) , 6.07 –6.02 (m, 1H) , 5.89 –5.76 (m, 2H) , 5.66 (d, J = 1.8 Hz, 1H) , 4.24 –4.06 (m, 2H) , 2.34 (br d, J = 6.6 Hz, 2H) , 1.21 (s, 1H) , 0.07 --0.09 (m, 1H) , -0.61 --0.73 (m, 4H) .

Example 48: Synthesis of compound 678

Step 1: Preparation of compound 678-2: 4- (3-acetyl-1H-pyrazol-1-yl) benzonitrile

To a solution of 1- (1H-pyrazol-3-yl) ethan-1-one (2.0 g, 18.16 mmol, 1.2 eq) and 4-bromobenzonitrile (2.7 g, 15.14 mmol, 1.0 eq) in DMSO (40 mL) was added K₂CO₃ (4.2 g, 30.27 mmol, 2.0 eq) , CuI (576 mg, 3.03 mmol, 0.2 eq) and L-Proline (697 mg, 6.05 mmol, 0.4 eq) . The resulting was stirred at 100 ℃ for 3 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (100 mL) , extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (905 mg, 4.28 mmol, 28.3%) .

MS (ESI, pos. ion) m/z: 212.0 [M+1] ⁺ , Rt=0.782/2min.

Step 2: Preparation of compound 678-3: methyl (E) -6- (3- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of 4- (3-acetyl-1H-pyrazol-1-yl) benzonitrile (905 mg, 4.28 mmol, 1.2 eq) and methyl 6-formylpicolinate (590 mg, 3.57 mmol, 1.0 eq) in Toluene (20 mL) was added K₃PO₄ (2.3 g, 10.72 mmol, 3.0 eq) . The resulting was stirred at 80 ℃ for 18 hours. After the reaction completion, the mixture was diluted with H₂O (40 mL) and extracted with DCM (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (384 mg, 1.07 mmol, 25.0%) .

MS (ESI, pos. ion) m/z: 358.9 [M+1] ⁺ , Rt=0.948/2min.

Step 3: Preparation of compound 678-4: methyl 6- (1- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) picolinate (384 mg, 1.07 mmol, 1.0 eq) and 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (360 mg, 1.34 mmol, 1.2 eq) , TEA (975 mg, 9.65 mmol, 9.0 eq) in a mixed solution of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (1407 mg, 16.76 mmol, 5.0 eq) . The resulting was stirred at 100 ℃ for 2 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (437 mg, 0.98 mmol, 92.1%) .

MS (ESI, neg. ion) m/z: 441.0 [M-1] ⁺, Rt=0.945/2min.

Step 4: Preparation of compound 678-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (437 mg, 0.98 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (570 mg, 1.28 mmol, 1.3 eq) in AcOH (16 mL) was added EtOH (4 mL) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction completion, the mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (661 mg, 0.77 mmol , 78.5%) .

MS (ESI, pos. ion) m/z: 851.1 [M+1] ⁺, Rt=1.25/2min

Step 5: Preparation of compound 678-6: methyl 6- (5- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate (360 mg, 0.42 mmol, 1.0 eq) in DCM (9 mL) was added TFA (3 mL) . The resulting was stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (220 mg, 0.36 mmol, 85.0%) .

MS (ESI, pos. ion) m/z: 611.10 [M+1] ⁺, Rt=1.125/2min

Step 6: Preparation of compound 678: 6- (5- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (5- (1- (4-cyanophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (220 mg, 0.36 mmol, 1.0 eq) in a mixed solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (60 mg, 1.44 mmol, 4.0 eq) in H₂O (2 mL) . The mixture was stirred at RT for 18 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (85 mg, 0.14 mmol, 39.5%) .

MS (ESI, pos. ion) m/z: 597.0 [M+1] ⁺, Rt=0.97/2min.

¹HNMR (400 MHz, DMSO-d₆₎ δ = 13.31 –12.64 (br s, 1H) , 8.64 (d, J = 2.8 Hz, 1H) , 7.98 –7.88 (m, 4H) , 7.87 –7.79 (m, 3H) , 7.72 (t, J = 7.8 Hz, 1H) , 7.58 (s, 2H) , 7.38 (s, 1H) , 7.02 –6.93 (m, 3H) , 5.95 (br s, 1H) , 6.02 –5.87 (m, 1H) , 3.32 –3.29 (m, 2H) , 1.01 –0.87 (m, 1H) , 0.32 –0.22 (m, 4H) .

Example 49: Synthesis of compound 724

Step 1: Preparation of compound 724-2: 1- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) ethan-1-one

To a stirred solution of 1- (1H-pyrazol-4-yl) ethan-1-one (1.00 g, 9.08 mmol, 1.0 eq) and (4-fluorophenyl) boranediol (1.27 g, 9.08 mmol, 1.0 eq) in DMF (10 mL) was added cupric bis (acetate) (1.24 g, 6.81 mmol, 0.75 eq) and pyridine (1.47 mL, 18.16 mmol, 2.0 eq) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by NaHCO₃ solution (10 mL) and extracted with EA (20 mL × 3) . The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 20%to 50%EtOAc in petroleum ether, to afford the title product as a white solid (1.5 g, 7.35 mmol, 81%) .

MS (ESI, pos. ion) m/z: 205.0 [M+1] ⁺, Rt=1.053/2min.

Step 2: Preparation of compound 724-3: methyl (E) -6- (3- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -3-oxoprop-1-en-1-yl) picolinate

To the solution of 1- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) ethan-1-one (500 mg, 2.45 mmol, 1.0 eq) and methyl 6-formylpicolinate (404 mg, 2.45 mmol , 1.0 eq) in toluene (20 mL) was added 4-methylbenzenesulfonic acid (126 mg, 0.73 mmol , 0.3 eq) . The reaction mixture was stirred at 140 ℃ to remove water by Dean-Stark trap for 18 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 30%to 60%EtOAc in petroleum ether, to afford the title product as a white solid (200 mg, 0.57 mmol, 23.25%) .

MS (ESI, pos. ion) m/z: 352.2 [M+1] ⁺, Rt=1.172/2min.

Step 3: Preparation of compound 724-4: methyl 6- (5-cyclopropyl-1- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -3-oxoprop-1-en-1-yl) picolinate (100 mg, 0.28 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3 -thiazol-3-ium chloride (92 mg, 0.34 mmol, 1.2 eq) , TEA (259 mg, 2.56 mmol, 9.0 eq) in a mixture solvent of dioxane (4 mL) in EtOH (1 mL) . The mixture was added 2-cyclopropylacetaldehyde (120 mg, 1.42 mmol, 5.0 eq) . The resulting was stirred at 100 ℃ for 1 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (5 mL) and extracted with EA (10 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (60 mg, 0.14 mol, 48%) .

MS (ESI, pos. ion) m/z: 436.2 [M+1] ⁺, Rt=1.269/2min.

Step 4: Preparation of compound 724-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5-cyclopropyl-1- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1, 4-dioxopentan-3-yl) picolinate (250 mg, 0.57 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (332 mg, 0.75 mmol, 1.3 eq) in EtOH (4 mL) was added AcOH (16 mL) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction completion, the mixture was diluted with H₂O (30 mL) , extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (300 mg, 0.36 mol, 62%) .

MS (ESI, pos. ion) m/z: 844.1 [M+1] ⁺, Rt=1.337/2min.

Step 5: Preparation of compound 724-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) picolinate

To a solution of 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) picolinate (300 mg, 0.36 mmol, 1.0 eq) in DCM (9 mL) was added TFA (3 mL) . The mixture was stirred at 30 ℃ for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 10%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (150 mg, 0.25 mol, 70%) .

MS (ESI, pos. ion) m/z: 604.4 [M+1] ⁺, Rt=1.340/2min.

Step 6: Preparation of compound 724: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) picolinate (150 mg, 0.25 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (2 mL) was added a solution of LiOH (52 mg, 1.24 mmol, 5.0 eq) in H₂O (2 mL) . The resulting was stirred at RT for 3 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 N HCl, diluted with H₂O (5 mL) , extracted with EA (5 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column (eluent: 45%to 95% (v/v) CH₃CN and H₂O with 0.1%HCOOH) to afford the title product as a yellow solid (77 mg, 0.13 mol, 53%) .

MS (ESI, pos. ion) m/z: 590.4 [M+1] ⁺ , Rt=1.430/3min.

¹HNMR (400 MHz, DMSO) δ 12.90 (s, 1H) , 8.60 (s, 1H) , 7.92 (t, J = 7.8 Hz, 1H) , 7.87 –7.81 (m, 3H) , 7.80 –7.76 (m, 2H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.58 (s, 2H) , 7.39 –7.32 (m, 2H) , 6.99 –6.85 (m, 3H) , 5.54 (s, 2H) , 3.27 (d, J = 6.8 Hz, 2H) , 0.89 (dt, J = 18.5, 6.8 Hz, 1H) , 0.35 –0.21 (m, 4H) .

Example 50: Synthesis of compound 725

Step 1: Preparation of compound 725-2: 1- (1- (4-fluorophenyl) -1H-imidazol-4-yl) ethan-1-one

To a solution of 1- (1H-imidazol-4-yl) ethan-1-one (3.0 g, 27.24 mmol, 1.0 eq) in DCM (30 mL) was added (4-fluorophenyl) boranediol (7.62 g, 54.48 mmol, 2.0 eq) , cupric bis (acetate) (5.44 g, 29.97 mmol, 1.2 eq) and TEA (11.36 mL, 81.73 mmol, 3.0 eq) . The mixture was stirred at 25 ℃ for 24 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0%to 80%EtOAc in petroleum ether as a gradient to give the title product as a yellow solid (400 mg, 7.19 %) .

MS (ESI, pos. ion) m/z: 205.0 [M+H] ⁺. Rt=1.04/3min.

¹HNMR (400 MHz, DMSO-d₆) δ = 8.47 (t, J = 1.2 Hz, 1H) , 8.35 (d, J = 1.6 Hz, 1H) , 7.82-7.79 (m, 2H) , 7.44-7.39 (m, 2H) , 2.46 (s, 3H) .

Step 2: Preparation of compound 725-3: methyl (E) -6- (3- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of 1- (1- (4-fluorophenyl) -1H-imidazol-4-yl) ethan-1-one (240 mg, 1.18 mmol, 1.0 eq) and methyl 6-formylpicolinate (291.16 mg, 1.76 mmol, 1.5 eq) in toluene (10 mL) was added K₃PO₄ (748.42 mg, 3.53 mmol, 3.0 eq) . The mixture was stirred at 120 ℃ for 18 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0%to 60%EtOAc in petroleum ether as a gradient to give the title product as a white solid (78 mg, 18.89 %) .

MS (ESI, pos. ion) m/z: 352.1 [M+H] ⁺. Rt=1.109/2min.

Step 3: Preparation of compound 725-4: methyl 6- (5-cyclopropyl-1- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -3-oxoprop-1-en-1-yl) picolinate (140 mg, 0.40 mmol, 1.0 eq) and 2-cyclopropylacetaldehyde (167 mg, 1.99 mmol, 4.0 eq) in dioxane (4 mL) and EtOH (1 mL) were added TEA (369 mg, 3.59 mmol, 9.0 eq) and 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (129 mg, 0.48 mmol, 1.2 eq) . The mixture was stirred at 100 ℃ for 18 h. The reaction was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0%to 10%MeOH in DCM as a gradient to give the title product as a yellow oil (160 mg, 92.20 %) .

MS (ESI, pos. ion) m/z: 435.9 [M+H] ⁺. Rt=1.225/2min.

Step 4: Preparation of compound 725-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -1H-pyrrol-3-yl) picolinate

A solution of methyl 6- (5-cyclopropyl-1- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -1, 4-dioxopentan-3-yl) picolinate (160 mg, 0.37 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (327 mg, 0.73 mmol, 2.0 eq) in HOAc (3 mL) was stirred at 100 ℃for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0%to 50%EtOAc in petroleum ether as a gradient to give the title product as a green oil (280 mg, 90.3%) .

MS (ESI, pos. ion) m/z: 844.2 [M+H] ⁺. Rt=1.487/2min.

Step 5: Preparation of compound 725-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -1H-pyrrol-3-yl) picolinate (280 mg, 0.33 mmol, 1.0 eq) in DCM (6 mL) was added TFA (3 mL) . The mixture was stirred at 30 ℃ for 18 h. The reaction was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0%to 10%MeOH in DCM as a gradient to give the title product as a yellow oil (190 mg, 94.87 %) .

MS (ESI, pos. ion) m/z: 604.2 [M+H] ⁺. Rt=1.204/2min.

Step 6: Preparation of compound 725: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -1H-imidazol-4-yl) -1H-pyrrol-3-yl) picolinate (190 mg, 0.31 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) and THF (2 mL) in H₂O (2 mL) was added LiOH·H₂O (66 mg, 1.57 mmol, 5.0 eq) . The mixture was stirred at rt for 2 h. The reaction was acidified by HCl (1 N) to pH = 5 and extracted with EA (20 mL x 2) . The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC ( (Waters-CORTECS-C18-2.7μm-4.6×30mm (eluent: 0%to 95% (v/v) CH₃CN and H₂O with 0.1%FA) ) to give the title product as a yellow solid (77.11 mg, 41.55 %) .

MS (ESI, pos. ion) m/z: 590.2 [M+H] ⁺. Rt=0.933/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 12.90 (s, 1H) , 8.23 (d, J = 1.2 Hz, 1H) , 7.96 (d, J = 1.2 Hz, 1H) , 7.92 (t, J = 7.6 Hz, 1H) , 7.81-7.78 (m, 2H) , 7.73-7.68 (m, 3H) , 7.57 (s, 2H) , 7.41-7.37 (m, 2H) , 7.00 (s, 1H) , 6.95 (d, J = 2.8 Hz, 1H) , 6.92 (s, 1H) , 5.86 (s, 2H) , 3.20 (d, J = 6.4 Hz, 2H) , 0.93-0.90 (m, 1H) , 0.26-0.21 (m, 4H) .

Example 51: Synthesis of compound 730

Step 1: Preparation of compound 730-2: 4- (4-fluorophenyl) oxazole

To a solution of 2-bromo-1- (4-fluorophenyl) ethan-1-one (20.0 g, 0.09 mol, 1.0 eq) and Ammonium formate (22.0 g, 0.35 mol, 3.8 eq) in FA (400 mL) was stirred at 130 ℃ for 4 hours. After the reaction completion, the mixture was diluted with H₂O (100 mL) and extracted with DCM (100 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (4.65g, 0.03 mol, 30.9%) .

MS (ESI, pos. ion) m/z: 164.0 [M+1] ⁺ , Rt=0.836/2min.

Step 2: Preparation of compound 730-3: 1- (4- (4-fluorophenyl) oxazol-2-yl) ethan-1-one

To the solution of 4- (4-fluorophenyl) oxazole (2000 mg, 12.26 mmol, 1.0 eq) in THF (20 mL) was added n-Butyllithium (8.6 mL, 13.48 mmol, 1.6 mol/L) portion wise with the temperature was kept at -78 ℃ under N₂. The reaction mixture was stirred at -78 ℃ for 30 mins. The resulting mixture was added a solution of 1-morpholinoethan-1-one (2374 mg, 18.39 mmol, 1.5 eq) in THF (5 mL) . The reaction mixture was stirred at -78 ℃ for 1 hour and stirred at rt for another 2 hours. The reaction mixture was poured into saturated NH4Cl aqueous solution (50 mL) and extracted with EA (30 mL × 3) . The combined organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 8%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (680 mg, 3.31 mmol, 27.0%) .

MS (ESI, pos. ion) m/z: 205.9 [M+1] ⁺ , Rt=0.894/2min.

Step 3: Preparation of compound 730-4: methyl (E) -6- (3- (4- (4-fluorophenyl) oxazol-2-yl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of 1- (4- (4-fluorophenyl) oxazol-2-yl) ethan-1-one (680 mg, 3.31 mmol, 1.2 eq) and methyl 6-formylpicolinate (456 mg, 2.76 mmol, 1.0 eq) in Toluene (20 mL) was added PTSA (236 mg, 1.38 mmol, 0.5 eq) . The mixture was stirred at 140 ℃ to remove water by Dean-Stark trap for 18 hours. After the reaction completion, the mixture was diluted with H₂O (20 mL) , extracted with DCM (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (110 mg, 0.31 mmol, 9.42%) .

MS (ESI, pos. ion) m/z: 352.9 [M+1] ⁺, Rt=0.998/2min.

Step 4: Preparation of compound 730-5: methyl 6- (5-cyclopropyl-1- (4- (4-fluorophenyl) oxazol-2-yl) -1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (4- (4-fluorophenyl) oxazol-2-yl) -3-oxoprop-1-en-1-yl) picolinate (110 mg, 0.31 mmol, 1.0 eq) and 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (105 mg, 0.39 mmol, 1.2 eq) , TEA (284 mg, 2.81 mmol, 9.0 eq) in a mixed solvent of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (131 mg, 1.55 mmol, 5.0 eq) . The resulting was stirred at 100 ℃ for 2 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (120 mg, 0.27 mmol, 88.0%) .

MS (ESI, pos. ion) m/z: 437.9 [M+1] ⁺, Rt=2.550/2min.

Step 5: Preparation of compound 730-6: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4- (4-fluorophenyl) oxazol-2-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5-cyclopropyl-1- (4- (4-fluorophenyl) oxazol-2-yl) -1, 4-dioxopentan-3-yl) picolinate (120 mg, 0.27 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (160 mg, 0.36 mmol, 1.3 eq) in AcOH (16 mL) was added EtOH (4 mL) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction completion, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (130 mg, 0.15 mmol , 55.9%) .

MS (ESI, pos. ion) m/z: 845.0 [M+1] ⁺, Rt=1.408/2min.

Step 6: Preparation of compound 730-7: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4- (4-fluorophenyl) oxazol-2-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4- (4-fluorophenyl) oxazol-2-yl) -1H-pyrrol-3-yl) picolinate (130 mg, 0.15 mmol, 1.0 eq) in DCM (9 mL) was added TFA (3 mL) . The mixture was stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (88 mg, 0.14 mmol, 94.5%) .

MS (ESI, pos. ion) m/z: 605.1 [M+1] ⁺, Rt=1.18/2min.

Step 7: Preparation of compound 730: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4- (4-fluorophenyl) oxazol-2-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4- (4-fluorophenyl) oxazol-2-yl) -1H-pyrrol-3-yl) picolinate (88 mg, 0.14 mmol, 1.0 eq) in a mixed solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (25 mg, 0.59 mmol, 4.0 eq) in H₂O (2 mL) . The mixture was stirred at RT for 18 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, washed with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm × 25 mm × 10 um column) (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (38 mg, 0.06 mmol, 44.2%) .

MS (ESI, pos. ion) m/z: 591.0 [M+1] ⁺, Rt=1.067/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.15 –12.90 (br s, 1H) , 8.56 (s, 1H) , 8.04 –7.91 (m, 2H) , 7.87 –7.81 (m, 1H) , 7.79 –7.68 (m, 3H) , 7.57 (d, J = 4.0 Hz, 3H) , 7.27 (t, J = 8.9 Hz, 2H) , 7.07 (d, J = 11.0 Hz, 1H) , 6.94 (d, J = 8.0 Hz, 1H) , 6.06 (br s, 1H) , 6.14 –5.95 (m, 1H) , 3.35 (br s, 2H) , 1.01 –0.88 (m, 1H) , 0.31 –0.22 (m, 4H) .

Example 52: Synthesis of compounds 766 and 767

Preparation of compound 698-1: 1- (1- (4-fluorophenyl) piperidin-3-yl) ethan-1-one

Step 1: Preparation of compound 698-b: methyl 1- (4-fluorophenyl) piperidine-3-carboxylate

A mixture of methyl piperidine-3-carboxylate (5 g, 34.92 mmol) in dioxane (50 mL) was added Cs₂CO₃ (22.76 g, 69.84 mmol) , RuPhos Pd G3 (1.46 g, 1.75 mmol) and 1-fluoro-4-iodo-benzene (9.30 g, 41.90 mmol) . The mixture was stirred at 80 ℃ for 16 hrs under N₂ atmosphere. The mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with THF/PE=0/100 to 2/10) to afford the title product as a brown oil (4 g, 48.3%) .

MS (ESI, pos. ion) m/z: 238.1 [M+1] ⁺. Rt=0.838/1.5min.

Step 2: Preparation of compound 698-c: 1- (4-fluorophenyl) piperidine-3-carboxylic acid

A mixture of methyl 1- (4-fluorophenyl) piperidine-3-carboxylate (4 g, 16.86 mmol) in MeOH (10 mL) and THF(10 mL) was added NaOH (3.37 g, 84.29 mmol) in H₂O (5 mL) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was diluted with 1 N HCl (30 mL) and extracted with EtOAc (30 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with THF/PE=0/100 to 3/10) to afford the title product as a brown oil (1.96 g, 52.1%) .

MS (ESI, pos. ion) m/z: 224.1 [M+1] ⁺. Rt=0.656/1.0min.

¹H NMR (400 MHz, CHLOROFORM-d) δ 6.99 (d, J = 6.5 Hz, 4H) , 3.75 (br t, J = 6.5 Hz, 1H) , 3.34 -3.28 (m, 1H) , 3.27 -3.19 (m, 1H) , 3.16 -3.08 (m, 1H) , 3.07 -2.99 (m, 1H) , 2.85 -2.75 (m, 1H) , 1.98 -1.83 (m, 4H) , 1.83 -1.73 (m, 1H) .

Step 3: Preparation of compound 698-d: 1- (4-fluorophenyl) -N-methoxy-N-methylpiperidine-3-carboxamide

A mixture of 1- (4-fluorophenyl) piperidine-3-carboxylic acid (1.96 g, 8.78 mmol) and N-methoxymethanamine hydrochloride (1.71 g, 17.56 mmol) in Dioxane (30 mL) was added DIEA (3.40 g, 26.34 mmol) and T₄P (7.59 g, 10.54 mmol) . The mixture was stirred at 100 ℃ for 2 hrs. The mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3) , The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with THF/PE=0/100 to 2/10) to afford the title product as a brown oil (1.78 g, 76.1%) .

MS (ESI, pos. ion) m/z: 267.2 [M+1] ⁺, Rt=0.750/1.5min.

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.00 -6.86 (m, 4H) , 3.72 (s, 3H) , 3.65 -3.52 (m, 2H) , 3.26 -3.15 (m, 3H) , 3.12 -2.99 (m, 1H) , 2.91 -2.78 (m, 1H) , 2.76 -2.64 (m, 1H) , 1.94 (br d, J = 12.7 Hz, 1H) , 1.87 -1.61 (m, 3H) .

Step 4: Preparation of compound 698-1: 1- (1- (4-fluorophenyl) piperidin-3-yl) ethan-1-one

A mixture of 1- (4-fluorophenyl) -N-methoxy-N-methyl-piperidine-3-carboxamide (1.78 g, 6.68 mmol) in THF(20 mL) was added dropwise MeMgBr (3 M, 6.68 mL) at -78 ℃ under N₂ atmosphere. The mixture was stirred at 25 ℃ for 1 hr. The mixture was diluted with sat. NH₄Cl (50 mL) and extracted with EtOAc (30 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with THF/PE=0/100 to 3/10) to afford the title product as a yellow oil (1.5 g, crude) .

MS (ESI, pos. ion) m/z: 222.2 [M+1] ⁺, Rt=0.741/1.5min.

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.01 -6.86 (m, 4H) , 3.63 -3.52 (m, 1H) , 3.47 -3.36 (m, 1H) , 2.90 -2.77 (m, 1H) , 2.76 -2.63 (m, 2H) , 2.25 -2.19 (m, 3H) , 2.11 -1.98 (m, 1H) , 1.90 -1.66 (m, 2H) , 1.58 -1.41 (m, 1H) .

Preparation of compound 698-2: methyl 2-formylpyrimidine-4-carboxylate

Step 1: Preparation of compound 698-f: methyl 2-vinylpyrimidine-4-carboxylate

A mixture of methyl 2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol) and potassium; trifluoro (vinyl) boranuide (582.16 mg, 4.35 mmol) in dioxane (5 mL) and H₂O (1 mL) was added K₃PO₄ (1.23 g, 5.79 mmol) and Pd (PPh₃) ₂Cl₂ (203.37 mg, 289.74 μmol) . The mixture was stirred at 80 ℃for 16 hrs under N₂ atmosphere. The mixture was diluted with H₂O (3 mL) and extracted with EtOAc (3 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 2/10) to afford the title product as a brown oil (680 mg, 71.5%) .

MS (ESI, pos. ion) m/z: 165.1 [M+1] ⁺. Rt=0.716/1.5min.

Step 2: Preparation of compound 698-2: methyl 2-formylpyrimidine-4-carboxylate

A mixture of methyl 2-vinylpyrimidine-4-carboxylate (680 mg, 4.14 mmol) in H₂O (2 mL) and dioxane (10 mL) was added 2, 6-LUTIDINE (887.71 mg, 8.28 mmol) , NaIO₄ (5.32 g, 24.85 mmol) and K₂OsO₄.2H₂O (76.31 mg, 207.11 μmol) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with THF/PE=0/100 to 6/10) to afford the title product as a yellow oil (320 mg, 23.3%) .

¹H NMR (400 MHz, DMSO-d₆) δ 10.07 -9.99 (m, 1H) , 9.38 -9.30 (m, 1H) , 8.27 -8.17 (m, 1H) , 4.00 -3.94 (m, 3H) .

Preparation of compound 698-6: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

Step 1: Preparation of compound 698-3: methyl (E) -2- (3- (1- (4-fluorophenyl) piperidin-3-yl) -3-oxoprop-1-en-1-yl) pyrimidine-4-carboxylate

A mixture of methyl 2-formylpyrimidine-4-carboxylate (320 mg, 1.93 mmol) and 1- [1- (4-fluorophenyl) -3-piperidyl] ethenone (639.30 mg, 2.89 mmol) in Tol. (5 mL) was added K₃PO₄ (1.23 g, 5.78 mmol) . The mixture was stirred at 85 ℃ for 16 hrs. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel(eluting with THF/PE=0/100 to 3/10) to afford the title product as a brown oil (100 mg, 14%) .

MS (ESI, pos. ion) m/z: 370.2 [M+1] ⁺, Rt=0.856/1.5min.

Step 2: Preparation of compound 698-4: methyl 2- (5-cyclopropyl-1- (1- (4-fluorophenyl) piperidin-3-yl) -1, 4-dioxopentan-3-yl) pyrimidine-4-carboxylate

A mixture of methyl 2- [ (E) -3- [1- (4-fluorophenyl) -3-piperidyl] -3-oxo-prop-1-enyl] pyrimidine-4-carboxylate (100 mg, 270.72 μmol) in EtOH (1 mL) and dioxane (3 mL) was added TEA (246.55 mg, 2.44 mmol) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (91.30 mg, 338.40 μmol) then suspension was degassed under vacuum and purged with N₂ for 3 times. Then 2-cyclopropylacetaldehyde (182.17 mg, 2.17 mmol) was added. The mixture was stirred at 100 ℃ for 16 hrs. The mixture was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL×3) , The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with THF/PE=0/100 to 2/10) to afford the title product as a yellow oil (130 mg, crude) .

MS (ESI, pos. ion) m/z: 454.1 [M+1] ⁺, Rt=0.887/1.5min.

Step 3: Preparation of compound 698-5: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

A mixture of methyl 2- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -3-piperidyl] -2-oxo-ethyl] -2-oxo-propyl] pyrimidine-4-carboxylate (130 mg, 286.66 μmol) in AcOH (3 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (133.80 mg, 300.99 μmol) . The mixture was stirred at 80 ℃ for 16 hrs. The mixture was diluted with brine (3 mL) and extracted with EtOAc (3 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with THF/PE=0/100 to 3/10) to afford the title product as a brown oil (80 mg, 32.4%) .

MS (ESI, pos. ion) m/z: 862.3 [M+1] ⁺, Rt=1.171/1.5min.

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.91 -8.84 (m, 1H) , 7.90 -7.80 (m, 1H) , 7.63 (d, J = 4.9 Hz, 1H) , 6.99 -6.88 (m, 8H) , 6.85 -6.66 (m, 6H) , 5.45 -5.19 (m, 2H) , 4.29 (s, 4H) , 4.01 (s, 3H) , 3.79 -3.71 (m, 7H) , 3.63 -3.43 (m, 2H) , 3.35 -3.08 (m, 2H) , 2.83 -2.64 (m, 2H) , 2.31 -2.23 (m, 2H) , 0.98 -0.89 (m, 1H) , 0.43 -0.29 (m, 4H) .

Step 4: Preparation of compound 698-6: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

A mixture of methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyrimidine-4-carboxylate (80 mg, 92.81 μmol) in DCM (2 mL) was added TFA (52.91 mg, 464.04 μmol) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was concentrated under vacuum. to afford the title product as a brown oil (140 mg, crude) .

MS (ESI, pos. ion) m/z: 622.2 [M+1] ⁺, Rt=0.957/1.5min.

Preparation of compound 766: (S) -2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

Step 1: Preparation of compound 766-1: methyl (S) -2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate and compound 767-1: methyl (R) -2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

Compound 698-5 (160 mg) was separated by SFC (column: DAICEL CHIRALCEL OD (250mm×30mm, 10um) ; mobile phase: [CO₂-EtOH (0.1%NH₃H₂O) ] ; B%: 50%%, isocratic elution mode) to afford 766-1 as a yellow oil (41.5 mg) and 767-1 as a yellow oil (49.0 mg) .

Step 2: Preparation of compound 766: (S) -2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

A mixture of methyl 2- [2- (cyclopropylmethyl) -5- [ (3R) -1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate (41.5 mg, 66.75 μmol) in THF (2 mL) and MeOH (2 mL) was added LiOH (15.99 mg, 667.53 μmol) in H₂O (1 mL) . The mixture was stirred at 25 ℃ for 1 hr. The mixture was diluted with 1N HCl (3 mL) and extracted with EtOAc (3 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150×30 mm×5 um; mobile phase: [Water (FA) -MeCN] ; gradient: 30%-70%B over 10 min) to afford the title product as a yellow solid (28.98 mg, 71%) .

MS (ESI, pos. ion) m/z: 608.1 [M+1] ⁺, Rt=0.896/1.5min.

¹H NMR (400 MHz, DMSO-d₆) δ 8.97 –8.82 (m, 1H) , 7.85 –7.74 (m, 1H) , 7.72 –7.62 (m, 2H) , 7.61 –7.52 (m, 1H) , 7.06 –6.89 (m, 3H) , 6.87 –6.76 (m, 2H) , 6.57 (br d, J = 9.2 Hz, 2H) , 5.49 –5.34 (m, 2H) , 3.59 –3.52 (m, 1H) , 3.23 –3.10 (m, 2H) , 2.75 –2.55 (m, 4H) , 1.92 –1.79 (m, 1H) , 1.78 –1.65 (m, 1H) , 1.63 –1.48 (m, 2H) , 0.94 –0.80 (m, 1H) , 0.35 –0.17 (m, 4H) .

Preparation of compound 767: (R) -2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

A mixture of methyl 2- [2- (cyclopropylmethyl) -5- [ (3S) -1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate (49 mg, 78.82 μmol) in THF (2 mL) and MeOH (2 mL) was added LiOH (18.88 mg, 788.17 μmol) in H₂O (1 mL) . The mixture was stirred at 25 ℃for 1 hr. The mixture was diluted with 1N HCl (3 mL) and extracted with EtOAc (3 mL×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150×30 mm×5 um; mobile phase: [Water (FA) -MeCN] ; gradient: 30%-70%B over 10 min) to afford the title product as a yellow solid (28.19 mg, 58.8%) .

MS (ESI, pos. ion) m/z: 608.2 [M+1] ⁺, Rt=0.888/1.5min.

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J = 5.1 Hz, 1H) , 7.85 –7.75 (m, 1H) , 7.73 –7.63 (m, 2H) , 7.61 –7.49 (m, 1H) , 7.02 –6.89 (m, 3H) , 6.88 –6.75 (m, 2H) , 6.69 –6.58 (m, 2H) , 5.49 –5.35 (m, 2H) , 3.60 –3.51 (m, 1H) , 3.24 –3.10 (m, 2H) , 2.79 –2.55 (m, 4H) , 1.93 (br d, J = 1.3 Hz, 1H) , 1.78 –1.64 (m, 1H) , 1.63 –1.46 (m, 2H) , 0.96 –0.78 (m, 1H) , 0.15 (br d, J = 1.8 Hz, 4H) .

Example 53: Synthesis of compounds 631

Step 1: Preparation of compound 631-2: methyl 6- [ (E) -3- (3-bromophenyl) -3-oxo-prop-1-enyl] pyridine-2-carboxylate

To a solution of methyl 6-formylpyridine-2-carboxylate (8.30 g, 50.24 mmol, 2 eq) in THF (150 mL) was added DBU (11.47 g, 75.36 mmol, 11.36 mL, 3 eq) and 1- (3-bromophenyl) 135thenone (5 g, 25.12 mmol, 3.32 mL, 1 eq) . The mixture was stirred at 25 ℃ for 16 hr. The combined reaction mixture was poured into water (50 mL) and the compound was precipitated from water. The mixture was filtered and the filter cake was washed with water and concentrated under vacuum to afford the title product as a brown solid (4.3 g, 49.45%) .

¹HNMR (400 MHz, DMSO-d₆) δ 8.32 –8.22 (m, 2H) , 8.18 –8.05 (m, 4H) , 7.95 –7.89 (m, 1H) , 7.78 –7.71 (m, 1H) , 7.60 –7.54 (m, 1H) , 3.99 –3.85 (m, 3H) .

Step 2: Preparation of compound 631-3: methyl 6- [1- [2- (3-bromophenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] pyridine-2-carboxylate

A mixture of methyl 6- [ (E) -3- (3-bromophenyl) -3-oxo-prop-1-enyl] pyridine-2-carboxylate (2 g, 5.78 mmol, 1 eq) in dioxane (20 mL) and EtOH (5 mL) was added TEA (5.26 g, 52.00 mmol, 7.24 mL, 9 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (1.95 g, 7.22 mmol, 1.25 eq) then suspension was degassed under vacuum and purged with N₂ for 3 times. Then, 2-cyclopropylacetaldehyde (4.0 g, 47.55 mmol, 8.23 eq) was added. The mixture was stirred at 100 ℃ for 16 hr. The mixture was diluted with brine (50 mL) and extracted with EtOAc (50 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 20/80) to afford the title product as a brown oil (2.15 g, 86.49%) .

MS (ESI, pos. ion) m/z: 430.1/432.1 [M+H] ⁺. Rt=1.063/1.5 min.

Step 3: Preparation of compound 631-4: methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromophenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] pyridine-4-carboxylate

A mixture of methyl 6- [1- [2- (3-bromophenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] pyridine-2-carboxylate (1 g, 2.32 mmol, 1 eq) in AcOH (20 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (1.24 g, 2.79 mmol, 1.2 eq) . The mixture was stirred at 80 ℃for 16 hr. The mixture was diluted with brine (20 mL) and extracted with EtOAc (10 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (1.4 g, 71.82%) .

MS (ESI, pos. ion) m/z: 838.2/840.2 [M+H] +. Rt=1.301/1.5 min.

Step 4: Preparation of compound 631-5: methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromophenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] pyridine-4-carboxylate (1.40 g, 1.67 mmol, 1 eq) in DCM (20 mL) was added TFA (7.68 g, 67.31 mmol, 5 mL, 40.33 eq) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (976 mg, 97.71%) .

MS (ESI, pos. ion) m/z: 598.0/600.0 [M+H] ⁺. Rt=1.100/1.5 min.

Step 5: Preparation of compound 631-6: methyl 6- [2- (cyclopropylmethyl) -5- [3- (3-fluorophenyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (100 mg, 167.09 μmol, 1 eq) in THF (3 mL) and H₂O (0.8 mL) was added (4-fluorophenyl) boronic acid (46.76 mg, 334.18 μmol, 2 eq) , K₃PO₄ (106.40 mg, 501.27 μmol, 3 eq) , and Xphos Pd G3 (14.14 mg, 16.71 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with H₂O (5 mL) and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (86.7 mg, 84.55%) .

MS (ESI, pos. ion) m/z: 614.2 [M+H] ⁺, Rt=1.105/1.5 min.

Step 6: Preparation of compound 631: 6- [2- (cyclopropylmethyl) -5- [3- (3-fluorophenyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -5- [3- (3-fluorophenyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (86.7 mg, 141.28 μmol, 1 eq) in THF (1 mL) and MeOH (3 mL) . A solution of LiOH (33.84 mg, 1.41 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water (FA) -MeCN] ; gradient: 45%-75%B over 9 min) to afford the title product as a yellow solid (25.4 mg, 29.98%) .

MS (ESI, pos. ion) m/z: 600.1 [M+H] ⁺, Rt=1.034/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.94 –7.86 (m, 2H) , 7.81 –7.71 (m, 2H) , 7.67 –7.62 (m, 2H) , 7.61 –7.53 (m, 4H) , 7.50 –7.44 (m, 1H) , 7.39 –7.34 (m, 1H) , 7.29 –7.22 (m, 2H) , 7.00 –6.95 (m, 2H) , 6.88 –6.83 (m, 1H) , 5.52 –5.37 (m, 2H) , 3.24 (br d, J = 6.5 Hz, 2H) , 1.02 –0.88 (m, 1H) , 0.34 –0.19 (m, 4H) .

Example 54: Synthesis of compounds 731

Step 1: Preparation of compound 731-2: 1- (4-bromothiazol-2-yl) ethan-1-one

To the solution of 2, 5-dibromo-1, 3-thiazole (2000 mg, 8.23 mmol, 1.0 eq) in THF (20 mL) was added n-BuLi (9.06 mL, 9.06 mmol, 1.1 eq) at -78 ℃ dropwise under N₂ atmosphere. After addition, the mixture was stirred 30 mins, and then the 1- (1, 4-oxazinan-4-yl) ethan-1-one (1595 mg, 12.35 mmol, 1.5 eq) was added to the mixture and stirred at 25 ℃ for 1.5 hours. After the reaction was completed, the reaction mixture was poured into saturated NH₄Cl aqueous solution (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product (800 mg, 3.88 mmol, 47%) .

MS (ESI, pos. ion) m/z: 205.8, 207.8 [M+1] ⁺, Rt=0.775/2min.

Step 2: Preparation of compound 731-3: 1- (4- (4-fluorophenyl) thiazol-2-yl) ethan-1-one

To a solution of 1- (4-bromothiazol-2-yl) ethan-1-one (800 mg, 3.88 mmol, 1.0 eq) in dioxane (18 mL) was added K₂CO₃ (1610 mg, 11.65 mmol, 3.0 eq) , Pd (dppf) Cl₂ (288 mg, 0.39 mmol, 0.1 eq) , (4-fluorophenyl) boronic acid (543 mg, 3.88 mmol, 1.0 eq) and H₂O (5 mL) . The reaction mixture was stirred 80 ℃ for 2 hours under N2 atmosphere. After the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted with EA (30 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated. The mixture was purified by column chromatography through silica gel eluting with 0: 100 to 60: 40 petroleum ether: ethyl acetate, to afford the title compound (600 mg, 2.71 mmol, 70%) .

MS (ESI, pos. ion) m/z: 221.9 [M+1] ⁺, Rt=1.033/2min.

Step 3: Preparation of compound 731-4: methyl (E) -6- (3- (4- (4-fluorophenyl) thiazol-2-yl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of 1- (4- (4-fluorophenyl) thiazol-2-yl) ethan-1-one (300 mg, 1.36 mmol, 1.0 eq) and methyl 6-formylpyrazine-2-carboxylate (187 mg, 1.13 mmol, 1.0 eq) in toluene (20 mL) was added PTSA (97 mg, 0.56 mmol, 0.5 eq) . The reaction mixture was stirred at 140 ℃ to remove water by Dean-Stark trap for 18 h.After the reaction was completed, the mixture was diluted with H₂O (20 mL) , extracted with DCM (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (280 mg, 0.76 mmol, 55.9%) .

Step 4: Preparation of compound 731-5: methyl 6- (5-cyclopropyl-1- (4- (4-fluorophenyl) thiazol-2-yl) -1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (4- (4-fluorophenyl) thiazol-2-yl) -3-oxoprop-1-en-1-yl) picolinate (280 mg, 0.76 mmol, 1.0 eq) and 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (256 mg, 0.95 mmol, 1.2 eq) , TEA (692 mg, 6.84 mmol, 9.0 eq) in a mixture solvent of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (575 mg, 6.84 mmol, 9.0 eq) . The reaction mixture was stirred at 100 ℃ for 2 hours under N₂. After the reaction was completed, the mixture was diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (260 mg, 0.57 mmol, 76%) .

MS (ESI, pos. ion) m/z: 452.9 [M+1] ⁺, Rt=1.350/2min.

Step 5: Preparation of compound 731-6: ethyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4- (4-fluorophenyl) thiazol-2-yl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (5-cyclopropyl-1- (4- (4-fluorophenyl) thiazol-2-yl) -1, 4-dioxopentan-3-yl) picolinate (230 mg, 0.51 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (294 mg, 0.66 mmol, 1.3 eq) in AcOH (8 mL) was added EtOH (2 mL) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was diluted with H₂O (30 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (320 mg, 0.37 mmol, 72%) .

Step 6: Preparation of compound 731-7: ethyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4- (4-fluorophenyl) thiazol-2-yl) -1H-pyrrol-3-yl) picolinate

To a solution of ethyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4- (4-fluorophenyl) thiazol-2-yl) -1H-pyrrol-3-yl) picolinate (320 mg, 0.37 mmol, 1.0 eq) in DCM (9 mL) was added TFA (3 mL) . The reaction mixture was stirred at 25 ℃ for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (200 mg, 0.32 mmol, 84%) .

Step 7: Preparation of compound 731: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4- (4-fluorophenyl) thiazol-2-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of ethyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4- (4-fluorophenyl) thiazol-2-yl) -1H-pyrrol-3-yl) picolinate (200 mg, 0.32 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (40 mg, 0.95 mmol, 3.0 eq) in H₂O (2 mL) . The reaction was stirred at 25 ℃ for 2 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (120 mg, 0.20 mmol, 63%) .

MS (ESI, pos. ion) m/z: 607.1 [M+1] ⁺ , Rt=1.311/1.5min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.06 (br s, 1H) , 8.04 -7.90 (m, 3H) , 7.84 (d, J = 7.3 Hz, 1H) , 7.80 -7.67 (m, 3H) , 7.60 (s, 2H) , 7.51 (s, 1H) , 7.23 (t, J = 8.9 Hz, 2H) , 7.05 (d, J = 11.1 Hz, 1H) , 6.95 (d, J = 8.3 Hz, 1H) , 6.03 (br s, 2H) , 3.35 (br d, J = 6.4 Hz, 2H) , 1.01 -0.87 (m, 1H) , 0.38 -0.19 (m, 4H) .

Example 55: Synthesis of compounds 749

Step 1: Preparation of compound 749-2: methyl (E) -2- (3- (1- (3-fluorophenyl) piperidin-3-yl) -3-oxoprop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of 1- [1- (3-fluorophenyl) -3-piperidyl] ethanone (200.00 mg, 0.903 mmol, 1 eq) in Tol. (5 mL) was added K₃PO₄ (575.6 g, 2.71 mmol, 3 eq) and methyl 2-formylpyrimidine-4-carboxylate (180.20 mg, 1.08 mmol, 1.2 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (5 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (60 mg, 8.99%) .

MS (ESI, pos. ion) m/z: 370.2 [M+H] ⁺. Rt=0.957/1.5 min.

Step 2: Preparation of compound 749-3: methyl 2- [3-cyclopropyl-1- [2- [1- (3-fluorophenyl) -3-piperidyl] -2-oxo-ethyl] -2-oxo-propyl] pyrimidine-4-carboxylate

A mixture of methyl 2- [ (E) -3- [1- (3-fluorophenyl) -3-piperidyl] -3-oxo-prop-1-enyl] pyrimidine-4-carboxylate (60 mg, 162.43 μmol, 1 eq) in dioxane (3 mL) and EtOH (1 mL) was added TEA (147.93 mg, 1.46 mmol, 203.48 μL, 9 eq) , 2-cyclopropylacetaldehyde (136.63 mg, 1.62 mmol, 10 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (54.78 mg, 203.04 μmol, 1.25 eq) , then suspension was degassed under vacuum and purged with N₂ for 3 times. The mixture was stirred at 100 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown oil (70 mg, 95.03%) .

MS (ESI, pos. ion) m/z: 454.2 [M+H] ⁺. Rt=1.003/1.5 min.

Step 3: Preparation of compound 749-4: methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyrimidine-4-carboxylate

To a solution of methyl 2- [3-cyclopropyl-1- [2- [1- (3-fluorophenyl) -3-piperidyl] -2-oxo-ethyl] -2-oxo-propyl] pyrimidine-4-carboxylate (70 mg, 154.35 μmol, 1 eq) in AcOH (3 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (72.04 mg, 162.07 μmol, 1.05 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (67.8 mg, 50.96%) .

MS (ESI, pos. ion) m/z: 862.3 [M+H] +. Rt=1.254/1.5 min.

Step 4: Preparation of compound 749-5: methyl 2- [2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate

To a solution of methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyrimidine-4-carboxylate (67.8 mg, 78.65 μmol, 1 eq) in DCM (3 mL) was added TFA (361.68 mg, 3.17 mmol, 235.62 μL, 40.33 eq) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was used for next step directly to afford the title product as a brown solid (90 mg, crude) .

MS (ESI, pos. ion) m/z: 622.3 [M+H] ⁺. Rt=1.055/1.5 min.

Step 5: Preparation of compound 749: 2- [2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- [2- (cyclopropylmethyl) -5- [1- (3-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate (90 mg, 144.77 μmol, 1 eq) in THF (1 mL) and MeOH (3 mL) . A solution of LiOH (34.67 mg, 1.45 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH = 5～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water (FA) -MeCN] ; gradient: 38%-78%B over 10 min) to afford the title product as a yellow solid (11 mg, 12.5%) .

MS (ESI, pos. ion) m/z: 608.3 [M+H] ⁺, Rt=0.976/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.96 -8.89 (m, 1H) , 7.81 -7.75 (m, 1H) , 7.65 (s, 2H) , 7.62 -7.57 (m, 1H) , 7.15 -7.05 (m, 1H) , 6.99 -6.92 (m, 1H) , 6.85 -6.77 (m, 2H) , 6.61 (br d, J = 13.2 Hz, 1H) , 6.48 -6.40 (m, 1H) , 6.39 -6.30 (m, 1H) , 5.48 -5.38 (m, 2H) , 3.75 -3.60 (m, 2H) , 3.29 -3.24 (m, 1H) , 3.20 -3.13 (m, 1H) , 2.84 -2.74 (m, 2H) , 2.70 -2.62 (m, 1H) , 1.91 -1.81 (m, 1H) , 1.72 -1.44 (m, 3H) , 0.93 -0.80 (m, 1H) , 0.30 -0.19 (m, 4H) .

Example 56: Synthesis of compound 777

Step 1: Preparation of compound 777-2: ethyl 1- (3, 4-difluorophenyl) piperidine-3-carboxylate

A suspension of ethyl piperidine-3-carboxylate (6.0 g, 38.17 mmol, 1.0 eq) , 4-bromo-1, 2-difluorobenzene (11.5 g, 57.25 mmol, 1.5 eq) , Cs₂CO₃ (24.8 g, 85.44 mmol, 3.0 eq) and RuPhosPdG4 (1.62 g, 1.91 mmol, 0.05 eq) in dioxane (40 mL) was degassed under vacuum and purged with H₂ several times and stirred at 90 ℃ for 16 hours. After the reaction completion, the mixture was diluted with H₂O (50 mL) , extracted with EA (40 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (7.0 g, 25.99 mmol, 70%) .

MS (ESI, pos. ion) m/z: 270.0 [M+1] ⁺ , Rt=1.29/2min.

Step 2: Preparation of compound 777-3: 1- (3, 4-difluorophenyl) piperidine-3-carboxylic acid

To a solution of ethyl 1- (3, 4-difluorophenyl) piperidine-3-carboxylate (7.0 g, 25.99 mmol, 1.0 eq) in a mixture solvent of MeOH (30 mL) in THF (60 mL) was added a mixture solution of NaOH (2000 mg, 51.99 mmol, 2.0 eq) in H₂O (30 mL) . The reaction mixture was stirred at 50 ℃ for 1 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 3 M HCl, diluted with H₂O (40 mL) and extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 100%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (6000 mg, 24.87 mmol, 98%) .

MS (ESI, pos. ion) m/z: 242.1 [M+1] ⁺ , Rt=0.81/2min.

Step 3: Preparation of compound 777-4: 1- (3, 4-difluorophenyl) -N-methoxy-N-methylpiperidine-3-carboxamide

To a solution of 1- (3, 4-difluorophenyl) piperidine-3-carboxylic acid (6000 mg, 24.87 mmol, 1.0 eq) , N, O-dimethylhydroxylamine (2900 mg, 29.85 mmol, 1.2 eq) , HATU (10.0 g, 27.36 mmol, 1.1 eq) in DMF (20 mL) was added N, N-Diisopropylethylamine (17.3 ml, 99.5 mmol, 4.0 eq) . The reaction mixture was stirred at RT for 2 hours. After the reaction completion, the mixture was diluted with H₂O (100 mL) , extracted with EA (40 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (6000 mg, 21 mmol, 84.8 %) .

MS (ESI, pos. ion) m/z: 285.0 [M+1] ⁺ , Rt=1.27/2min.

Step 4: Preparation of compound 777-5: 1- (1- (3, 4-difluorophenyl) piperidin-3-yl) ethan-1-one

To a solution of 1- (3, 4-difluorophenyl) -N-methoxy-N-methylpiperidine-3-carboxamide (6000 mg, 21 mmol, 1.0 eq) in THF (10 mL) was added Methylmagnesium Bromide (14.0 ml, 42 mmol, 2 eq) dropwise at 0 ℃. After addition, the reaction mixture was stirred at 0 ℃ for 1 hours. After the reaction completion, the mixture was quenched with H₂O (40 mL) and extracted with EA (40 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (3800 mg, 15.88 mmol, 75%) .

MS (ESI, pos. ion) m/z: 240.0 [M+1] ⁺ , Rt=1.32/2min.

Step 5: Preparation of compound 777-6: methyl (E) -6- (3- (1- (3, 4-difluorophenyl) piperidin-3-yl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of 1- (1- (3, 4-difluorophenyl) piperidin-3-yl) ethan-1-one (1800 mg, 7.52 mmol, 1.0 eq) , methyl 6-formylpicolinate (1366 mg, 8.28 mmol, 1.1 eq) in toluene (36 mL) was added K₃PO₄ (3992 mg, 18.81 mmol, 2.5 eq) . The reaction mixture was stirred at 85 ℃ for 16 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (60 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 16%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (700 mg, 1.81 mmol , 24%) .

MS (ESI, pos. ion) m/z: 387.2 [M+1] ⁺ , Rt=2.00/3min.

Step 6: Preparation of compound 777-7: methyl 6- (5-cyclopropyl-1- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl (E) -6- (3- (1- (3, 4-difluorophenyl) piperidin-3-yl) -3-oxoprop-1-en-1-yl) picolinate (1100 mg, 2.85 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (960 mg, 3.56 mmol, 1.25 eq) and TEA (2592 mg, 25.62 mmol, 9.0 eq) in a mixture solvent of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (3.67 g, 14.25 mmol, 5.0 eq, 32%in DCM) . The mixture was stirred at 100 ℃ for 2 hours under N₂. After the reaction completion, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 23%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (1250 mg, 2.66 mmol , 93%) .

MS (ESI, pos. ion) m/z: 471.3 [M+1] ⁺, Rt=2.106/3min.

Step 7: Preparation of compound 777-8: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) picolinate

A solution of methyl 6- (5-cyclopropyl-1- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1, 4-dioxopentan-3-yl) picolinate (1250 mg, 2.66 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (1770 mg, 3.98 mmol, 1.5 eq) in AcOH (10 mL) was stirred at 120 ℃for 16 hours. After the reaction completion, the mixture was concentrated to remove solvent. The residue was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (1100 mg, 1.25 mmol, 47%) .

MS (ESI, pos. ion) m/z: 879.3 [M+1] ⁺, Rt=1.368/2min.

Step 8: Preparation of compound 777-9: methyl 6- (2- (cyclopropylmethyl) -5- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) picolinate (1100 mg, 1.25 mmol, 1.0 eq) in DCM (12 mL) was added TFA (4 mL) . The reaction mixture was stirred at RT for 16 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (700 mg, 1.1 mmol, 87%) .

MS (ESI, pos. ion) m/z: 639.2 [M+1] ⁺ , Rt=1.668/3min.

Step 9: Preparation of compound 777: 6- (2- (cyclopropylmethyl) -5- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -5- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (700 mg, 1.1 mmol, 1.0 eq) in a mixture solvent of MeOH (3 mL) in THF (3 mL) was added a mixture solution of LiOH·H₂O (184 mg, 4.83 mmol, 4.0 eq) in H₂O (3 mL) . The mixture was stirred at RT for 1 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 3 M HCl, diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%FA) to afford the title product as a yellow solid (500 mg, 1.1 mmol, 72.7%) .

MS (ESI, pos. ion) m/z: 625.2 [M+1] ⁺ , Rt=1.472/3min.

¹HNMR (DMSO-d₆) δ: 12.82 (br s, 1H) , 7.84-7.90 (m, 1H) , 7.72-7.80 (m, 3H) , 7.65 (s, 2H) , 7.09-7.17 (m, 1H) , 6.93-6.98 (m, 1H) , 6.89 (ddd, J = 14.4, 7.0, 2.9 Hz, 1H) , 6.82 (d, J = 8.8 Hz, 1H) , 6.64 (s, 1H) , 6.37 (br d, J = 8.9 Hz, 1H) , 5.41 (s, 2H) , 3.52-3.67 (m, 2H) , 3.12-3.25 (m, 2H) , 2.63-2.75 (m, 3H) , 1.85 (br d, J = 9.5 Hz, 1H) , 1.64-1.76 (m, 1H) , 1.48-1.63 (m, 2H) , 0.79-0.89 (m, 1H) , 0.15-0.27 (m, 4H) .

Preparation of (R) -6- (2- (cyclopropylmethyl) -5- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid (compound 972) and (S) -6- (2- (cyclopropylmethyl) -5- (1- (3, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid (compound 973)

Analytical separation method:

Instrument: Waters UPC2 analytical SFC (SFC-H)

Column: ChiralPak OJ, 100×4.6mm I. D., 3μm

Mobile phase: A for CO₂ and B for Methanol (0.1%DEA)

Gradient: B 5-45%, 4min

Flow rate: 3.0 mL/min

Back pressure: 2000 psi

Column temperature: 40℃

Wavelength: 214nm

Preparative separation method:

Instrument: WATERS 150 preparative SFC (SFC-01)

Column: ChiralPak OJ, 250×30mm I. D., 5μm

Mobile phase: A for CO₂ and B for Methanol [0.1%NH3 (7M in MeOH) ]

Gradient: B 45%

Flow rate: 100 mL /min

Back pressure: 100 bar

Column temperature: 35℃

Wavelength: 217nm

Cycle time: ～8.5min

P1 (230 mg, 0.36 mmol, 46%) .

MS (ESI, pos. ion) m/z: 625.2 [M+1] ⁺ , Rt=1.455/3min.

¹HNMR (400 MHz, DMSO-d₆) δ : 8.30 (br s, 2H) , 7.76-7.84 (m, 2H) , 7.68 (d, J=7.8 Hz, 2H) , 7.13 (q, J =9.5 Hz, 1H) , 6.93-6.99 (m, 1H) , 6.89 (ddd, J = 14.4, 6.9, 2.9 Hz, 1H) , 6.82 (d, J = 8.3 Hz, 1H) , 6.61 (s, 1H) , 6.37 (br d, J=8.8 Hz, 1H) , 5.40 (s, 2H) , 3.52-3.68 (m, 2H) , 3.12-3.25 (m, 2H) , 2.63-2.76 (m, 3H) , 1.84 (br s, 1H) , 1.70 (br d, J = 6.8 Hz, 1H) , 1.47-1.66 (m, 2H) , 0.75-0.91 (m, 1H) , 0.14-0.31 (m, 4H) .

P2 (245 mg, 0.39 mmol, 49%) .

MS (ESI, pos. ion) m/z: 625.2 [M+1] ⁺ , Rt=1.456/3min.

¹HNMR (400 MHz, DMSO-d₆) δ: 8.31 (br s, 2H) , 7.75-7.83 (m, 2H) , 7.68 (dd, J = 7.8, 2.3 Hz, 2H) , 7.13 (q, J = 9.5 Hz, 1H) , 6.96 (d, J = 11.3 Hz, 1H) , 6.89 (ddd, J = 14.4, 7.0, 2.9 Hz, 1H) , 6.85-6.93 (m, 1H) , 6.82 (d, J = 8.5 Hz, 1H) , 6.60 (s, 1H) , 6.37 (br d, J = 8.8 Hz, 1H) , 5.40 (s, 2H) , 3.52-3.67 (m, 2H) , 3.11-3.26 (m, 2H) , 2.63-2.76 (m, 3H) , 1.84 (br s, 1H) , 1.70 (br d, J = 6.3 Hz, 1H) , 1.46-1.66 (m, 2H) , 0.75-0.90 (m, 1H) , 0.14-0.29 (m, 4H) .

Example 57: Synthesis of compound 779

Step 1: Preparation of compound 779-2: 5-acetyl-1- (4-fluorophenyl) pyridin-2 (1H) -one

To a solution of (4-fluorophenyl) boranediol (6.12 g, 43.75 mmol, 2.0 eq) and 1- (6-hydroxypyridin-3-yl) ethan-1-one (3.0 g, 21.88 mmol, 1.0 eq) in DCM (30 mL) was added Cu (OAc) ₂ (4.4 g, 21.88 mmol, 1.0 eq) and Pyridine (17.0 g, 218.75 mmol, 10.0 eq) . The reaction was stirred at room temperature under O₂ atmosphere for 16 h. After the reaction was completed, The reaction mixture was diluted with EA (100 mL) . The organic layer was washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE : EA = 100: 0 -90: 10 –80: 20) , to afford the title product as a white solid (4.3 g, 18.16 mmol, 83.0%) .

MS (ESI, pos. ion) m/z: 232.0 [M+1] ⁺, Rt=0.77/2min.

Step 2: Preparation of compound 779-3: methyl (E) -6- (3- (1- (4-fluorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) -3-oxoprop-1-en-1-yl) picolinate

To a solution of 5-acetyl-1- (4-fluorophenyl) -1, 2-dihydropyridin-2-one (1.5 g, 6.49 mmol, 1.0 eq) and methyl 6-formylpyridine-2-carboxylate (1.1 g, 6.49 mmol, 1.0 eq) in methylbenzene (8 mL) was added tripotassium phosphate (3.4 g, 16.22 mmol, 2.5 eq) . The reaction was stirred at 80 ℃ for 16 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) , washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -70: 30) , to afford the title product as a yellow solid (400 mg, 1.06 mmol, 16.3%) .

MS (ESI, pos. ion) m/z: 379.1 [M+1] ⁺, Rt=0.99/2min.

Step 3: Preparation of compound 779-4: methyl 6- (5-cyclopropyl-1- (1- (4-fluorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dioxopentan-3-yl) picolinate

To a solution of methyl 4- [ (1E) -3- (3, 4-difluorophenyl) -3-oxoprop-1-enyl] pyrimidine-2-carboxylate (200 mg, 0.52 mmol, 1.0 eq) and 2-cyclopropylacetaldehyde (978 mg, 3.72 mmol, 7.0 eq, 32%in DCM) in a mixture solvent of dioxane (4 mL) in ethanol (1 mL) was added 3-Benzyl-5- (2-hydroxyethyl) -4-methylthiazol-3-ium chloride (178 mg, 0.66 mmol, 1.25 eq) and Et₃N (534 mg, 5.29 mmol, 10.0 eq) . The reaction was stirred at 100 ℃ for 2 h. After the reaction was completed, the reaction mixture was diluted with EA (20 mL) . The organic layer was washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 –60: 40) , to afford the title product as a yellow oil (200 mg, 0.43 mmol, 81.8%) .

MS (ESI, pos. ion) m/z: 463.2 [M+1] ⁺, Rt=1.24/2min.

Step 4 : Preparation of compound 779-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrol-3-yl) picolinate

A solution of methyl 6- {5-cyclopropyl-1- [1- (4-fluorophenyl) -6-oxopyridin-3-yl] -1, 4-dioxopent-3-yl} pyridine-2-carboxylate (200 mg, 0.43 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (288 mg, 0.65 mmol, 1.5 eq) in acetic acid (4 mL) . The reaction was stirred at 120 ℃ for 16 h. After the reaction was completed, the reaction mixture was concentrated and diluted with EA (20 mL) . The organic layer was washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA =100: 0 -80: 20 –50: 50) , to afford the title product as a yellow solid (210 mg, 0.24 mmol, 56.1%) .

MS (ESI, pos. ion) m/z: 871.2 [M+1] ⁺, Rt=1.44/2min.

Step 5 : Preparation of compound 779-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrol-3-yl) picolinate To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrol-3-yl) picolinate (210 mg, 0.24 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL, 13.07 mmol, 54.2 eq) . The reaction was stirred at room temperature for 48 h. After the reaction was completion, the mixture was added dropwise sodium bicarbonate aqueous solution (10 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was used directly for the next step without purification.

MS (ESI, pos. ion) m/z: 631.2 [M+1] ⁺, Rt=1.30/2min.

Step 6: Preparation of compound 779: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrol-3-yl) picolinic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.19 mmol, 1.0 eq) in a mixture solvent of methanol (3 mL) in tetrahydrofuran (1 mL) was added a solution of LiOH·H₂O (48 mg, 1.14 mmol, 6.0 eq ) in water (1 mL) . The reaction was stirred at 50 ℃ for 3 h. After the reaction was completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (10 mL) , extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (44 mg, 0.07 mmol, 37.5%) .

MS (ESI, pos. ion) m/z: 617.1 [M+1] ⁺ , Rt=1.23/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.93 -7.85 (m, 1H) , 7.82 -7.69 (m, 3H) , 7.65 (s, 2H) , 7.57 (d, J = 2.4 Hz, 1H) , 7.49 (dd, J = 2.6, 9.4 Hz, 1H) , 7.43 -7.27 (m, 4H) , 7.01 -6.90 (m, 1H) , 6.88 -6.79 (m, 2H) , 6.48 (d, J = 9.4 Hz, 1H) , 5.38 (s, 2H) , 3.22 (br d, J = 6.5 Hz, 2H) , 0.98 -0.89 (m, 1H) , 0.33 -0.18 (m, 4H) .

Example 58: Synthesis of compound 785

Step 1: Preparation of compound 785-2: methyl 2- [ (E) -3- (3-bromo-4-fluoro-phenyl) -3-oxo-prop-1-enyl] pyrimidine-4-carboxylate

To a solution of methyl 2-formylpyrimidine-4-carboxylate (300 mg, 1.81 mmol, 1.2 eq) for 9 batches in parallel in Tol. (10 mL) was added K₃PO₄ (958.28 mg, 4.51 mmol, 3 eq) and 1- (3-bromo-4-fluoro-phenyl) ethanone (326.60 mg, 1.50 mmol, 1 eq) . The mixture was stirred at 80 ℃ for 16 hr. The 9 batches in parallel of the mixture was diluted with brine (50 mL) and extracted with EtOAc (30 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown solid (1.09 g, 22.04%) .

MS (ESI, pos. ion) m/z: 365.0/367.0 [M+H] ⁺. Rt=0.982/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 9.24 -9.16 (m, 1H) , 8.40 -8.34 (m, 1H) , 8.29 -8.20 (m, 1H) , 8.19 -8.13 (m, 1H) , 8.05 -7.99 (m, 1H) , 7.63 -7.55 (m, 2H) , 4.01 -3.92 (m, 3H) .

Step 2: Preparation of compound 785-3: methyl 2- [1- [2- (3-bromo-4-fluoro-phenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] pyrimidine-4-carboxylate

A mixture of methyl 2- [ (E) -3- (3-bromo-4-fluoro-phenyl) -3-oxo-prop-1-enyl] pyrimidine-4-carboxylate (2.0 g, 5.48 mmol, 1 eq) in dioxane (60 mL) and EtOH (15 mL) was added TEA (4.99 g, 49.29 mmol, 6.86 mL, 9 eq) and 2-cyclopropylacetaldehyde (3.69 g, 43.82 mmol, 8 eq) , then suspension was degassed under vacuum and purged with N₂ for 3 times. Then, 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (1.85 g, 6.85 mmol, 1.25 eq) was added. The mixture was stirred at 100 ℃ for 16 hr. The mixture was diluted with brine (100 mL) and extracted with EtOAc (50 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown oil (2.42 g, 98.35%) .

MS (ESI, pos. ion) m/z: 449.1/451.1 [M+H] ⁺. Rt=1.046/1.5 min.

Step 3: Preparation of compound 785-4: methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] pyrimidine-4-carboxylate

To a solution of methyl 2- [1- [2- (3-bromo-4-fluoro-phenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] pyrimidine-4-carboxylate (2.42 g, 5.39 mmol, 1 eq) in AcOH (50 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (2.63 g, 5.93 mmol, 1.1 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (50 mL) and extracted with EtOAc (30 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (2 g, 43.29%) .

MS (ESI, pos. ion) m/z: 857.2/859.2 [M+H] +. Rt=1.256/1.5 min.

Step 4: Preparation of compound 785-5: methyl 2- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate

To a solution of methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] pyrimidine-4-carboxylate (2 g, 2.33 mmol, 1 eq) in DCM (20 mL) was added TFA (7.68 g, 67.31 mmol, 5 mL, 28.87 eq) . The mixture was stirred at 25 ℃for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 50/50) to afford the title product as a brown solid (560 mg, 38.90%) .

MS (ESI, pos. ion) m/z: 617.1/619.1 [M+H] ⁺. Rt=1.066/1.5 min.

Step 5: Preparation of compound 785-6: methyl 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- (3-hydroxy-3-methyl-but-1-ynyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate

To a solution of methyl 2- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate (200 mg, 323.91 μmol, 1 eq) in DMF (3 mL) was added TEA (98.33 mg, 971.72 μmol, 135.25 μL, 3 eq) , 2-methylbut-3-yn-2-ol (81.74 mg, 971.72 μmol, 94.93 μL, 3 eq) and Pd (PPh₃) ₂Cl₂ (22.74 mg, 32.39 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (200 mg, 99.48%) .

MS (ESI, pos. ion) m/z: 621.2 [M+H] ⁺, Rt=1.011/1.5 min.

Step 6: Preparation of compound 785: 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- (3-hydroxy-3-methyl-but-1-ynyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- (3-hydroxy-3-methyl-but-1-ynyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate (200 mg, 322.24 μmol, 1 eq) in THF (1.5 mL) and MeOH (4 mL) . A solution of LiOH (77.18 mg, 3.22 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was 6～7 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water (FA) -MeCN] ; gradient: 32%-62%B over 9 min) to afford the title product as a yellow solid (72 mg, 36.83%) .

MS (ESI, pos. ion) m/z: 607.2 [M+H] ⁺, Rt=0.946/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 9.01 -8.93 (m, 1H) , 7.74 -7.67 (m, 1H) , 7.65 (d, J = 5.0 Hz, 1H) , 7.63 -7.58 (m, 2H) , 7.45 -7.36 (m, 2H) , 7.32 -7.24 (m, 1H) , 7.04 -7.00 (m, 1H) , 6.91 -6.85 (m, 1H) , 6.78 -6.73 (m, 1H) , 5.59 -5.50 (m, 1H) , 5.44 -5.34 (m, 2H) , 3.22 (br d, J = 6.5 Hz, 3H) , 1.47 -1.44 (m, 6H) , 1.03 -0.89 (m, 1H) , 0.34 -0.24 (m, 4H) .

Example 59: Synthesis of compound 787

Step 1: Preparation of compound 787-1: methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

A mixture of methyl 2- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate (200 mg, 323.91 μmol) and 3-ethynyl-3-methyl-oxetane (93.41 mg, 971.72 μmol) in DMF (5 mL) was added TEA (98.33 mg, 971.72 μmol) and Pd (PPh₃) ₂Cl₂ (22.74 mg, 32.39 μmol) . The mixture was stirred at 80 ℃ for 2 hrs under N₂ atmosphere. The mixture was diluted with brine (5 mL) and extacted with EtOAc (5 mL*3) . The organic layer was concentrated under vacuum to afford the title product as a brown oil (250 mg, crude) .

MS (ESI, pos. ion) m/z: 633.2 [M+1] ⁺. Rt=1.082/1.5min.

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.90 (d, J = 4.8 Hz, 1H) , 7.90 -7.80 (m, 1H) , 7.73 -7.61 (m, 2H) , 7.51 -7.40 (m, 1H) , 7.24 -7.19 (m, 2H) , 7.14 -6.99 (m, 2H) , 6.91 -6.83 (m, 1H) , 6.79 -6.71 (m, 1H) , 5.28 (s, 2H) , 4.81 (d, J = 5.5 Hz, 2H) , 4.54 -4.46 (m, 2H) , 4.01 (s, 3H) , 3.26 (d, J = 6.8 Hz, 2H) , 1.71 -1.64 (s, 3H) , 1.00 (s, 1H) , 0.44 -0.31 (m, 4H) .

Step 2: Preparation of compound 787: 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

A mixture of methyl 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- [2- (3-methyloxetan-3-yl) ethynyl] phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyrimidine-4-carboxylate (250 mg, 395.15 μmol) in THF(2 mL) and H₂O (1 mL) was added NaOH (79.03 mg, 1.98 mmol) in MeOH (2 mL) . The mixture was stirred at 25 ℃ for 1 hr. The mixture was diluted with 1 N HCl (3 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water (FA) -ACN] ; gradient: 45%-65%B over 11 min) to afford the title product as a yellow solid (90.07 mg) .

MS (ESI, pos. ion) m/z: 619.2 [M+1] ⁺. Rt=0.993/1.5min.

¹H NMR (400 MHz, DMSO-d₆) δ 9.00 -8.90 (m, 1H) , 7.74 -7.57 (m, 4H) , 7.50 -7.44 (m, 1H) , 7.44 -7.36 (m, 1H) , 7.33 -7.25 (m, 1H) , 7.06 -6.98 (m, 1H) , 6.92 -6.85 (m, 1H) , 6.79 -6.71 (m, 1H) , 5.40 (s, 2H) , 4.77 -4.66 (m, 2H) , 4.44 (d, J = 5.5 Hz, 2H) , 3.23 (br d, J = 6.2 Hz, 2H) , 1.67 -1.56 (s, 3H) , 1.05 -0.90 (m, 1H) , 0.35 -0.21 (m, 4H) .

Example 60: Synthesis of compound 960

Step 1: Preparation of compound 960-2: methyl (E) -2- (3- (3-iodophenyl) -3-oxoprop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of 1- (3-iodophenyl) ethan-1-one (2.96 g, 12.04 mmol, 1.0 eq) and 4-methylbenzene-1-sulfonamide (1.04 g, 6.07 mmol, 0.5 eq) in toluene (30 mL) was added methyl 2-formylpyrimidine-4-carboxylate (2.0 g, 12.04 mmol, 1.0 eq) . The mixture was stirred at 140 ℃ for 18 hours. After the reaction completion, the mixture was concentrated and filtered. The filtrate was diluted with H₂O (20 mL) and extracted with DCM (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 18%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (500 mg, 1.27 mmol, 10%) .

MS (ESI, pos. ion) m/z: 395.0 [M+H] ⁺ , Rt=0.967/2min.

Step 2: Preparation of compound 960-3: methyl 2- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) pyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (3-iodophenyl) -3-oxoprop-1-en-1-yl) pyrimidine-4-carboxylate (500 mg, 1.27 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (428 mg, 1.59 mmol, 1.2 eq) , TEA (1.58 mL, 11.42 mmol, 9.0 eq) in a mixture solvent of EtOH (5 mL) in dioxane (20 mL) was added 2-cyclopropylacetaldehyde (3.0 g, 11.42 mmol, 9.0 eq, 32%in DCM) . The reaction mixture was stirred at 100 ℃ for 1 hour under N₂. After the reaction completion, the mixture was concentrated under vacuum, diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (360 mg, 0.75 mmol, 59%) .

MS (ESI, pos. ion) m/z: 479.3 [M+H] ⁺, Rt=1.067/2min.

Step 3: Preparation of compound 960-4: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) pyrimidine-4-carboxylate (360 mg, 0.75 mmol, 1.0 eq) in AcOH (8 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (435 mg, 0.98 mmol, 1.3 eq) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction completion, the mixture was concentrated under vacuum, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (400 mg, 0.45 mmol, 60%) .

MS (ESI, neg. ion) m/z: 885.2 [M-H] ⁺, Rt=1.375/2min.

Step 4: Preparation of compound 960-5: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (400 mg, 0.45 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The mixture was stirred at RT for 18 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (170 mg, 0.26 mmol, 58%) .

MS (ESI, pos. ion) m/z: 647.3 [M+H] ⁺, Rt=1.133/2min.

Step 5: Preparation of compound 960-6: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (1-hydroxycyclobutyl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (90 mg, 0.14 mmol, 1.0 eq) , 1-ethynylcyclobutan-1-ol (40 mg, 0.42 mmol, 3.0 eq) , CuI (3 mg, 0.01 mmol, 0.1 eq) , Pd (PPh₃) ₂Cl₂ (10 mg, 0.01 mmol, 0.1 eq) , Et₃N (42 mg, 0.42 mmol, 3 eq) and DMF (4 mL) . The reaction mixture was degassed for 10 minutes and stirred at 40 ℃ for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was purified by column chromatography through silica gel eluting with 0: 100 to 60: 40 petroleum ether: ethyl acetate, to afford the title compound (70 mg, 0.11 mmol, 82 %yield) .

MS (ESI, pos. ion) m/z: 615.8 [M+1] ⁺, Rt=1.058/2min.

Step 6: Preparation of compound 960: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (1-hydroxycyclobutyl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (1-hydroxycyclobutyl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (70 mg, 0.11 mmol, 1.0 eq) , THF (2 mL) and MeOH (2 mL) . A solution of 1 M aqueous LiOH (0.5 mL, 4.5 eq) was added to the mixture, and then the resulting was stirred at RT for 1 h. The mixture was acidified with 1 M aqueous HCl solution until the pH was ～6 and extracted with ethyl acetate (10 mL × 3) . The organic layers were combined, washed with saturated aqueous NaHCO₃ solution and brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product (30 mg, 0.05 mmol, 43%) .

MS (ESI, pos. ion) m/z: 601.1 [M+1] ⁺ Rt=0.958/2min.

¹HNMR (DMSO-d₆) δ: 8.95 (d, J = 4.8 Hz, 1H) , 7.71 (t, J = 7.8 Hz, 1H) , 7.66 -7.58 (m, 3H) , 7.42 (s, 1H) , 7.40 -7.26 (m, 3H) , 7.05 (s, 1H) , 6.89 (br d, J = 11.2 Hz, 1H) , 6.77 (d, J = 8.6 Hz, 1H) , 5.87 (s, 1H) , 5.44 (s, 2H) , 3.23 (br d, J = 6.6 Hz, 2H) , 2.41 -2.30 (m, 2H) , 2.27 -2.14 (m, 2H) , 1.82 -1.71 (m, 2H) , 1.06 -0.92 (m, 1H) , 0.39 -0.22 (m, 4H) .

Example 61: Synthesis of compound 961

Step 1: Preparation of compound 961-1: methyl 2- (4- (cyclopropylmethyl) -1- (4-fluoro-3-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (50 mg, 0.08 mmol, 1.0 eq) in DMF (1 mL) was added CuI (2 mg, 0.01 mmol, 0.12 eq) , TEA (0.03 mL, 0.24 mmol, 4.0 eq) , Pd (PPh₃) ₂Cl₂ (5 mg, 0.01 mmol, 0.12 eq) and 3-ethynyl-3-methyloxetane (76 mg, 0.80 mmol, 10 eq) . The mixture was stirred at 40 ℃ for 12 hours under N2.After the reaction completion, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (40 mg, 0.07 mmol, 84%) .

MS (ESI, pos. ion) m/z: 615.8 [M+1] ⁺, Rt=1.094/2min.

Step2: Preparation of compound 961: 2- (4- (cyclopropylmethyl) -1- (4-fluoro-3-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

To a solution of methyl 2- (4- (cyclopropylmethyl) -1- (4-fluoro-3-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (40 mg, 0.07 mmol, 1.0 eq) in a mixture solvent of THF (1 mL) in H₂O (0.8 mL) was added hydroxylithium hydrate (8 mg, 0.20 mmol, 3.0 eq) . The mixture was stirred at rt for 2 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 65%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid ( (20 mg, 0.03 mmol, 51.2%) .

MS (ESI, pos. ion) m/z: 601.8 [M+1] ⁺ , Rt=1.024/2min.

¹HNMR (400 MHz, DMSO-d₆) δ =8.97 (d, J = 5.0 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.67 -7.64 (m, 1H) , 7.61 (s, 2H) , 7.43-7.32 (m, 4H) , 7.06 (s, 1H) , 6.90 (d, J = 10.8 Hz, 1H) , 6.77 (d, J = 8.5 Hz, 1H) , 5.43 (s, 2H) , 4.73 (d, J = 5.5 Hz, 2H) , 4.42 (d, J = 5.5 Hz, 2H) , 3.23 (br d, J = 6.5 Hz, 2H) , 1.62 (s, 3H) , 1.04 -0.95 (m, 1H) , 0.39 -0.18 (m, 4H) .

Example 62: Synthesis of compound 966

Step 1: Preparation of compound 966-2: methyl 2- [ (E) -3- (3-bromo-4-fluoro-phenyl) -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylate

To a solution of methyl 2-formyl-6-methyl-pyrimidine-4-carboxylate (717.21 mg, 3.98 mmol, 1.2 eq) in Tol. (10 mL) was added K₃PO₄ (2.11 g, 9.95 mmol, 3 eq) and 1- (3-bromo-4-fluoro-phenyl) ethanone (720 mg, 3.32 mmol, 1 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (20 mL) and extracted with EtOAc (10 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown solid (280 mg, 18.28%) .

MS (ESI, pos. ion) m/z: 379.0/381.0 [M+H] ⁺. Rt=1.001/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 8.31 (dd, J = 2.1, 6.7 Hz, 1H) , 8.26 -8.18 (m, 1H) , 8.07 -8.02 (m, 1H) , 7.87 -7.84 (m, 1H) , 7.83 -7.80 (m, 1H) , 7.24 (s, 1H) , 4.07 -4.03 (m, 3H) , 2.72 -2.67 (m, 3H) .

Step 2: Preparation of compound 966-3: methyl 2- [1- [2- (3-bromo-4-fluoro-phenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] -6-methyl-pyrimidine-4-carboxylate

A mixture of methyl 2- [ (E) -3- (3-bromo-4-fluoro-phenyl) -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylate (280 mg, 738.44 μmol, 1 eq) in dioxane (5 mL) and EtOH (1 mL) was added TEA (672.50 mg, 6.65 mmol, 925.04 μL, 9 eq) , 2-cyclopropylacetaldehyde (496.91 mg, 5.91 mmol, 8 eq) and 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (249.03 mg, 923.04 μmol, 1.25 eq) , then suspension was degassed under vacuum and purged with N₂ for 3 times. The mixture was stirred at 100 ℃ for 16 hr. The mixture was diluted with brine (10 mL) and extracted with EtOAc (5 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown oil (318 mg, 92.95%) .

MS (ESI, pos. ion) m/z: 463.1/465.1 [M+H] ⁺. Rt=1.051/1.5 min.

Step 3: Preparation of compound 966-4: methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate

To a solution of methyl 2- [1- [2- (3-bromo-4-fluoro-phenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] -6-methyl-pyrimidine-4-carboxylate (318 mg, 555.97 μmol, 1 eq) in AcOH (5 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (296.57 mg, 667.17 μmol, 1.2 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (10 mL) and extracted with EtOAc (5 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 50/50) to afford the title product as a brown solid (300 mg, 61.90%) .

MS (ESI, pos. ion) m/z: 871.2/873.2 [M+H] ⁺. Rt=1.266/1.5 min.

Step 4: Preparation of compound 966-5: methyl 2- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate

To a solution of methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (300 mg, 344.12 μmol, 1 eq) in DCM (3 mL) was added TFA (1.58 g, 13.88 mmol, 1.03 mL, 40.33 eq) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 50/50) to afford the title product as a brown solid (150 mg, 69.03%) .

MS (ESI, pos. ion) m/z: 631.1/633.1 [M+H] ⁺. Rt=1.105/1.5 min.

Step 5: Preparation of compound 966-6: 2- [2- (cyclopropylmethyl) -5- (4-fluorophenyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylic acid

To a solution of methyl 2- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (30 mg, 47.51 μmol, 1 eq) in DMF (2 mL) was added TEA (14.42 mg, 142.52 μmol, 19.84 μL, 3 eq) , 2-methylbut-3-yn-2-ol (11.99 mg, 142.52 μmol, 13.92 μL, 3 eq) and Pd (PPh₃) ₂Cl₂ (3.33 mg, 4.75 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (30 mg, 99.50%) .

MS (ESI, pos. ion) m/z: 635.3 [M+H] ⁺. Rt=1.066/1.5 min.

Step 6: Preparation of compound 966: 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- (3-hydroxy-3-methyl-but-1-ynyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- (3-hydroxy-3-methyl-but-1-ynyl) phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (30 mg, 47.27 μmol, 1 eq) in THF (1 mL) and MeOH (2 mL) . A solution of LiOH (11.32 mg, 0.472 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water (FA) -MeCN] ; gradient: 34%-74%B over 10 min) to afford the title product as a yellow solid (13.14 mg, 44.79%) .

MS (ESI, pos. ion) m/z: 621.3 [M+H] ⁺, Rt=0.985/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.74 -7.67 (m, 1H) , 7.64 -7.58 (m, 2H) , 7.57 -7.53 (m, 1H) , 7.45 -7.36 (m, 2H) , 7.32 -7.24 (m, 1H) , 7.04 -6.99 (m, 1H) , 6.90 -6.83 (m, 1H) , 6.77 -6.72 (m, 1H) , 5.57 -5.50 (m, 1H) , 5.43 -5.35 (m, 2H) , 3.22 (br d, J = 6.2 Hz, 2H) , 2.54 (d, J = 2.0 Hz, 3H) , 1.45 (s, 6H) , 1.03 -0.89 (m, 1H) , 0.34 -0.24 (m, 4H) .

Example 63: Synthesis of compound 967

Step 1: Preparation of compound 967-1: methyl 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- [2- (1-hydroxycyclobutyl) ethynyl] phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate

To a solution of methyl 2- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (40 mg, 63.34 μmol, 1 eq) in DMF (2 mL) was added TEA (19.23 mg, 190.03 μmol, 26.45 μL, 3 eq) , 1-ethynylcyclobutanol (18.27 mg, 190.03 μmol, 3 eq) and Pd (PPh₃) ₂Cl₂ (4.45 mg, 6.33 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (40 mg, 97.65%) .

MS (ESI, pos. ion) m/z: 647.3 [M+H] ⁺. Rt=1.080/1.5 min.

Step 2: Preparation of compound 967: 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- [2- (1-hydroxycyclobutyl) ethynyl] phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- [2- (1-hydroxycyclobutyl) ethynyl] phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (40 mg, 61.85 μmol, 1 eq) in THF (1 mL) and MeOH (2 mL) . A solution of LiOH (14.81 mg, 0.618 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water (FA) -MeCN] ; gradient: 36%-76%B over 10 min) to afford the title product as a yellow solid (14.03 mg, 35.85%) .

MS (ESI, pos. ion) m/z: 633.2 [M+H] ⁺, Rt=1.005/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.70 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.58 -7.55 (m, 1H) , 7.52 -7.45 (m, 1H) , 7.44 -7.36 (m, 1H) , 7.32 -7.25 (m, 1H) , 7.05 -7.00 (m, 1H) , 6.87 (d, J = 10.8 Hz, 1H) , 6.78 -6.73 (m, 1H) , 5.99 -5.89 (m, 1H) , 5.46 -5.35 (m, 2H) , 3.22 (br d, J = 6.6 Hz, 2H) , 2.54 (s, 3H) , 2.40 -2.29 (m, 2H) , 2.26 -2.15 (m, 2H) , 1.84 -1.69 (m, 2H) , 1.04 -0.89 (m, 1H) , 0.36 -0.23 (m, 4H) .

Example 64: Synthesis of compound 968

Step 1: Preparation of compound 968-1: methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A mixture of methyl 2- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (30 mg, 47.51 μmol) and 3-ethynyl-3-methyl-oxetane (13.70 mg, 142.52 μmol) in DMF (2 mL) was added TEA (14.42 mg, 142.52 μmol) and Pd (PPh₃) ₂Cl₂ (3.33 mg, 4.75 μmol) . The mixture was stirred at 80 ℃ for 2 hrs under N₂ atmosphere. The mixture was diluted with brine (5 mL) and extacted with EtOAc (5 mL*) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum to afford the title product as a brown oil (95 mg, crude) .

MS (ESI, pos. ion) m/z: 647.2 [M+1] ⁺. Rt=1.114/1.5min.

Step 2: Preparation of compound 968: 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

A mixture of methyl 2- [2- (cyclopropylmethyl) -5- [4-fluoro-3- [2- (3-methyloxetan-3-yl) ethynyl] phenyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (95 mg, crude) in THF(1 mL) and MeOH (1 mL) was added NaOH (29.38 mg, 734.50 μmol) in H₂O (0.5 mL) . The mixture was stirred at 25 ℃ for 1 hr. The mixture was diluted with 1 N HCl (3 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (FA) -MeCN] ; gradient: 46%-66%B over 10 min) to afford the title product as a yellow solid (15.36 mg, 16.2%yield) .

MS (ESI, pos. ion) m/z: 633.2 [M+1] ⁺. Rt=1.031/1.5min.

¹H NMR (400 MHz, DMSO-d₆) δ 7.74 -7.65 (m, 1H) , 7.61 (s, 2H) , 7.57 (s, 1H) , 7.50 -7.45 (m, 1H) , 7.44 -7.37 (m, 1H) , 7.33 -7.24 (m, 1H) , 7.02 (s, 1H) , 6.87 (d, J = 10.8 Hz, 1H) , 6.79 -6.71 (m, 1H) , 5.44 -5.33 (m, 2H) , 4.78 -4.68 (m, 2H) , 4.44 (d, J = 5.5 Hz, 2H) , 3.23 (br d, J = 7.0 Hz, 2H) , 2.54 (s, 3H) , 1.67 -1.55 (m, 3H) , 1.04 -0.90 (m, 1H) , 0.36 -0.21 (m, 4H) .

Example 65: Synthesis of compound 778 (compound 964 and compound 965)

Step 1: Preparation of compound 778-2: ethyl 1- (2, 4-difluorophenyl) piperidine-3-carboxylate

To the solution of ethyl piperidine-3-carboxylate (5.0 g, 31.80 mmol, 1.0 eq) , K₂CO₃ (8.79 g, 63.61 mmol, 2.0 eq) , copper (1+) iodide (1.21 g, 6.36 mmol, 0.2 eq) and L-proline (1.46 g, 12.72 mmol, 0.4 eq) in DMSO (30 mL) was added 2, 4-difluoro-1-iodobenzene (11.45 g, 47.71 mmol, 1.5 eq) under N₂. The reaction mixture was stirred at 100 ℃ overnight. TLC and LCMS showed that ethyl piperidine-3-carboxylate was consumed and the desired product was detected. The reaction mixture was poured into water (40 mL) and extracted with EA (40 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 3%EtOAc in petroleum ether as a gradient, to afford the title product as a white oil (1.548 g, 5.75 mmol, 18.1%) .

MS (ESI, pos. ion) m/z: 270.1 [M+1] ⁺ , Rt=2.111/3min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.17 (ddd, J = 2.9, 9.1, 12.3 Hz, 1H) , 7.09 (dt, J = 6.0, 9.4 Hz, 1H) , 7.02 -6.95 (m, 1H) , 4.11 -4.01 (m, 2H) , 3.29 (dd, J = 3.8, 11.5 Hz, 1H) , 3.11 -3.05 (m, 1H) , 2.87 (dd, J =9.4, 11.4 Hz, 1H) , 2.74 -2.63 (m, 2H) , 1.94 -1.86 (m, 1H) , 1.83 -1.73 (m, 1H) , 1.68 -1.50 (m, 2H) , 1.19 (t, J = 7.1 Hz, 3H) .

Step 2: Preparation of compound 778-3: 1- (2, 4-difluorophenyl) piperidine-3-carboxylic acid

To the solution of ethyl 1- (2, 4-difluorophenyl) piperidine-3-carboxylate (1.55 g, 5.75 mmol, 1.0 eq) in a mixture solvent of tetrahydrofuran (4 mL) and methanol (4 mL) in water (2 mL) was added sodium hydroxide (460 mg, 11.50 mmol, 2.0 eq) . The reaction mixture was stirred at 50 ℃ for 1 h. LCMS showed that ethyl 1- (2, 4-difluorophenyl) piperidine-3-carboxylate was consumed and the desired product was detected. The reaction mixture was adjusted to pH=3-5 with 2N HCl and extracted with EA (20 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the title product as a yellow oil (1.38 g, 5.72 mmol, 99.5%) .

MS (ESI, pos. ion) m/z: 242.0 [M+1] ⁺, Rt=1.266/3min.

Step 3: Preparation of compound 778-4: 1- (2, 4-difluorophenyl) -N-methoxy-N-methylpiperidine-3-carboxamide

To the solution of 1- (2, 4-difluorophenyl) piperidine-3-carboxylic acid (1.38 g, 5.72 mmol, 1.0 eq) and N, O-dimethylhydroxylamine hydrochloride (840 mg, 8.58 mmol, 1.5 eq) and HATU (2.39 g, 6.29 mmol, 1.1 eq) in DMF (8 mL) was added DIEA (3.78 mL, 22.88 mmol, 2.0 eq) . The reaction mixture was stirred at 25 ℃ for 1 h. LCMS showed that 1- (2, 4-difluorophenyl) piperidine-3-carboxylic acid was consumed and the desired product was detected. The reaction mixture was poured into water (40 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 10%EtOAc in petroleum ether as a gradient, to afford the title product as a white oil (1.59 g, 5.57 mmol, 97.4%) .

MS (ESI, pos. ion) m/z: 285.1 [M+1] ⁺, Rt=1.351/3min.

Step 4: Preparation of compound 778-5: 1- (1- (2, 4-difluorophenyl) piperidin-3-yl) ethan-1-one

To the solution of 1- (2, 4-difluorophenyl) -N-methoxy-N-methylpiperidine-3-carboxamide (1.38 g, 4.87 mmol, 1.0 eq) in THF (8 mL) was added CH₃MgBr (3.3 mL, 9.74 mmol, 2.0 eq) dropwise with the temperature was kept at -78 ℃ under N₂. The reaction mixture was stirred at 25 ℃ for 1 h. LCMS showed that 1- (2, 4-difluorophenyl) -N-methoxy-N-methylpiperidine-3-carboxamide was consumed and the desired product was detected. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 13%EtOAc in petroleum ether as a gradient, to afford the title product as a white oil (1.05 g, 4.40 mmol, 90.5%) .

MS (ESI, pos. ion) m/z: 240.0 [M+1] ⁺, Rt=1.432/3min.

Step 5: Preparation of compound 778-6: methyl (E) -6- (3- (1- (2, 4-difluorophenyl) piperidin-3-yl) -3-oxoprop-1-en-1-yl) picolinate

To the solution of methyl 6-formylpicolinate (759 mg, 4.60 mmol, 1.0 eq) and tripotassium phosphate (2440 mg, 11.49 mmol, 2.5 eq) in toluene (10 mL) was added 1- (1- (2, 4-difluorophenyl) piperidin-3-yl) ethan-1-one (1100 mg, 4.60 mmol, 1.0 eq) . The reaction mixture was stirred at 85 ℃ for overnight. LCMS showed that 40%1- (1- (2, 4-difluorophenyl) piperidin-3-yl) ethan-1-one was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was poured into water (30 mL) and extracted with EA (30 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (800 mg, 2.07 mmol, 45.0%) .

MS (ESI, pos. ion) m/z: 387.1 [M+1] ⁺, Rt=1.529/3min.

Step 6: Preparation of compound 778-7: methyl 6- (5-cyclopropyl-1- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1, 4-dioxopentan-3-yl) picolinate

To the solution of methyl (E) -6- (3- (1- (2, 4-difluorophenyl) piperidin-3-yl) -3-oxoprop-1-en-1-yl) picolinate (780 mg, 2.02 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (681 mg, 2.52 mmol, 1.25 eq) and Et₃N (2.04 mL, 20.19 mmol, 10.0 eq) in a mixture solvent of dioxane (4 mL) in ethanol (1 mL) was added 2-cyclopropylacetaldehyde (3919 mg, 12.11 mmol, 6.0 eq, 26%wt. in DCM) . The reaction mixture was stirred at 100 ℃ for 1 h. LCMS showed that methyl (E) -6- (3- (1- (2, 4-difluorophenyl) piperidin-3-yl) -3-oxoprop-1-en-1-yl) picolinate was consumed and the desired product was detected. The reaction mixture was poured into water (15 mL) and extracted with EA (20 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 10%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (940 mg, 2.00 mmol, 99.0%) .

MS (ESI, pos. ion) m/z: 471.2 [M+1] ⁺, Rt=1.594/3min.

Step 7: Preparation of compound 778-8: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (5-cyclopropyl-1- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1, 4-dioxopentan-3-yl) picolinate (940 mg, 2.00 mmol, 1.0 eq) in acetic acid (8 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (1.33 g, 3.00 mmol, 2.0 eq) . The reaction mixture was stirred at 120 ℃ for overnight. LCMS showed that methyl 6- (5-cyclopropyl-1- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1, 4-dioxopentan-3-yl) picolinate was consumed and the desired product was detected. The reaction mixture was poured into water (15 mL) and extracted with EA (20 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (713 mg, 0.81 mmol, 40.6%) .

MS (ESI, pos. ion) m/z: 879.3 [M+1] ⁺, Rt=1.386/2min.

Step 8: Preparation of compound 778-9: methyl 6- (2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) picolinate (713 mg, 0.81 mmol, 1.0 eq) in DCM (12 mL) was added TFA (4 mL) . The reaction mixture was stirred at 25 ℃ for overnight. LCMS showed that methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1H-pyrrol-3-yl) picolinate was consumed and the desired product was detected. The reaction mixture was adjusted to pH=7 with NaHCO₃ solution and extracted with EA (20 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (495 mg, 0.77 mmol, 95.5%) .

MS (ESI, pos. ion) m/z: 639.2 [M+1] ⁺, Rt=1.682/3min.

Step 9: Preparation of compound 778: 6- (2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid: (R) -6- (2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid (compound 974) and (S) -6- (2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid (compound 975)

To the solution of methyl 6- (2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (495 mg, 0.77 mmol, 1.0 eq) in a mixture solvent of tetrahydrofuran (2 mL) and methanol (2 mL) in water (1 mL) was added lithium hydroxide (74 mg, 3.10 mmol, 4.0 eq) . The reaction mixture was stirred at 40 ℃ for 1 h. LCMS showed that methyl 6- (2- (cyclopropylmethyl) -5- (1- (2, 4-difluorophenyl) piperidin-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate was consumed and the desired product was detected. The reaction mixture was adjusted to pH=7 with 2N HCl and extracted with EA (20 mL × 2) . The combined organic layer was washed with saturated NaCl solution, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by pre-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) and SFC (Instrument: Waters UPC2 analytical SFC (SFC-H) Column: ChiralPak OJ, 100×4.6mm I. D., 3μm Mobile phase: A for CO₂ and B for Methanol (0.1%DEA) Gradient: B 5-45%, 4 min Flow rate: 3.0 mL/min Back pressure: 2000 psi Column temperature: 40 ℃Wavelength: 214 nm) to afford the title product as a yellow solid (P₁, 138 mg, 0.22 mmol) and (P₂, 151 mg, 0.24 mmol) .

P₁-MS (ESI, pos. ion) m/z: 625.2 [M+1] ⁺, Rt=1.464/3min.

P₂-MS (ESI, pos. ion) m/z: 625.2 [M+1] ⁺, Rt=1.464/3min.

P₁-¹H NMR (400 MHz, DMSO-d₆) δ = 7.88 -7.82 (m, 1H) , 7.77 -7.70 (m, 3H) , 7.17 -7.07 (m, 1H) , 7.05 -6.98 (m, 1H) , 6.98 -6.88 (m, 2H) , 6.81 (d, J = 8.1 Hz, 1H) , 6.64 (s, 1H) , 5.47 -5.32 (m, 2H) , 3.26 -3.21 (m, 2H) , 3.20 -3.12 (m, 2H) , 2.78 -2.61 (m, 3H) , 1.93 -1.84 (m, 1H) , 1.81 -1.70 (m, 1H) , 1.68 -1.57 (m, 1H) , 1.57 -1.46 (m, 1H) , 0.87 -0.78 (m, 1H) , 0.26 -0.16 (m, 4H) .

P₁-¹HNMR (400 MHz, DMSO-d₆, T=75) δ = 7.88 -7.82 (m, 1H) , 7.79 -7.70 (m, 3H) , 7.08 -6.96 (m, 2H) , 6.95 -6.82 (m, 3H) , 6.61 (s, 1H) , 5.45 -5.31 (m, 2H) , 3.29 -3.22 (m, 2H) , 3.17 -3.13 (m, 2H) , 2.83 -2.66 (m, 3H) , 1.94 -1.86 (m, 1H) , 1.82 -1.74 (m, 1H) , 1.72 -1.61 (m, 1H) , 1.60 -1.49 (m, 1H) , 0.90 -0.81 (m, 1H) , 0.26 -0.15 (m, 4H) .

P₂-¹HNMR (400 MHz, DMSO-d₆) δ = 7.85 -7.80 (m, 1H) , 7.75 (t, J = 7.8 Hz, 1H) , 7.70 (t, J = 7.2 Hz, 2H) , 7.16 -7.08 (m, 1H) , 7.05 -6.98 (m, 1H) , 6.97 -6.88 (m, 2H) , 6.81 (d, J = 8.4 Hz, 1H) , 6.62 (s, 1H) , 5.45 -5.33 (m, 2H) , 3.27 -3.21 (m, 2H) , 3.20 -3.12 (m, 2H) , 2.80 -2.60 (m, 3H) , 1.93 -1.85 (m, 1H) , 1.79 -1.72 (m, 1H) , 1.71 -1.58 (m, 1H) , 1.57 -1.44 (m, 1H) , 0.87 -0.77 (m, 1H) , 0.27 -0.15 (m, 4H) .

P₂-¹HNMR (400 MHz, DMSO-d₆, T=75) δ = 7.86 -7.81 (m, 1H) , 7.79 -7.74 (m, 1H) , 7.73 -7.69 (m, 2H) , 7.07 -6.96 (m, 2H) , 6.94 -6.90 (m, 1H) , 6.90 -6.84 (m, 2H) , 6.60 (s, 1H) , 5.45 -5.31 (m, 2H) , 3.29 -3.23 (m, 2H) , 3.18 -3.11 (m, 2H) , 2.82 -2.66 (m, 3H) , 1.95 -1.86 (m, 1H) , 1.81 -1.74 (m, 1H) , 1.73 -1.61 (m, 1H) , 1.60 -1.48 (m, 1H) , 0.91 -0.80 (m, 1H) , 0.24 -0.18 (m, 4H) .

Example 66: Synthesis of compound 985

Step 1: Preparation of compound 985-b: methyl 6-methyl-2-vinylpyrimidine-4-carboxylate

To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (15.0 g, 80.39 mmol, 1.0 eq) and potassium vinyl trifluoroborate (15.25 g, 160.78 mmol, 2.00 eq) in a mixture solvent of dioxane (60 mL) in H₂O (15 mL) was added potassium carbonate (33.33 g, 241.17 mmol, 3.0 eq) and Pd (dppf) ₂Cl₂ (2.94 g, 4.02 mmol, 0.05 eq) at room temperature under N₂ atmosphere. The reaction mixture was stirred at 80 ℃for 2 h under N₂ atmosphere. After the reaction was completed, the reaction mixture was diluted with EA (500 mL) . The organic layer was washed with brine (300 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20) to afford the title product as a yellow oil liquid (12 g, 67.34 mmol, 83.87%) .

MS (ESI, pos. ion) m/z: 179.0 [M+1] ⁺, Rt=0.94/2min.

Step 2: Preparation of compound 985-c: methyl 2-formyl-6-methylpyrimidine-4-carboxylate

Ozone was bubbled into a solution of methyl 6-methyl-2-vinylpyrimidine-4-carboxylate (6.0 g, 33.67 mmol, 1.0 eq) in DCM (55 mL) at -78 ℃ for 2 h. After excess O₃ was purged by N₂, Me₂S (5 mL, 61.73 mmol, 1.83 eq) was added at 0 ℃. The reaction was stirred at room temperature for 6 h. After the reaction was completed, the reaction mixture was diluted with DCM (240 mL) . The organic layer was washed with brine (270 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -90: 10 -80: 20) to afford the title product as a white solid (3.1 g, 17.21 mmol, 51.10%) .

Step 3: Preparation of compound 985-2: methyl (E) -2- (3- (3-iodophenyl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To a solution of 1- (3-iodophenyl) ethan-1-one (4.23 g, 17.21 mmol, 1.0 eq) and methyl 2-formyl-6-methylpyrimidine-4-carboxylate (3.1 g, 17.21 mmol, 1.0 eq) in toluene (50 mL) was added tripotassium phosphate (9.13 g, 43.02 mmol, 2.5 eq) at room temperature. The reaction was stirred at 100 ℃ for 3 h. After the reaction was completed, the reaction mixture was diluted with EA (100 mL) . The organic layer was washed with brine (200 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20) , to afford the title product as a yellow solid (1.38 g, 3.38 mmol, 19.65%) .

MS (ESI, pos. ion) m/z: 409.0 [M+1] ⁺, Rt=1.27/2min.

Step 4: Preparation of compound 985-3: methyl 2- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (3-iodophenyl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (1.36 g, 3.33 mmol) and 2-cyclopropylacetaldehyde (6.09 g, 16.66 mmol, 5.0 eq, 23%wt. in DCM) in a mixture solvent of dioxane (12 mL) in ethanol (3 mL) was added 3-Benzyl-5- (2-hydroxyethyl) -4-methylthiazol-3-ium chloride (1.12 g, 4.16 mmol, 1.25 eq) and Et₃N (4.61 mL, 33.32 mmol, 9.0 eq) at room temperature. The reaction mixture was stirred at 100 ℃ for 2 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) . The organic layer was washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -90: 10 -80: 20) to afford the title product as a yellow oil (1.42 g, 2.88 mmol, 86.57%) .

MS (ESI, pos. ion) m/z: 493.1 [M+1] ⁺, Rt=1.48/2min.

Step 5: Preparation of compound 985-4: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A solution of methyl 2- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (1.40 g, 2.84 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (1.90 g, 4.27 mmol, 1.5 eq) in acetic acid (10 mL) was stirred at 120 ℃ for 16 h. After the reaction was completed, the reaction mixture was diluted with EA (90 mL) . The organic layer was washed with brine (120 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -70: 30) to afford the title product as a yellow oil (1.95 g, 2.16 mmol, 76.12%) .

MS (ESI, pos. ion) m/z: 901.2 [M+1] ⁺, Rt=1.75/2min.

Step 6 : Preparation of compound 985-5: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (1.90 g, 2.11 mmol, 1.0 eq) in DCM (15 mL) was added 2, 2, 2-trifluoroacetic acid (5.0 mL, 65.34 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated, and the residue was quenched with sat. NaHCO₃ aqueous solution (30 mL) and extracted with DCM (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -50: 50) to afford the title product as a yellow solid (732 mg, 1.11 mmol, 52.54%) .

MS (ESI, pos. ion) m/z: 661.0 [M+1] ⁺, Rt=1.417/2min.

Step 7: Preparation of compound 985-6: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To the solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (370 mg, 0.56 mmol, 1.0 eq) , Pd (PPh₃) ₂Cl₂ (39 mg, 0.06 mmol, 0.1 eq) , copper (1+) iodide (11 mg, 0.06 mmol, 0.1 eq) and Et₃N (2.33 mL, 1.68 mmol, 3.0 eq) in DMF (4 mL) was added 2-methylbut-3-yn-2-ol (0.11 mL, 1.12 mmol, 2.0 eq) under N₂. The reaction mixture was stirred at 40 ℃ for 1 h. After the reaction was completed, the reaction mixture was poured into water (15 mL) and extracted with EA (20 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 50%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (330 mg, 0.54 mmol, 95.52%) .

MS (ESI, pos. ion) m/z: 617.3 [M+1] ⁺ , Rt=1.694/3min.

Step 8: Preparation of compound 985: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To the solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (320 mg, 0.52 mmol, 1.0 eq) in a mixture solvent of tetrahydrofuran (2 mL) and methanol (2 mL) in water (1 mL) was added lithium hydroxide (50 mg, 2.08 mmol, 4.0 eq) . The reaction mixture was stirred at 25 ℃ for 1 h. After the reaction was completed, the reaction mixture was adjusted to pH=7 with 2N HCl and extracted with EA (20 mL ×2) . The combined organic layer was washed with saturated NaCl solution, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by pre-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (112 mg, 0.19 mmol, 35.81%) .

MS (ESI, pos. ion) m/z: 603.2 [M+1] ⁺, Rt=1.446/3min.

¹H NMR (400 MHz, DMSO-d₆) δ = 7.70 (t, J = 7.8 Hz, 1H) , 7.62 -7.56 (m, 3H) , 7.38 -7.35 (m, 3H) , 7.33 -7.28 (m, 1H) , 7.04 (s, 1H) , 6.89 -6.84 (m, 1H) , 6.78 -6.74 (m, 1H) , 5.47 -5.40 (m, 3H) , 3.23 (br d, J =6.5 Hz, 2H) , 2.54 (s, 3H) , 1.45 (s, 6H) , 1.03 -0.92 (m, 1H) , 0.34 -0.25 (m, 4H) .

Example 67: Synthesis of compound 986

Step 1: Preparation of compound 986-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (1-hydroxycyclobutyl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.30 mmol, 1.0 eq) and 1-ethynylcyclobutan-1-ol (87 mg, 0.91 mmol, 3.0 eq) in DMF (2 mL) was added Pd (PPh₃) Cl₂ (21 mg, 0.03 mmol, 0.10 eq) , copper (1+) iodide (12 mg, 0.06 mmol, 0.20 eq) and Et₃N (92 mg, 0.91 mmol, 3.0 eq) at room temperature under N₂ atmosphere. The reaction mixture was stirred at 40 ℃ under N₂ atmosphere for 2 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) . The organic layer was washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -50: 50) to afford the title product as a white solid (180 mg, 0.29 mmol, 94.55%) .

MS (ESI, pos. ion) m/z: 629.2 [M+1] ⁺, Rt=1.43/2min.

Step 2: Preparation of compound 986: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (1-hydroxycyclobutyl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (1-hydroxycyclobutyl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (170 mg, 0.27 mmol, 1.0 eq) in a mixture solvent of methanol (4 mL) and tetrahydrofuran (1 mL) in water (1 mL) was added lithium hydroxide (39 mg, 1.62 mmol, 6.0 eq) at room temperature. The reaction mixture was stirred at 50 ℃ for 1 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (99 mg, 0.16 mmol, 59.56%) .

MS (ESI, pos. ion) m/z: 615.2 [M+1] ⁺, Rt=2.58/5min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.70 (t, J = 7.9 Hz, 1H) , 7.60 (s, 2H) , 7.57 (s, 1H) , 7.42 (s, 1H) , 7.41 -7.33 (m, 3H) , 7.05 (s, 1H) , 6.87 (d, J = 10.8 Hz, 1H) , 6.77 (d, J = 8.0 Hz, 1H) , 5.86 (s, 1H) , 5.44 (s, 2H) , 3.28 -3.20 (m, 2H) , 2.57 -2.53 (m, 3H) , 2.40 -2.31 (m, 2H) , 2.26 -2.14 (m, 2H) , 1.85 -1.69 (m, 2H) , 1.06 -0.91 (m, 1H) , 0.39 -0.22 (m, 4H) .

Example 68: Synthesis of compound 987

Step 1: Preparation of compound 987-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.30 mmol, 1.0 eq) and 3-ethynyl-3-methyloxetane (87 mg, 0.91 mmol, 3.0 eq) in DMF (2 mL) was added Pd (PPh₃) Cl₂ (21 mg, 0.03 mmol, 0.10 eq) , copper (1+) iodide (12 mg, 0.06 mmol, 0.20 eq) and Et₃N (92 mg, 0.91 mmol, 3.0 eq) at room temperature under N₂ atmosphere. The reaction mixture was stirred at 40 ℃ under N₂ atmosphere for 2 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) . The organic layer was washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -50: 50) to afford the title product as a white solid (180 mg, 0.29 mmol, 94.55%) .

MS (ESI, pos. ion) m/z: 629.2 [M+1] ⁺, Rt=1.48/2min.

Step 2: Preparation of compound 987: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (170 mg, 0.27 mmol, 1.0 eq) in a mixture solvent of methanol (4 mL) and tetrahydrofuran (1 mL) in water (1 mL) was added lithium hydroxide (39 mg, 1.62 mmol, 6.0 eq) at room temperature. The reaction mixture was stirred at 50 ℃ for 1 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (120 mg, 0.20 mmol, 72.2%) .

MS (ESI, pos. ion) m/z: 615.2 [M+1] ⁺, Rt=2.54/5min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.71 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.58 (s, 1H) , 7.46 -7.30 (m, 4H) , 7.06 (s, 1H) , 6.93 -6.84 (m, 1H) , 6.77 (d, J = 8.3 Hz, 1H) , 5.44 (s, 2H) , 4.74 (d, J = 5.3 Hz, 2H) , 4.42 (d, J = 5.5 Hz, 2H) , 3.28 -3.21 (m, 2H) , 2.58 -2.53 (m, 3H) , 1.62 (s, 3H) , 1.06 -0.92 (m, 1H) , 0.37 -0.25 (m, 4H) .

Example 69: Synthesis of compound 992

Step 1: Preparation of compound 992-1: methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (1-hydroxycyclobutyl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (50 mg, 83.54 μmol, 1 eq) in DMF (3 mL) was added TEA (25.36 mg, 250.63 μmol, 34.89 μL, 3 eq) , 1-ethynylcyclobutanol (24.09 mg, 250.63 μmol, 3 eq) and Pd (PPh₃) ₂Cl₂ (5.86 mg, 8.35 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (50 mg, 97.52%) .

MS (ESI, pos. ion) m/z: 614.3 [M+H] ⁺, Rt=1.058/1.5 min.

Step 2: Preparation of compound 992: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (1-hydroxycyclobutyl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (1-hydroxycyclobutyl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylate (50 mg, 81.47 μmol, 1 eq) in THF (1 mL) and MeOH (2 mL) . A solution of LiOH (19.51 mg, 0.814 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL ×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (FA) -ACN] ; gradient: 45%-65%B over 11 min) to afford the title product as a yellow solid (11 mg, 22.51%) .

MS (ESI, pos. ion) m/z: 600.2 [M+H] ⁺, Rt=0.960/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.93 -7.86 (m, 2H) , 7.80 -7.76 (m, 1H) , 7.73 -7.67 (m, 1H) , 7.60 (s, 2H) , 7.46 -7.41 (m, 1H) , 7.40 -7.32 (m, 3H) , 6.97 -6.92 (m, 1H) , 6.90 -6.84 (m, 1H) , 6.78 (br d, J = 8.1 Hz, 1H) , 5.94 -5.79 (m, 1H) , 5.46 -5.35 (m, 2H) , 3.21 (br d, J = 6.4 Hz, 2H) , 2.38 -2.30 (m, 2H) , 2.25 -2.15 (m, 2H) , 1.81 -1.70 (m, 2H) , 1.00 -0.88 (m, 1H) , 0.30 -0.21 (m, 4H) .

Example 70: Synthesis of compound 993

Step 1: Preparation of compound 993-1: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinate

A mixture of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (48.54 mg, 81.11 μmol) and 3-ethynyl-3-methyl-oxetane (23.39 mg, 243.32 μmol) in DMF (3 mL) was added TEA (24.62 mg, 243.32 μmol) and Pd (PPh₃) ₂Cl₂ (5.69 mg, 8.11 μmol) . The mixture was stirred at 80 ℃ for 16 hrs under N₂ atmosphere. The mixture was diluted with brine (5 mL) and extracted with EtOAc (5 mL*) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum to afford the title product as a brown oil (50 mg, crude) .

MS (ESI, pos. ion) m/z: 614.3 [M+1] ⁺. Rt=1.104/1.5min.

Step 2: Preparation of compound 993: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (3-methyloxetan-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinic acid

A mixture of methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (3-methyloxetan-3-yl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylate (50 mg, 81.47 μmol) in MeOH (2 mL) and THF (2 mL) was added NaOH (16.29 mg, 407.37 μmol) in H₂O (1 mL) . The mixture was stirred at 25 ℃for 1 hr. The mixture was diluted with 1 N HCl (3 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (FA) -ACN] ; gradient: 45%-65%B over 11 min) to afford the title product as a yellow solid (10.48 mg, 21.1%yield) .

MS (ESI, pos. ion) m/z: 600.2 [M+1] ⁺. Rt=0.997/1.5min.

¹H NMR (400 MHz, DMSO-d₆) δ 7.94 -7.84 (m, 2H) , 7.80 -7.66 (m, 2H) , 7.61 -7.53 (m, 2H) , 7.43 -7.31 (m, 4H) , 6.96 -6.83 (m, 2H) , 6.82 -6.72 (m, 1H) , 5.44 -5.37 (m, 2H) , 4.75 -4.68 (m, 2H) , 4.46 -4.37 (m, 2H) , 3.21 (br d, J = 6.8 Hz, 2H) , 1.66 -1.57 (m, 3H) , 1.02 -0.87 (m, 1H) , 0.32 -0.17 (m, 4H) .

Example 71: Synthesis of compound 994

Step 1: Preparation of compound 994-2: 1-ethoxycyclopropanol

To a solution of (1-ethoxycyclopropoxy) -trimethyl-silane (10 g, 57.37 mmol, 11.53 mL, 1 eq) in MeOH (100 mL) . The mixture was stirred at 25 ℃ for 16hr. The reaction mixture was concentrated under reduced pressure to afford the title product as colourless oil (5.0 g, 85.34%yield) .

¹H NMR (400 MHz, CHLOROFORM-d) δ 3.76 (q, J = 7.2 Hz, 2H) , 3.50 (s, 1H) , 1.22 (t, J = 7.1 Hz, 3H) , 1.04 -0.85 (m, 4H) .

Step 2: Preparation of compound 994-3: 1- (2-trimethylsilylethynyl) cyclopropanol

To a solution (S1) of 1-ethoxycyclopropanol (1.8 g, 17.62 mmol, 1 eq) in THF (20 mL) was added dropwise MeMgBr (3.0 M, 7.64 mL, 1.3 eq) at 0 ℃. After addition, the mixture was stirred at 0 ℃ for 1 hr. To a solution (S2) of ethynyl (trimethyl) silane (2.08 g, 21.15 mmol, 2.93 mL, 1.2 eq) in THF was added dropwise n-BuLi (2.5 M, 9.16 mL, 1.3 eq) at -78 ℃, the mixture was stirred at this temperature for 15 min, the mixture (S2) was added dropwise to previous reaction (S1) at 0 ℃, After addition, The resulting mixture was stirred at 40 ℃ for 16 hrs. The reaction mixture was quenched by addition sat. NH₄Cl 20 mL at 0 ℃, extracted with EtOAC 45 mL (15 mL *3) . The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel, eluting with 0%to 4.0%EtOAc in petroleum ether as a gradient, to afford the title product as colourless oil (1.0 g, 36.78%yield) .

¹H NMR (400 MHz, DMSO-d₆) δ 6.17 (s, 1H) , 0.85 (td, J = 2.8, 13.5 Hz, 4H) , 0.12 (s, 9H) .

Step 3: Preparation of compound 994-4: 1-ethynylcyclopropanol

To a solution of 1- (2-trimethylsilylethynyl) cyclopropanol (140 mg, 907.43 μmol, 1 eq) in DMF (2 mL) was added KF (158.16 mg, 2.72 mmol, 3 eq) . The mixture was stirred at 25 ℃ for 3hr. The reaction mixture was filtered to afford the title product as colourless oil (2.5 g, rude) .

Step 4: Preparation of compound 994-5: 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid

To a solution of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (116 mg, 193.82 μmol, 1 eq) in MeOH (10 mL) , THF (5 mL) and H₂O (1 mL) was added LiOH (46.42 mg, 1.94 mmol, 10 eq) . The mixture was stirred at 25 ℃ for 16hrs. The reaction mixture was quenched by addition water 20 mL at 25 ℃ and adjust to PH = 3～5 by HCl (1M) , extracted with EtOAC 30 mL (10 mL *3) . The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to afford the title product as a white solid (112 mg, 98.87%yield) .

MS (ESI, pos. ion) m/z: 586.0 [M+H] ⁺, Rt = 1.018/1.5 min.

Step 5: Preparation of compound 994: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (1-hydroxycyclopropyl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylic acid

A mixture of 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid (25 mg, 42.77 μmol, 1 eq) , 1-ethynylcyclopropanol (70.24 mg, 855.50 μmol, 20 eq) , dichloropalladium; triphenylphosphane (3.00 mg, 4.28 μmol, 0.1 eq) , TEA (12.99 mg, 128.32 μmol, 17.86 μL, 3 eq) in DMF (2 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 75 ℃ for 16hrs under N₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water (NH₃H₂O-NH₄HCO₃) -MeCN] ; gradient: 23%-43%B over 10 min) to afford the title product as a white solid (3.5 mg, 13.97%yield) .

MS (ESI, pos. ion) m/z: 586.0 [M+H] ⁺, Rt = 2.293/4 min.

¹H NMR (400 MHz, DMSO-d₆) δ 7.91 -7.81 (m, 2H) , 7.77 -7.66 (m, 2H) , 7.39 (s, 1H) , 7.37 -7.33 (m, 2H) , 7.30 (br dd, J = 2.0, 6.3 Hz, 1H) , 6.90 (s, 1H) , 6.85 (br d, J = 11.5 Hz, 1H) , 6.76 (d, J = 8.0 Hz, 1H) , 6.30 (s, 1H) , 5.41 (s, 2H) , 3.19 (br s, 2H) , 0.99 -0.91 (m, 5H) , 0.28 -0.20 (m, 4H) .

Example 72: Synthesis of compound 995

Step 1: Preparation of compound 995-1: methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (3-hydroxyoxetan-3-yl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (50.00 mg, 83.54 μmol, 1 eq) in DMF (2 mL) was added TEA (25.36 mg, 250.63 μmol, 34.88 μL, 3 eq) , 3-ethynyloxetan-3-ol (24.59 mg, 250.63 μmol, 3 eq) and Pd (PPh3) ₂Cl₂ (5.86 mg, 8.35 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (18 mg, 34.99%) .

MS (ESI, pos. ion) m/z: 616.2 [M+H] ⁺, Rt=1.000/1.5 min.

Step 2: Preparation of compound 995: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (3-hydroxyoxetan-3-yl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [3- [2- (3-hydroxyoxetan-3-yl) ethynyl] phenyl] pyrrol-3-yl] pyridine-2-carboxylate (18 mg, 29.24 μmol, 1 eq) in THF (1 mL) and MeOH (2 mL) . A solution of LiOH (7.00 mg, 0.292 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (3 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (FA) -ACN] ; gradient: 45%-65%B over 11 min) to afford the title product as a yellow solid (5.5 mg, 31.27%) .

MS (ESI, pos. ion) m/z: 602.2 [M+H] ⁺, Rt=0.889/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.93 -7.86 (m, 2H) , 7.79 -7.75 (m, 1H) , 7.73 -7.66 (m, 1H) , 7.64 -7.56 (m, 2H) , 7.54 -7.48 (m, 1H) , 7.44 -7.35 (m, 3H) , 6.96 -6.92 (m, 1H) , 6.89 -6.83 (m, 1H) , 6.77 (d, J = 8.8 Hz, 1H) , 6.67 -6.54 (m, 1H) , 5.46 -5.39 (m, 2H) , 4.77 -4.71 (m, 2H) , 4.63 -4.56 (m, 2H) , 3.22 (br s, 2H) , 1.01 -0.87 (m, 1H) , 0.32 -0.17 (m, 4H) .

Example 73: Synthesis of compound 1003

Step 1: Preparation of compound 1003-2: 3- ( (tetrahydro-2H-pyran-2-yl) oxy) benzaldehyde

To a solution of 3-hydroxybenzene-1-carbaldehyde (5 g, 40.94 mmol, 1.0 eq) and 3, 4-dihydro-2H-pyran (4.22 mL, 49.13 mmol, 1.2 eq) in DCM (50 mL) was added PPTS (1.03 g, 4.09 mmol, 0.1 eq) . The mixture was stirred at RT for 16 hours. After the reaction completion, the mixture was diluted with water (100 mL) and extracted with DCM (100 mL × 2) . The organic layer was washed with brine (500 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 14%EtOAc in petroleum ether and DCM as a gradient, to afford the title product as a colorless oil (8000 mg, 38.79 mmol, 94.7%) .

Step 2: Preparation of compound 1003-3: 1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-2-yn-1-ol

To a solution of 3- ( (tetrahydro-2H-pyran-2-yl) oxy) benzaldehyde (8.0 g, 38.79 mmol, 1.0 eq) in THF (80 mL) was added bromo (ethynyl) magnesium (100.85 mL, 50.43 mmol, 1.3 eq) dropwise at cooled to 0 ℃. The mixture was stirred at 0 ℃ for 2 hrs. After the reaction completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2) . The organic layer was washed with brine (500 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 11%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (6500 mg, 27.98 mmol, 72.1%) .

Step 3: Preparation of compound 1003-4: methyl (E) -6- (3-oxo-3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of 1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-2-yn-1-ol (2000 mg, 8.61 mmol, 1.0 eq) and methyl 2-chloropyrimidine-4-carboxylate (1486 mg, 8.61 mmol, 1.0 eq) in dioxane (60 mL) was added TEA (3.58 mL, 25.83 mmol, 3.0eq) , CuI (164 mg, 0.86 mmol, 0.1 eq) , PPh₃ (452 mg, 1.72 mmol, 0.2 eq) and Pd (PPh₃) ₂Cl₂ (604 mg, 0.86 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 12 hours under N₂ atmosphere. After the reaction completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2) . The organic layer was washed with brine (200 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (1600 mg, 4.34 mmol, 50.4%) .

MS (ESI, pos. ion) m/z: 369.3 [M+1] ⁺, Rt=0.987/2min

Step 4: Preparation of compound 1003-5: methyl 6- (5-cyclopropyl-1, 4-dioxo-1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) pentan-3-yl) pyrimidine-4-carboxylate

To a solution of methyl (E) -6- (3-oxo-3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-1-en-1-yl) pyrimidine-4-carboxylate (1600 mg, 4.34 mmol, 10 eq) and 2-cyclopropylacetaldehyde (7307 mg, 21.72 mmol, 5.0 eq, 25%wt. in DCM) in a mixture solvent of dioxane (20 mL) in EtOH (5 mL) was added 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (1465 mg, 5.43 mmol, 1.25 eq) , TEA (5.42 mL, 39.09 mmol, 9.0 eq) . The mixture was stirred at 100 ℃ for 1 hr. After the reaction completion, the mixture was concentrated under vacuo and diluted with H₂O (50 mL) and extracted with EA (60 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 38%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (1600 mg, 3.54 mmol, 81.4%) .

MS (ESI, pos. ion) m/z: 453.5 [M+1] ⁺, Rt=1.064/2min

Step 5: Preparation of compound 1003-6: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-hydroxyphenyl) -1H-pyrrol-3yl) pyrimidine-4-carboxylate

To a solution of methyl 6- (5-cyclopropyl-1, 4-dioxo-1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) pentan-3-yl) pyrimidine-4-carboxylate (1600 mg, 3.54 mmol, 1.0 eq) in AcOH (30 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (2358 mg, 5.30 mmol, 1.5 eq) . The mixture was stirred at 100 ℃ for 12 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 40%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (1300 mg, 1.67 mmol, 47.3%) .

MS (ESI, pos. ion) m/z: 777.1 [M+1] ⁺, Rt=1.28/2min.

Step 6: Preparation of compound 1003-7: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-hydroxyphenyl) -1H-pyrrol-3yl) pyrimidine-4-carboxylate (1300 mg, 1.67 mmol, 1.0 eq) and DIEA (0.44 mL, 2.51 mmol, 1.5 eq) in DCM (20 mL) was added trifluoromethanesulfonic anhydride (0.34 mL, 2.01 mmol, 1.2 eq) at 0 ℃ dropwise. The mixture was stirred at 0 ℃ for 1 hr. After the reaction completion, the mixture was concentrated under vacuum to afford the crude title product as a yellow oil (1300 mg, 1.43 mmol, 85.5%) .

Step 7: Preparation of compound 1003-8: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (1300 mg, 1.43 mmol, 1.0 eq) in DCM (15 mL) was added TFA (7.5 mL) . The mixture was stirred at rt for 16 hrs. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 45%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (800 mg, 1.20 mmol, 83.7%) .

Step 8: Preparation of compound 1003-9: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (100 mg, 0.15 mmol, 1.0 eq) and 3-ethynyltetrahydrofuran (43 mg, 0.45 mmol, 3.0 eq) in DMF (3 mL) was added TEA (0.06 mL, 0.45 mmol, 3.0 eq) , PPh₃ (7.85 mg, 0.03 mmol, 0.2 eq) , CuI (3 mg, 0.015 mmol, 0.1 eq) and Pd (PPh₃) ₄ (17 mg, 0.015 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 16 hours under N₂. After the reaction completion, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (60 mg, 0.10 mmol, 65.3%) .

MS (ESI, pos. ion) m/z: 615.5 [M+1] +, Rt=1.082/2min.

Step 9: Preparation of compound 1003: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

To a solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (60 mg, 0.10 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) in H₂O (2 mL) was added LiOH (12 mg, 0.30 mmol, 3.0 eq) . The mixture was stirred at RT for 3 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (24.39 mg, 0.04 mmol, 41.60%) .

MS (ESI, pos. ion) m/z: 601.4 [M+1] ⁺ , Rt=0.991/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 8.97 (d, J = 5.0 Hz, 1H) , 7.74 -7.68 (m, 1H) , 7.68 -7.64 (m, 1H) , 7.64 -7.57 (m, 2H) , 7.41 -7.28 (m, 4H) , 7.04 (s, 1H) , 6.89 (d, J = 11.0 Hz, 1H) , 6.77 (d, J = 8.1 Hz, 1H) , 5.42 (s, 2H) , 3.96 (t, J = 7.6 Hz, 1H) , 3.87 -3.69 (m, 2H) , 3.58 (dd, J = 6.9, 7.9 Hz, 1H) , 3.28 -3.19 (m, 3H) , 2.29 -2.19 (m, 1H) , 1.97 -1.88 (m, 1H) , 1.04 -0.92 (m, 1H) , 0.38 -0.21 (m, 4H) .

Example 74: Synthesis of compound 1008

Step 1: Preparation of compound 1008-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.30 mmol, 1.0 eq) and 3-ethynyltetrahydrofuran (87 mg, 0.91 mmol, 3.00 eq) in DMF (3 mL) was added Pd (PPh₃) Cl₂ (21 mg, 0.03 mmol, 0.10 eq) , copper (1+) iodide (12 mg, 0.06 mmol, 1.2 eq) and Et₃N (92 mg, 0.91 mmol, 3.0 eq) at room temperature under N₂ atmosphere. The reaction mixture was stirred at 40 ℃ under N₂ atmosphere for 1 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) . The organic layer was washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -50: 50) to afford the title product as a white solid (170 mg, 0.27 mmol, 89.30%) .

MS (ESI, pos. ion) m/z: 629.5 [M+1] ⁺, Rt=1.45/2min.

Step 2: Preparation of compound 1008: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of m methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (170 mg, 0.27 mmol, 1.0 eq) in a mixture solvent of methanol (4 mL) and tetrahydrofuran (1 mL) in water (1 mL) was added lithium hydroxide (39 mg, 1.62 mmol, 6.0 eq) at room temperature. The reaction mixture was stirred at 50 ℃ for 1 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (110 mg, 0.18 mmol, 66.18%) .

MS (ESI, pos. ion) m/z: 615.2 [M+1] ⁺, Rt=2.63/5min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.71 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.58 (s, 1H) , 7.40 -7.29 (m, 4H) , 7.04 (s, 1H) , 6.88 (d, J = 11.0 Hz, 1H) , 6.77 (d, J = 9.0 Hz, 1H) , 5.43 (s, 2H) , 3.96 (t, J = 7.6 Hz, 1H) , 3.87 -3.70 (m, 2H) , 3.64 -3.52 (m, 1H) , 3.28 -3.19 (m, 3H) , 2.57 -2.53 (m, 3H) , 2.32 -2.16 (m, 1H) , 1.98 -1.87 (m, 1H) , 1.04 -0.93 (m, 1H) , 0.37 -0.24 (m, 4H) .

Example 75: Synthesis of compound 1009

Step 1: Preparation of compound 1009-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinate

To the solution of methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate (200 mg, 0.31 mmol, 1.0 eq) , 3-ethynyltetrahydrofuran (90 mg, 0.93 mmol, 3.0 eq) , CuI (6 mg, 0.03 mmol, 0.1 eq) and Pd (PPh₃) ₂Cl₂ (22 mg, 0.03 mmol, 0.1 eq) in DMF (4 mL) was added TEA (0.13 mL, 0.93 mmol, 3.0 eq) . The reaction mixture was stirred at 40 ℃ for 3 hours under N₂. The mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/2 to 1/1) to afford the title product as a yellow solid (120 mg, 0.20 mmol, 63%) .

MS (ESI, pos. ion) m/z: 614.4 [M+1] ⁺, Rt=1.117/2 min.

Step 2: Preparation of compound 1009: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.20 mmol, 1.0 eq) , THF (2 mL) and MeOH (2 mL) . A solution of LiOH (33 mg, 0.78 mmol, 4.0 eq) in H₂O (2 mL) was added to the mixture, and the resulting was stirred at RT overnight. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (10 mL ×2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 65%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (60 mg, 0.10 mmol, 50%) .

MS (ESI, pos. ion) m/z: 600.0 [M+1] ⁺, Rt=0.983/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 12.92 (br s, 1H) , 7.94 -7.86 (m, 2H) , 7.78 (dd, J = 2.2, 6.2 Hz, 1H) , 7.71 (t, J = 7.8 Hz, 1H) , 7.60 (s, 2H) , 7.38 (s, 1H) , 7.37 -7.27 (m, 3H) , 6.93 (s, 1H) , 6.88 (d, J = 11.0 Hz, 1H) , 6.81 -6.75 (m, 1H) , 5.41 (s, 2H) , 3.95 (t, J = 7.6 Hz, 1H) , 3.83 (dt, J = 5.8, 8.1 Hz, 1H) , 3.78 -3.69 (m, 1H) , 3.57 (dd, J = 6.6, 7.8 Hz, 1H) , 3.27 -3.16 (m, 3H) , 2.30 -2.18 (m, 1H) , 1.97 -1.85 (m, 1H) , 1.00 -0.86 (m, 1H) , 0.32 -0.19 (m, 4H) .

Example 76: Synthesis of compound 1024

Step 1: Preparation of compound 1024-2: methyl (E) -6-methyl-2- (3-oxo-3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of 1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-2-yn-1-ol (4000 mg, 17.22 mmol, 1.0 eq) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3213 mg, 17.22 mmol, 1.0 eq) in dioxane (80 mL) was added TEA (7.16 mL, 51.66 mmol, 3.0 eq) , CuI (328 mg, 1.72 mmol, 0.1 eq) , PPh₃ (903 mg, 3.44 mmol, 0.2 eq) and Pd (PPh₃) ₂Cl₂ (1209 mg, 1.72 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 12 hours under N2 atmosphere. After the reaction completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2) . The organic layer was washed with brine (200 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (3500 mg, 9.15 mmol, 53.1%) .

MS (ESI, pos. ion) m/z: 383.2 [M+1] +, Rt=1.37/2min.

Step 2: Preparation of compound 1024-3: methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -6-methyl-2- (3-oxo-3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-1-en-1-yl) pyrimidine-4-carboxylate (3500 mg, 9.15 mmol, 1.0 eq) and 2-cyclopropylacetaldehyde (12.83 g, 45.76 mmol, 30%wt. in DCM) in a mixture solvent of dioxane (60 mL) in EtOH (15 mL) was added 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (3086 mg, 11.44 mmol, 1.25 eq) , TEA (11.42 mL, 82.37 mmol, 9.0 eq) . The mixture was stirred at 100 ℃ for 1 h. After the reaction completion, the mixture was concentrated under vacuo, diluted with H₂O (150 mL) and extracted with EA (200 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 38%EtOAc in petroleum ether as a gradient, to afford the title product as a white solid (4000 mg, 8.57 mmol, 93.7%) .

MS (ESI, pos. ion) m/z: 467.3 [M+1] ⁺, Rt=1.43/2min.

Step 3: Preparation of compound 1024-4: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-hydroxyphenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate (4000 mg, 8.57 mmol, 1.0 eq) in AcOH (100 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (5717 mg, 12.86 mmol, 1.5 eq) . The mixture was stirred at 100 ℃ for 12 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 40%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (5200 mg, 6.57 mmol, 76.7%) .

MS (ESI, neg. ion) m/z: 789.4 [M-1] ⁺, Rt=1.27/2min.

Step 4: Preparation of compound 1024-5: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-hydroxyphenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (5.0 g, 6.32 mmol, 1.0 eq) and DIEA (1.66 mL, 9.48 mmol, 1.5 eq) in DCM (80 mL) was added trifluoromethanesulfonic anhydride (1.27 mL, 7.59 mmol, 1.2 eq) dropwise at 0 ℃ . The mixture was stirred at 0 ℃ for 1 h. After the reaction completion, the mixture was concentrated under vacuum to afford the crude title product as a yellow oil (5200 mg, 5.45 mmol, 89.1%) .

Step 5: Preparation of compound 1024-6: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (5200 mg, 5.45 mmol, 1.0 eq) in DCM (60 mL) was added TFA (30 mL) . The mixture was stirred at rt for 16 hrs. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 45%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (3350 mg, 4.9 mmol, 87.1%) .

MS (ESI, pos. ion) m/z: 683.1 [M+1] ⁺, Rt=1.191/2min.

Step 6: Preparation of compound 1024-7: methyl 2- (5- (3- (cyclopropylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.29 mmol, 1.0 eq) and (cyclopropylethynyl) trimethylsilane (41 mg, 0.29 mmol, 1.0 eq) in DMF (4 mL) was added CuI (6 mg, 0.03 mmol, 0.1 eq) , PPh₃ (15 mg, 0.06 mmol, 0.2 eq) , TEA (0.12 mL, 0.88 mmol, 3.0 eq) , K₂CO₃ (40 mg, 0.29 mmol, 1.0 eq) and Pd (PPh₃) ₄ (34 mg, 0.03 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 16 hours under N₂. After the reaction completion, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was and purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (90 mg, 0.15 mmol, 51.3%) .

MS (ESI, pos. ion) m/z: 599.2 [M+1] +, Rt=1.224/2min.

Step 7: Preparation of compound 1024: 2- (5- (3- (cyclopropylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (3- (cyclopropylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (90 mg, 0.15 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) in H₂O (2 mL) was added LiOH (19 mg, 0.45 mmol, 3.0 eq) . The mixture was stirred at RT for 3 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (56 mg, 0.10 mmol, 63.7%) .

MS (ESI, pos. ion) m/z: 585.1 [M+1] ⁺ , Rt=1.096/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.70 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.57 (s, 1H) , 7.35 (s, 1H) , 7.34 -7.30 (m, 2H) , 7.30-7.26 (m, 1H) , 7.03 (s, 1H) , 6.86 (d, J = 11.0 Hz, 1H) , 6.78 -6.73 (m, 1H) , 5.42 (s, 2H) , 3.23 (br d, J = 6.8 Hz, 2H) , 2.55 (s, 3H) , 1.53 (tt, J = 5.0, 8.3 Hz, 1H) , 1.02 -0.94 (m, 1H) , 0.91 -0.85 (m, 2H) , 0.75 -0.68 (m, 2H) , 0.38 -0.22 (m, 4H) .

Example 77: Synthesis of compound 1025

Step 1: Preparation of compound 1025-1: methyl 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.29 mmol) and ethynylcyclobutane (48 mg, 0.58 mmol, 2.0 eq) in DMF (4 mL) was added TEA (0.12 mL, 0.87 mmol, 3.0 eq) , PPh₃ (15 mg, 0.06 mmol, 0.2 eq) , CuI (6 mg, 0.03 mmol, 0.1 eq) and Pd (PPh₃) ₄ (34 mg, 0.03 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 16 h under N₂. After the reaction completion, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (92 mg, 0.15 mmol, 51.2%) .

MS (ESI, pos. ion) m/z: 613.25 [M+1] ⁺, Rt=1.25/2min.

Step 2: Preparation of compound 1025: 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (92 mg, 0.15 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) in H₂O (2 mL) was added LiOH (19 mg, 0.45 mmol, 3.0 eq) . The mixture was stirred at RT for 3 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 65%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (46 mg, 0.08 mmol, 51.2%) .

MS (ESI, pos. ion) m/z: 599.3 [M+1] ⁺ , Rt=1.168/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.71 (t, J = 7.8 Hz, 1H) , 7.61 (s, 2H) , 7.57 (s, 1H) , 7.38 -7.32 (m, 3H) , 7.32 -7.28 (m, 1H) , 7.04 (s, 1H) , 6.88 (d, J = 11.0 Hz, 1H) , 6.76 (d, J = 8.3 Hz, 1H) , 5.43 (s, 2H) , 3.27 (d, J = 8.5 Hz, 1H) , 3.25 -3.21 (m, 2H) , 2.55 (s, 3H) , 2.34 -2.25 (m, 2H) , 2.18 -2.06 (m, 2H) , 1.98 -1.83 (m, 2H) , 1.05 -0.93 (m, 1H) , 0.37 -0.24 (m, 4H) .

Example 78: Synthesis of compound 1026

Step 1: Preparation of compound 1026-1: methyl 2- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.29 mmol, 1.0 eq) and ethynylcyclobutane (52 mg, 0.58 mmol, 2.0 eq) in DMF (4 mL) was added TEA (0.12 mL, 0.88 mmol, 3.0 eq) , PPh₃ (15 mg, 0.06 mmol, 0.2 eq) , CuI (6 mg, 0.03 mmol, 0.1 eq) and Pd (PPh₃) ₄ (34 mg, 0.03 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 16 h under N₂. After the reaction completion, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 34%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (50 mg, 0.08 mmol, 27.5%) .

MS (ESI, pos. ion) m/z: 627.2 [M+1] ⁺, Rt=1.29/2min.

Step 2: Preparation of compound 1026: 2- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (50 mg, 0.08 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) in H₂O (2 mL) was added LiOH (10 mg, 0.24 mmol, 3.0 eq) . The mixture was stirred at RT for 3 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 65%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (25 mg, 0.04 mmol, 51.1%) .

MS (ESI, pos. ion) m/z: 613.2 [M+1] ⁺ , Rt=1.196/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.71 (t, J = 7.9 Hz, 1H) , 7.59 (d, J = 12.5 Hz, 3H) , 7.38 -7.31 (m, 3H) , 7.31 -7.26 (m, 1H) , 7.04 (s, 1H) , 6.88 (d, J = 11.0 Hz, 1H) , 6.77 (d, J = 8.3 Hz, 1H) , 5.42 (s, 2H) , 3.23 (br d, J = 6.8 Hz, 2H) , 2.89 -2.80 (m, 1H) , 2.55 (s, 3H) , 2.01 -1.91 (m, 2H) , 1.77 -1.65 (m, 2H) , 1.64 -1.48 (m, 4H) , 1.03 -0.93 (m, 1H) , 0.43 -0.19 (m, 4H) .

Example 79: Synthesis of compound 1027

Step 1: Preparation of compound 1027-1: methyl 2- (5- (3- (cyclopropylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To the solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (200 mg, 0.30 mmol, 1.0 eq) in DMF (10 mL) was added CuI (6 mg, 0.03 mmol, 0.1 eq) , TEA (91 mg, 0.90 mmol, 3.0 eq) , Pd (PPh₃) ₄ (35 mg, 0.03 mmol, 0.1 eq) , K₂CO₃ (41 mg, 0.30 mmol, 1.0 eq) and (cyclopropylethynyl) trimethylsilane (124 mg, 0.90 mmol, 3.0 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 18 hours under N₂ atmosphere. After the reaction was completed, the reaction mixture was poured into H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether to afford the title product as a yellow solid (90 mg, 0.15 mmol, 51.46 %) .

MS (ESI, neg. ion) m/z: 583.2 [M-1] ⁺, Rt=1.133/2min.

Step 2: Preparation of compound 1027: 2- (5- (3- (cyclopropylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (3- (cyclopropylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (90 mg, 0.15 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of lithium hydroxide (25 mg, 0.60 mmol, 4.0 eq) in H₂O (2 mL) . The reaction mixture was stirred at RT for 1 hour. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (64.0 mg, 0.11 mmol, 72.89%) .

MS (ESI, pos. ion) m/z: 571.2 [M+1] ⁺ , Rt=1.067/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.80 -13.44 (m, 1H) , 8.98 (d, J = 5.0 Hz, 1H) , 7.70 (t, J = 7.9 Hz, 1H) , 7.66 (d, J = 4.8 Hz, 1H) , 7.61 (s, 2H) , 7.37 -7.25 (m, 4H) , 7.03 (s, 1H) , 6.88 (d, J = 11.3 Hz, 1H) , 6.76 (d, J = 9.0 Hz, 1H) , 5.42 (s, 2H) , 3.22 (br d, J = 6.8 Hz, 2H) , 1.53 (s, 1H) , 1.03 -0.93 (m, 1H) , 0.92 -0.85 (m, 2H) , 0.75 -0.68 (m, 2H) , 0.33 -0.23 (m, 4H) .

Example 80: Synthesis of compound 1028

Step 1: Preparation of compound 1028-1: methyl 2- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To the solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (180 mg, 0.27 mmol, 1.0 eq) , CuI (5 mg, 0.03 mmol, 0.1 eq) , TEA (0.11 mL, 0.81 mmol, 3.0 eq) , Pd (PPh₃) ₄ (31 mg, 0.03 mmol, 0.1 eq) in DMF (10 mL) was added ethynylcyclopentane (150 mg, 1.62 mmol, 6.0 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was poured into H₂O (50 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether, to afford the title product as a yellow solid (110 mg, 0.18 mmol, 66.69 %) .

Step 2: Preparation of compound 1028: 2- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (110 mg, 0.18 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of lithium hydroxide (30 mg, 0.73 mmol, 4.0 eq) in H₂O (2 mL) . The mixture was stirred at RT for 1 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, washed with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (64.0 mg, 0.11 mmol, 59.57%) .

MS (ESI, pos. ion) m/z: 599.2 [M+1] ⁺ , Rt=1.158/2min.

¹H NMR (400 MHz, DMSO-d₆) δ = 13.79 -13.41 (m, 1H) , 8.97 (d, J = 5.0 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.65 (d, J = 5.0 Hz, 1H) , 7.59 (s, 2H) , 7.37 -7.27 (m, 4H) , 7.04 (s, 1H) , 6.89 (d, J = 10.8 Hz, 1H) , 6.78 (d, J = 8.3 Hz, 1H) , 5.42 (s, 2H) , 3.22 (br d, J = 6.5 Hz, 2H) , 2.84 (t, J = 7.5 Hz, 1H) , 2.00 -1.91 (m, 2H) , 1.75 -1.66 (m, 2H) , 1.63 -1.52 (m, 4H) , 0.97 (br d, J = 6.5 Hz, 1H) , 0.34 -0.25 (m, 4H) .

Example 81: Synthesis of compound 1031

Step 1: Preparation of compound 1031-2: 4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) benzaldehyde

To a solution of 3-hydroxybenzene-1-carbaldehyde (5 g, 40.94 mmol, 1.0 eq) and 3, 4-dihydro-2H-pyran (3.68 mL, 42.82 mmol, 1.05 eq) in DCM (60 mL) was added PPTS (0.90 g, 3.57 mmol, 0.09 eq) . The mixture was stirred at RT for 16 hours. After the reaction completion, the mixture was diluted with water (100 mL) and extracted with DCM (100 mL × 2) . The organic layer was washed with brine (500 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 11%EtOAc in petroleum ether and DCM as a gradient, to afford the title product as a colorless oil (6500 mg, 28.99 mmol, 81.2%) .

Step 2: Preparation of compound 1031-3: 1- (4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-2-yn-1-ol

To a solution of 4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) benzaldehyde (6.36 g, 28.36 mmol, 1.0 eq) in THF (80 mL) was added dropwise bromo (ethynyl) magnesium (85.09 mL, 42.55 mmol, 1.5 eq) at 0 ℃ . The reaction mixture was stirred at 0 ℃ for 2 hrs. After the reaction completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2) . The organic layer was washed with brine (500 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product. which was purified by column chromatography through silica gel, eluting with 0%to 14%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (6000 mg, 23.97 mmol, 84.5%) .

Step 3: Preparation of compound 1031-4: methyl (E) -2- (3- (4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To a solution of 1- (4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-2-yn-1-ol (6.0 g, 23.97 mmol, 1.0 eq) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (4.47 g, 23.97 mmol, 1.0 eq) in dioxane (80 mL) was added TEA (9.97 mL, 71.92 mmol, 3.0 eq) , CuI (0.46 g, 2.40 mmol, 0.1 eq) , PPh₃ (1.26 g, 4.79 mmol, 0.2 eq) and Pd (PPh₃) ₂Cl₂ (1.68 g, 2.40 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 12 hours under N₂ atmosphere. After the reaction completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2) . The organic layer was washed with brine (200 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (4500 mg, 11.24 mmol, 46.9%) .

MS (ESI, pos. ion) m/z: 401.3 [M+1] ⁺, Rt=1.048/2min

Step 4: Preparation of compound 1031-5: methyl 2- (5-cyclopropyl-1- (4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (4.5 g, 11.24 mmol, 1.0 eq) and 2-cyclopropylacetaldehyde (18.91 g, 56.19 mmol, 5.0 eq, 25%wt. in DCM) in a mixture solvent of dioxane (60 mL) in EtOH (15 mL) was added 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (3.79 g, 14.05 mmol, 1.25 eq) , TEA (14.02 mL, 101.15 mmol, 9.0 eq) . The mixture was stirred at 100 ℃ for 1 h. After the reaction completion, the mixture was concentrated under vacuo, diluted with H₂O (100 mL) and extracted with EA (100 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 38%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (4800 mg, 9.91 mmol, 88.2%) .

MS (ESI, pos. ion) m/z: 485.6 [M+1] ⁺, Rt=1.108/2min

Step 5: Preparation of compound 1031-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4-fluoro-3-hydroxyphenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1- (4-fluoro-3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (4.5 g, 9.29 mmol, 1.0 eq) in AcOH (60 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (6.19 g, 13.93 mmol, 1.5 eq) . The mixture was stirred at 100 ℃ for 12 hours. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 40%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (5000 mg, 6.06 mmol, 65.2%) .

MS (ESI, pos. ion) m/z: 809.3 [M+1] ⁺, Rt=1.245/2min.

Step 6: Preparation of compound 1031-7: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4-fluoro-3-hydroxyphenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (5 g, 6.18 mmol, 1.0 eq) and DIEA (1.62 mL, 9.27 mmol, 1.5 eq) in DCM (20 mL) was added trifluoromethanesulfonic anhydride (1.25 mL, 7.42 mmol, 1.2 eq) at ℃ . The mixture was stirred at 0 ℃for 1 h. After the reaction completion, the mixture was concentrated under vacuum to afford the crude title product as a brown oil (5200 mg, 5.53 mmol, 89.4%) .

Step 7: Preparation of compound 1031-8: methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (4-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (5.2 g, 5.53 mmol, 1.0 eq) in DCM (60 mL) was added TFA (30 mL) . The mixture was stirred at rt for 16 hrs. After the reaction completion, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 45%EtOAc in petroleum ether as a gradient, to afford the title product as an off-white solid (3000 mg, 4.07 mmol, 73.6%) ) .

MS (ESI, pos. ion) m/z: 701.5 [M+1] ⁺, Rt=1.151/2min.

Step 8: Preparation of compound 1031-9: methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.29 mmol, 1.0 eq) and 3-ethynyltetrahydrofuran (55 mg, 0.58 mmol, 2.0 eq) in DMF (4 mL) was added TEA (0.12 mL, 0.87 mmol, 3.0 eq) , PPh₃ (15 mg, 0.06 mmol, 0.2 eq) , CuI (5 mg, 0.03 mmol, 0.1 eq) and Pd (PPh₃) ₄ (33 mg, 0.03 mmol, 1.0 eq) . The mixture was stirred at 100 ℃ for 16 h under N₂. After the reaction completion, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (120 mg, 0.17 mmol, 59.8%) .

MS (ESI, pos. ion) m/z: 647.6 [M+1] ⁺, Rt=1.141/2min.

Step 9: Preparation of compound 1031: 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (100 mg, 0.15 mmol, 1.0 eq ) in mixture solvent of THF (3 mL) in H₂O (3 mL) was added LiOH (19 mg, 0.45 mmol, 3.0 eq) . The mixture was stirred at RT for 3 hours. After the reaction completion, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 55%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as an yellow solid (54.45 mg, 0.08 mmol, 52.3%) .

MS (ESI, pos. ion) m/z: 633.3 [M+1] ⁺ , Rt=2.43/5min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.74 -7.52 (m, 3H) , 7.42 (dd, J = 2.3, 6.8 Hz, 1H) , 7.40 -7.35 (m, 1H) , 7.33 (s, 1H) , 7.24 (s, 1H) , 6.96 (s, 1H) , 6.87 (d, J = 11.0 Hz, 1H) , 6.75 (d, J = 8.3 Hz, 1H) , 5.38 (s, 2H) , 3.97 (t, J = 7.6 Hz, 1H) , 3.86 -3.80 (m, 1H) , 3.79 -3.72 (m, 1H) , 3.59 (dd, J = 6.5, 8.0 Hz, 1H) , 3.33 -3.27 (m, 1H) , 3.24 (br d, J = 6.8 Hz, 2H) , 2.45 (s, 3H) , 2.29 -2.21 (m, 1H) , 1.98 -1.89 (m, 1H) , 1.00 -0.90 (m, 1H) , 0.39 -0.20 (m, 4H) .

Example 82: Synthesis of compound 1032

Step 1: Preparation of compound 1032-2: methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate

To the solution of methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (200 mg, 0.29 mmol, 1.0 eq) , 3-ethynyltetrahydrofuran (84 mg, 0.78 mmol, 3.0 eq) , CuI (6 mg, 0.03 mmol, 0.1 eq) and Pd (PPh₃) ₂Cl₂ (22 mg, 0.03 mmol, 0.1 eq) in DMF (4 mL) was added TEA (0.13 mL, 0.93 mmol, 3.0 eq) . The reaction mixture was stirred at 100 ℃ overnight under N₂. The mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The organic layer was combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/2 to 1/1) to afford the title product as a yellow solid (140 mg, 0.22 mmol, 75%) .

Step 2: Preparation of compound 1032: 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( (tetrahydrofuran-3-yl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (140 mg, 0.22 mmol, 1.0 eq) , THF (2 mL) and MeOH (2 mL) . A solution of LiOH (38 mg, 0.89 mmol, 4.0 eq) in H₂O (2 mL) was added, and the mixture was stirred at RT overnight. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (10 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 65%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (92 mg, 67%) .

MS (ESI, pos. ion) m/z: 619.1 [M+1] ⁺, Rt=1.000/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.52 (br s, 1H) , 8.95 (d, J = 5.0 Hz, 1H) , 7.70 (t, J = 7.8 Hz, 1H) , 7.63 (d, J = 5.0 Hz, 1H) , 7.58 (s, 2H) , 7.42 (dd, J = 2.3, 6.8 Hz, 1H) , 7.40 -7.33 (m, 1H) , 7.30 -7.22 (m, 1H) , 7.02 (s, 1H) , 6.88 (d, J = 10.8 Hz, 1H) , 6.76 (d, J = 8.2 Hz, 1H) , 5.39 (s, 2H) , 3.96 (t, J = 7.8 Hz, 1H) , 3.83 (dt, J = 6.0, 8.0 Hz, 1H) , 3.78 -3.70 (m, 1H) , 3.59 (dd, J = 6.5, 8.0 Hz, 1H) , 3.26 (m, 1H) , 3.24 -3.20 (m, 2H) , 2.31 -2.19 (m, 1H) , 1.99 -1.86 (m, 1H) , 0.97 (td, J = 6.4, 13.0 Hz, 1H) , 0.35 -0.23 (m, 4H) .

Example 83: Synthesis of compound 1033

Step 1: Preparation of compound 1033-2: methyl 6- [ (E) -3- (3-bromo-4-fluoro-phenyl) -3-oxo-prop-1-enyl] pyridine-2-carboxylate

To a solution of methyl 6-formylpyridine-2-carboxylate (247.30 mg, 1.50 mmol, 1.3 eq) for 4 batches in parallel in Tol. (8 mL) was added K₃PO₄ (733.53 mg, 3.46 mmol, 3 eq) and 1- (3-bromo-4-fluoro-phenyl) ethanone (250 mg, 1.15 mmol, 1 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (50 mL) and extracted with EtOAc (30 mL *3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 20/80) to afford the title product as a brown solid (750 mg, 44.70%) .

MS (ESI, pos. ion) m/z: 363.9/365.9 [M+H] ⁺. Rt=1.009/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) 8.48 -8.43 (m, 1H) , 8.35 -8.28 (m, 1H) , 8.21 -8.07 (m, 4H) , 7.79 -7.71 (m, 1H) , 7.65 -7.58 (m, 1H) , 3.94 -3.90 (m, 3H) .

Step 2: Preparation of compound 1033-3: methyl 6- [1- [2- (3-bromo-4-fluoro-phenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] pyridine-2-carboxylate

A mixture of methyl 6- [ (E) -3- (3-bromo-4-fluoro-phenyl) -3-oxo-prop-1-enyl] pyridine-2-carboxylate (750 mg, 2.06 mmol, 1 eq) in dioxane (40 mL) and EtOH (10 mL) was added TEA (1.88 g, 18.54 mmol, 2.58 mL, 9 eq) and 2-cyclopropylacetaldehyde (1.39 g, 16.48 mmol, 8 eq) , then suspension was degassed under vacuum and purged with N₂ for 3 times. Then, 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (694.54 mg, 2.57 mmol, 1.25 eq) was added. The mixture was stirred at 100 ℃ for 16 hr. The mixture was diluted with brine (50 mL) and extracted with EtOAc (20 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 25/75) to afford the title product as a brown oil (391 mg, 42.35%) .

MS (ESI, pos. ion) m/z: 448.0/450.0 [M+H] ⁺. Rt=1.043/1.5 min.

Step 3: Preparation of compound 1033-4: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [1- [2- (3-bromo-4-fluoro-phenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] pyridine-2-carboxylate (391 mg, 872.22 μmol, 1 eq) in AcOH (5 mL) was added methyl 6- [1- [2- (3-bromo-4-fluoro-phenyl) -2-oxo-ethyl] -3-cyclopropyl-2-oxo-propyl] pyridine-2-carboxylate (391 mg, 872.22 μmol, 1 eq) . The mixture was stirred at 80 ℃ for 16 hr. The mixture was diluted with brine (20 mL) and extracted with EtOAc (10 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (434 mg, 58.08%) .

MS (ESI, pos. ion) m/z: 857.2/859.2 [M+H] +. Rt=1.256/1.5 min.

Step 4: Preparation of compound 1033-5: methyl 6- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) pyrrol-3-yl] pyridine-2-carboxylate (434 mg, 506.55 μmol, 1 eq) in DCM (5 mL) was added TFA (2.31 g, 20.26 mmol, 1.51 mL, 40 eq) . The mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 40/60) to afford the title product as a brown solid (300 mg, 96.07%) .

MS (ESI, pos. ion) m/z: 616.0/618.0 [M+H] ⁺. Rt=1.066/1.5 min.

Step 5: Preparation of compound 1033-6: methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [4-fluoro-3- (2-tetrahydrofuran-3-ylethynyl) phenyl] pyrrol-3-yl] pyridine-2-carboxylate

To a solution of methyl 6- [5- (3-bromo-4-fluoro-phenyl) -2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate (100 mg, 162.21 μmol, 1 eq) in DMF (3 mL) was added TEA (49.24 mg, 486.64 μmol, 67.73 μL, 3 eq) , 3-ethynyltetrahydrofuran (38.98 mg, 405.53 μmol, 2.5 eq) and Pd (PPh₃) ₂Cl₂ (11.39 mg, 16.22 μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred at 80 ℃for 16 hr. The mixture was diluted with brine (5 mL) and extracted with EtOAc (3 mL*3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=0/100 to 35/65) to afford the title product as a brown solid (83 mg, 81.00%) .

MS (ESI, pos. ion) m/z: 632.2 [M+H] ⁺, Rt=1.058/1.5 min.

Step 6: Preparation of compound 1033: 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [4-fluoro-3- (2-tetrahydrofuran-3-ylethynyl) phenyl] pyrrol-3-yl] pyridine-2-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- [2- (cyclopropylmethyl) -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] -5- [4-fluoro-3- (2-tetrahydrofuran-3-ylethynyl) phenyl] pyrrol-3-yl] pyridine-2-carboxylate (83 mg, 131.39 μmol, 1 eq) in THF (1.5 mL) and MeOH (4 mL) . A solution of LiOH (31.47 mg, 1.31 mmol, 10.0 eq) was added and the mixture was stirred at 25 ℃ for 16 hr. The mixture was acidified with 1 N aqueous HCl solution until the pH was 6～7 at 0 ℃ and extracted with EA (3 mL ×3) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [Water (FA) -MeCN] ; gradient: 40%-80%B over 10 min) to afford the title product as a yellow solid (37.9 mg, 46.70%) .

MS (ESI, pos. ion) m/z: 618.2 [M+H] ⁺, Rt=0.951/1.5 min.

¹HNMR (400 MHz, DMSO-d₆) δ 7.95 -7.85 (m, 2H) , 7.81 -7.75 (m, 1H) , 7.73 -7.67 (m, 1H) , 7.64 -7.58 (m, 2H) , 7.47 -7.41 (m, 1H) , 7.40 -7.33 (m, 1H) , 7.32 -7.24 (m, 1H) , 6.92 -6.86 (m, 2H) , 6.80 -6.74 (m, 1H) , 5.45 -5.30 (m, 2H) , 3.96 (t, J = 7.7 Hz, 1H) , 3.86 -3.79 (m, 1H) , 3.78 -3.71 (m, 1H) , 3.58 (dd, J =6.6, 7.9 Hz, 1H) , 3.29 (br s, 1H) , 3.21 (br d, J = 6.6 Hz, 2H) , 2.32 -2.20 (m, 1H) , 1.98 -1.83 (m, 1H) , 0.99 -0.88 (m, 1H) , 0.29 -0.19 (m, 4H) .

Example 84: Synthesis of compound 1051

Step 1: Preparation of compound 1051-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (trimethylsilyl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (150 mg, 0.22 mmol, 1.0 eq) and ethynyltrimethylsilane (43 mg, 0.44 mmol, 2.0 eq) in DMF (4 mL) was added CuI (4 mg, 0.02 mmol, 0.1 eq) , PPh₃ (12 mg, 0.04 mmol, 2.0 eq) , TEA (0.09 mL, 0.66 mmol, 3.0 eq) and Pd (PPh₃) ₄ (25 mg, 0.02 mmol, 0.1 eq) . The reaction mixture was stirred at 100 ℃ for 16 h under N₂. After the reaction was completed, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (70 mg, 0.11 mmol, 49.4%) .

MS (ESI, pos. ion) m/z: 631.3 [M+1] ⁺, Rt=1.303/2min.

Step 2: Preparation of compound 1051: 2- (2- (cyclopropylmethyl) -5- (3-ethynylphenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (trimethylsilyl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (60 mg, 0.09 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) and MeOH (2 mL) in H₂O (1 mL) was added LiOH (20 mg, 0.48 mmol, 5.0 eq) . The reaction mixture was stirred at RT for 3 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 65%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (17.5 mg, 0.03 mmol, 34.1%) .

MS (ESI, pos. ion) m/z: 545.3 [M+1] ⁺ , Rt=1.004/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.70 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.57 (s, 1H) , 7.49 (s, 1H) , 7.45 -7.36 (m, 3H) , 7.05 (s, 1H) , 6.87 (d, J = 11.0 Hz, 1H) , 6.77 (d, J = 8.5 Hz, 1H) , 5.43 (s, 2H) , 4.21 (s, 1H) , 4.25 -4.17 (m, 1H) , 3.23 (br d, J = 6.5 Hz, 2H) , 2.55 (s, 3H) , 1.01 -0.93 (m, 1H) , 0.35 -0.23 (m, 4H) .

Example 85: Synthesis of compound 1060

Step 1: Preparation of compound 1060-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (200 mg, 0.29 mmol, 1.0 eq) and trimethyl (prop-1-ynyl) silane (65 mg, 0.58 mmol, 2.0 eq) in DMF (4 mL) was added TEA (0.12 mL, 0.87 mmol, 3.0 eq) , PPh₃ (15 mg, 0.06 mmol, 0.2 eq) , CuI (6 mg, 0.03 mmol, 0.1 eq) and Pd (PPh₃) ₄ (33 mg, 0.03 mmol, 0.1 eq) . The mixture was stirred at 100 ℃ for 16 h under N₂. After the reaction was completed, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a brown oil (100 mg, 0.17 mmol, 59.0%) .

MS (ESI, pos. ion) m/z: 573.6 [M+1] ⁺, Rt=1.150/2min.

Step 2: Preparation of compound 1060: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

A 10 mL single-necked round bottom flask equipped with mechanical stirrer was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (100 mg, 0.17 mmol, 1.0 eq) , THF (2 mL) , H₂O (2 mL) and LiOH. H₂O (22 mg, 0.51 mmol, 3.0 eq) . The mixture was stirred at RT for 3 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 55%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (33 mg, 0.06 mmol, 34.2%) .

MS (ESI, pos. ion) m/z: 559.6 [M+1] ⁺ , Rt=1.043/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.70 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.57 (s, 1H) , 7.37 (s, 1H) , 7.35 -7.32 (m, 2H) , 7.32 -7.29 (m, 1H) , 7.03 (s, 1H) , 6.86 (d, J = 11.0 Hz, 1H) , 6.76 (d, J = 8.3 Hz, 1H) , 5.42 (s, 2H) , 3.23 (br d, J = 6.8 Hz, 2H) , 2.55 (s, 3H) , 2.03 (s, 3H) , 1.02 -0.94 (m, 1H) , 0.34 -0.25 (m, 4H) .

Example 86: Synthesis of compound 1061

Step 1: Preparation of compound 1061-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3, 3, 3-trifluoroprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A 8 mL single-necked round bottom flask equipped with mechanical stirrer was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (trimethylsilyl) ethynyl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (80 mg, 0.12 mmol, 1.0 eq) and diphenyl (trifluoromethyl) sulfanium trifluoromethanesulfonate (103 mg, 0.24 mmol, 2.0 eq) in DMF (2 mL) was added Bipyridine (20 mg, 0.12 mmol, 1.0 eq) , K₂CO₃ (18 mg, 0.12 mmol, 1.0 eq) and CuI (24 mg, 0.12 mmol, 1.0 eq) . The mixture was stirred at 60 ℃ for 18 h under N₂. After the reaction was completed, the mixture was concentrated under vacuo. The residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product as a brown oil (80 mg, 0.10 mmol, 82.2%) , which was used directly next step without purification.

MS (ESI, pos. ion) m/z: 627.6 [M+1] ⁺, Rt=1.201/2min.

Step 2: Preparation of compound 1061: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3, 3, 3-trifluoroprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

A 8 mL single-necked round bottom flask equipped with mechanical stirrer was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3, 3, 3-trifluoroprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (80 mg, 0.10 mmol, 1.0 eq) , THF (2 mL) , H₂O (1 mL) and LiOH. H₂O (13 mg, 0.30 mmol, 3.0 eq) . The mixture was stirred at rt for 3 hrs. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 65%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (18 mg, 0.03 mmol, 28.5%) .

MS (ESI, pos. ion) m/z: 613.2 [M+1] ⁺ , Rt=1.122/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.81 (s, 1H) , 7.71 -7.67 (m, 1H) , 7.66 -7.61 (m, 2H) , 7.61 -7.58 (m, 3H) , 7.53 -7.47 (m, 1H) , 7.10 (s, 1H) , 6.86 (d, J = 11.0 Hz, 1H) , 6.75 (d, J = 8.3 Hz, 1H) , 5.47 (s, 2H) , 3.26 (br d, J = 6.8 Hz, 2H) , 2.55 (s, 3H) , 1.03 -0.95 (m, 1H) , 0.37 -0.25 (m, 4H) .

Example 87: Synthesis of compound 1063

Step 1: Preparation of compound 1063-2: 1- (4-chlorophenyl) -1H-pyrazole-3-carbaldehyde

To the solution of 1H-pyrazole-3-carbaldehyde (2 g, 20.81 mmol, 1.0 eq) , K₂CO₃ (5.75 g, 41.63 mmol, 2.0 eq) , copper (1+) iodide (0.40 g, 2.08 mmol, 0.2 eq) and L-proline (0.96 g, 8.33 mmol, 0.4 eq) in DMSO (30 mL) was added 1-chloro-4-iodobenzene (7.44 g, 31.22 mmol, 1.5 eq) under N₂ . The reaction mixture was stirred at 110 ℃ for overnight. TLC and LCMS showed that most 1-chloro-4-iodobenzene was consumed and the desired product was given. The reaction mixture was poured into water (40 mL) and extracted with EA (60 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 10%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (446 mg, 2.16 mmol, 10.4%) .

MS (ESI, pos. ion) m/z: 207.0 [M+1] ⁺ , Rt=1.289/3min.

¹HNMR (400 MHz, DMSO-d₆) δ = 10.02 (s, 1H) , 8.73 (d, J = 2.8 Hz, 1H) , 8.02 -7.97 (m, 2H) , 7.67 -7.63 (m, 2H) , 7.07 (d, J = 2.8 Hz, 1H) .

Step 2: Preparation of compound 1063-3: 1- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol

To the solution of 1- (4-chlorophenyl) -1H-pyrazole-3-carbaldehyde (446 mg, 2.16 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added ethynylmagnesium bromide (8.6 mL, 4.32 mmol, 2.0 eq) dropwise with the temperature was kept at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 h. LCMS showed that 1- (4-chlorophenyl) -1H-pyrazole-3-carbaldehyde was consumed and the desired product was given. The reaction mixture was poured into water (20 mL) and extracted with EA (30 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (438 mg, 1.88 mmol, 87.2%) .

MS (ESI, pos. ion) m/z: 233.1 [M+1] ⁺, Rt=1.183/3min.

Step 3: Preparation of compound 1063-4: methyl (E) -2- (3- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To the solution of 1- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol (425 mg, 1.83 mmol, 1.0 eq) , methyl 2-chloro-6-methylpyrimidine-4-carboxylate (351 mg, 1.83 mmol, 1.0 eq) , Pd (PPh₃) ₂Cl₂ (128 mg, 0.18 mmol, 0.1 eq) , copper (1+) iodide (35 mg, 0.18 mmol, 0.1 eq) and triphenylphosphane (96 mg, 0.37 mmol, 0.2 eq) in dioxane (5 mL) was added Et₃N (0.78 mL, 5.48 mmol, 3.0 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 3 h. LCMS showed that 1- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol was consumed and the desired product was given. The reaction mixture was poured into water (20 mL) and extracted with EA (30 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 25%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (168 mg, 0.44 mmol, 24.0%) .

MS (ESI, pos. ion) m/z: 383.2 [M+1] ⁺ , Rt=1.675/3min.

¹HNMR (400 MHz, DMSO-d6) δ = 8.75 (d, J = 2.8 Hz, 1H) , 8.41 (d, J = 15.8 Hz, 1H) , 8.02 (d, J = 8.8 Hz, 2H) , 7.94 (s, 1H) , 7.73 -7.66 (m, 3H) , 7.18 (d, J = 2.5 Hz, 1H) , 3.97 (s, 3H) , 2.67 (s, 3H)

Step 4: Preparation of compound 1063-5: methyl 2- (1- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To the solution of methyl (E) -2- (3- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (155 mg, 0.40 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (137 mg, 0.51 mmol, 1.25 eq) and Et₃N (0.28 mL, 2.02 mmol, 5.0 eq) in a mixture solvent of dioxane (4 mL) in ethanol (1 mL) was added 2-cyclopropylacetaldehyde (401 mg, 0.81 mmol, 2.0 eq) . The reaction mixture was stirred at 100 ℃ for 1 h. LCMS showed that methyl (E) -2- (3- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate was consumed and the desired product was given. The reaction mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (170 mg, 0.30 mmol, 75.9%) .

MS (ESI, pos. ion) m/z: 467.2 [M+1] ⁺, Rt=1.690/3min.

Step 5: Preparation of compound 1063-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To the solution of methyl 2- (1- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (160 mg, 0.29 mmol, 1.0 eq) in acetic acid (3 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (191 mg, 0.43 mmol, 2.0 eq) . The reaction mixture was stirred at 100 ℃ for overnight. LCMS showed that methyl 2- (1- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate was consumed and the desired product was given. The reaction mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 50%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (243 mg, 0.27 mmol, 95.8%) .

MS (ESI, pos. ion) m/z: 875.4 [M+1] ⁺, Rt=1.400/2min.

Step 6: Preparation of compound 1063-7: methyl 2- (5- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To the solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (230 mg, 0.26 mmol, 1.0 eq) in DCM (10 mL) was added TFA (4 mL) . The reaction mixture was stirred at 25 ℃ for 24 h. LCMS showed that methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate was consumed and the desired product was given. The reaction mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (160 mg, 0.25 mmol, 97.2%) .

MS (ESI, pos. ion) m/z: 635.3 [M+1] ⁺, Rt=1.781/3min.

Step 7: Preparation of compound 1063: 2- (5- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To the solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (150 mg, 0.24 mmol, 1.0 eq) in a mixture solvent of tetrahydrofuran (2 mL) and methanol (2 mL) in water (1 mL) was added lithium hydroxide (40 mg, 0.96 mmol, 4.0 eq) . The reaction mixture was stirred at 25 ℃ for 1 h. LCMS showed that methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-chlorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate was consumed and the desired product was given. The reaction mixture was adjusted to pH=5 with 2N HCl and extracted with EA (20 mL × 2) . The combined organic layer was washed with saturated NaCl solution, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by pre-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 55%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (105 mg, 0.17 mmol, 71.2%) .

MS (ESI, pos. ion) m/z: 621.3 [M+1] ⁺, Rt=1.699/3min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.57 (s, 1H) , 8.49 (d, J = 2.5 Hz, 1H) , 7.73 -7.67 (m, 3H) , 7.60 -7.55 (m, 3H) , 7.53 -7.49 (m, 2H) , 7.40 (s, 1H) , 6.98 -6.91 (m, 3H) , 5.95 (br s, 2H) , 3.36 -3.33 (m, 2H) , 2.56 (s, 3H) , 1.02 -0.90 (m, 1H) , 0.35 -0.25 (m, 4H) .

Example 88: Synthesis of compound 1064

Step 1: Preparation of compound 1064-2: 1- (4-methoxyphenyl) -1H-pyrazole-3-carbaldehyde

To a solution of 1-iodo-4-methylbenzene (4.00 g, 17.09 mmol, 1.0 eq) in DMSO (60 mL) was added 1H-pyrazole-4-carbaldehyde (1.80 g, 18.73 mmol, 1.1 eq) , L-proline (0.80 g, 6.95 mmol, 0.4 eq) , CuI (0.67g, 3.52 mmol, 0.2 eq) and K₂CO₃ (4.70 g, 34.01 mmol, 2.0 eq) . The reaction mixture was stirred for 18 hours at 100 ℃ overnight under N₂ atmosphere. After the reaction was completed, the reaction mixture was filtered. The filtrate was diluted with EA (100 mL) . The organic layer was washed with H₂O (30 mL × 3) and brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10 to 1/5) to afford the title product (0.45 g, 13%) .

MS (ESI, pos. ion) m/z: 203.0 [M+1] ⁺, Rt=0.790/2 min.

Step 2: Preparation of compound 1064-3: 1- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol

To a solution of 1- (4-methoxyphenyl) -1H-pyrazole-3-carbaldehyde (350 mg, 1.73 mmol, 1.0 eq) in THF (10 mL) was added ethynylmagnesium bromide (4.5 mL, 2.25 mmol, 1.5 eq, 0.5 N) at 0 ℃ dropwise under N₂. After addition, the reaction mixture was stirred for 2 hours at 0 ℃. After the reaction was completed, the reaction mixture was quenched with NH₄Cl aqueous solution (30 mL) and extracted with EA (50 mL ×2) . The organic layer was washed with brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10) to afford the title product (300 mg, 76%) .

Step 3: Preparation of compound 1064-4: methyl (E) -2- (3- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To a solution of 1- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol (650 mg, 2.65 mmol, 1.0 eq) in dioxane (30 mL) was added methyl 2-chloro-6-methylpyrimidine-4-carboxylate (500 mg, 2.65 mmol, 1.0 eq) , Pd (PPh₃) ₂Cl₂ (200 mg, 0.27 mmol, 0.1 eq) , PPh₃ (150 mg, 0.57 mmol, 0.2 eq) , CuI (50 mg, 0.27 mmol, 0.1 eq) and TEA (1.20 mL, 8.66 mmol, 3.2 eq) . The reaction mixture was stirred for 18 hours at 100 ℃ under N₂ atmosphere. After the reaction was completed, the reaction mixture was filtered. The filtrate was diluted with EA (50 mL) . The organic layer was washed with brine (20 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product (300 mg, 30%) .

MS (ESI, pos. ion) m/z: 379.0 [M+1] ⁺, Rt=0.975/2 min.

Step 4: Preparation of compound 1064-5: methyl 2- (5-cyclopropyl-1- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (300 mg, 0.68 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (230 mg, 0.85 mmol, 1.25 eq) and TEA (0.30 mL, 2.16 mmol, 3.2 eq) in a mixture solvent of dioxane (12 mL) in EtOH (3 mL) was added 2-cyclopropylacetaldehyde (1000 mg, 2.02 mmol, 17%wt in DCM, 3.0 eq) . The resulting was stirred at 100 ℃ for 1 h. After the reaction was completed, the mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The organic layer was washed with brine (20 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/3) to afford the title product (120 mg, 37%) .

MS (ESI, pos. ion) m/z: 463.6 [M+1] ⁺, Rt=1.08/2 min.

Step 5: Preparation of compound 1064-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (120 mg, 0.26 mmol, 1.0 eq) in AcOH (10 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (180 mg, 0.38 mmol, 1.5 eq) . The mixture was stirred at 100 ℃ for 18 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with EA (30 mL) and washed with saturated NaHCO₃ aqueous solution (10 mL × 2) and brine (10 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product (150 mg, 53%) .

MS (ESI, pos. ion) m/z: 871.3 [M+1] ⁺, Rt=1.275 /2 min.

Step 6: Preparation of compound 1064-7: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (150 mg, 0.14 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL) . The mixture was stirred at 25 ℃ for 48 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM (30 mL) . The organic layer was washed with H₂O (10 mL × 2) and brine (10 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was used for next step directly. (80 mg, 84%) .

MS (ESI, pos. ion) m/z: 631.6 [M+1] ⁺, Rt=1.150/2 min.

Step 7: Preparation of compound 1064: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (80 mg, 0.13 mmol, 1.0 eq) in a mixture solvent of THF (3 mL) in MeOH (1 mL) was added a solution of LiOH (20 mg, 0.48 mmol, 3.7 eq) in H₂O (1 mL) . The mixture was stirred at 25 ℃ for 1 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (50 mg, 62%) .

MS (ESI, pos. ion) m/z: 617.2 [M+1] ⁺, Rt=1.057/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.77 -13.38 (m, 1H) , 8.36 (d, J = 2.5 Hz, 1H) , 7.70 (t, J = 7.9 Hz, 1H) , 7.63 -7.53 (m, 5H) , 7.35 (s, 1H) , 7.03 -6.90 (m, 4H) , 6.83 (d, J = 2.5 Hz, 1H) , 5.96 (br s, 2H) , 3.78 (s, 3H) , 3.32 -3.30 (m, 2H) , 2.56 (s, 3H) , 1.03 -0.90 (m, 1H) , 0.37 -0.22 (m, 4H) .

Example 89: Synthesis of compound 1066

Step 1: Preparation of compound 1066-2: 1- (4- (trifluoromethyl) phenyl) -1H-pyrazole-3-carbaldehyde

To a solution of 1H-pyrazole-3-carbaldehyde (2 g, 20.81 mmol, 1.0 eq) and 4-iodo-1- (trifluoromethyl) benzene (3.67 mL, 24.98 mmol, 1.20 eq) in DMSO (40 mL) was added copper (1+) iodide (0.80 g, 4.20 mmol, 0.20 eq) , L-Proline (0.24 g, 2.08 mmol, 0.10 eq) and potassium carbonate (5.75 g, 41.63 mmol, 2.00 eq) at room temperature. The reaction was stirred at 105 ℃ overnight under N₂. The reaction mixture was poured into water (40 mL) and extracted with EA (60 mL × 2) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 20%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (2.33 g, 9.69 mmol, 46.6%yield) .

¹HNMR (400 MHz, DMSO-d₆) δ = 10.05 (s, 1H) , 10.07 -9.99 (m, 1H) , 8.85 (d, J = 2.5 Hz, 1H) , 8.20 (d, J = 8.5 Hz, 2H) , 7.96 (d, J = 8.6 Hz, 2H) , 7.11 (d, J = 2.6 Hz, 1H) .

Step 2: Preparation of compound 1066-3: 1- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol

A 50 mL three-necked round bottom flask equipped with mechanical stirrer, addition funnel and thermometer were charged with 1- (4- (trifluoromethyl) phenyl) -1H-pyrazole-3-carbaldehyde (2.0 g, 7.49 mmol, 1.0 eq) and tetrahydrofuran (10 mL) . The resulting was added bromo (ethynyl) magnesium (24.8 mL, 12.38 mmol, 1.65 eq) dropwise at 0 ℃ under N₂ atmosphere. The reaction was stirred at room temperature for 1 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with NH₄Cl aq., diluted with H₂O (100 mL) and extracted with EA (60 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20) , to afford the title product as a yellow oil liquid (1.6 g, 5.65 mmol, 75.4 %) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.61 (d, J = 2.5 Hz, 1H) , 8.06 (d, J = 8.5 Hz, 2H) , 7.87 (d, J = 8.8 Hz, 2H) , 6.63 (d, J = 2.8 Hz, 1H) , 6.17 (d, J = 6.3 Hz, 1H) , 5.44 (dd, J = 2.3, 6.3 Hz, 1H) , 3.50 (d, J = 2.3 Hz, 1H) .

Step 3: Preparation of compound 1066-4: methyl (E) -6-methyl-2- (3-oxo-3- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) prop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of 1- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol (1.6 g, 6.01 mmol, 1.0 eq) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.05 g, 5.63 mmol, 0.94 eq) in dioxane (10 mL) was added Pd (PPh₃) Cl₂ (0.42 g, 0.60 mmol, 0.10 eq) , triphenylphosphane (0.32 g, 1.20 mmol, 0.20 eq) , copper (1+) iodide (0.11 g, 0.60 mmol, 0.10 eq) and Et₃N (2.5 mL, 18.03 mmol, 3.00 eq) at room temperature. The reaction was stirred at 100 ℃ under N₂ atmosphere for 3 h. After the reaction was completed, the reaction mixture was diluted with EA (180 mL) . The organic layer was washed with brine (270 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20) , to afford the title product as a yellow solid (500 mg, 1.14 mmol, 19.0%) .

MS (ESI, pos. ion) m/z: 417.1 [M+1] +, Rt=1.55/2min.

Step 4: Preparation of compound 1066-5: methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -6-methyl-2- (3-oxo-3- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) prop-1-en-1-yl) pyrimidine-4-carboxylate (490 mg, 1.12 mmol, 1.00 eq) and 2-cyclopropylacetaldehyde (1150 mg, 2.32 mmol, 2.08 eq, 17%wt. in DCM) in a mixture solvent of dioxane (4 mL) in ethanol (1 mL) was added 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (381 mg, 1.41 mmol, 1.26 eq) and Et₃N (0.5 mL, 3.60 mmol, 3.22 eq) at room temperature. The reaction was stirred at 100 ℃ for 1.5 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) . The organic layer was washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -90: 10 -80: 20) , to afford the title product as a yellow oil liquid (518 mg, 0.72 mmol, 64.8%) .

MS (ESI, pos. ion) m/z: 501.2 [M+1] +, Rt=1.49/2min.

Step 5 : Preparation of compound 1066-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate (735 mg, 1.57 mmol, 1.00 eq) in acetic acid (8 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (1.05 g, 2.36 mmol, 1.50 eq) . The reaction was stirred at 100 ℃ for 16 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) . The organic layer was washed with brine (100 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA =100: 0 -80: 20 -70: 30) , to afford the title product as a yellow oli liquid (535 mg, 0.44 mmol, 60.9%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.65 (d, J = 2.8 Hz, 1H) , 7.92 -7.83 (m, 3H) , 7.79 (d, J = 8.8 Hz, 2H) , 7.64 (s, 1H) , 7.43 (s, 1H) , 7.09 -7.03 (m, 2H) , 6.99 (br d, J = 11.5 Hz, 1H) , 6.85 (d, J = 8.5 Hz, 4H) , 6.68 (d, J = 8.8 Hz, 4H) , 6.09 -5.96 (m, 2H) , 4.15 (s, 4H) , 3.94 (s, 3H) , 3.67 (s, 6H) , 3.39 -3.34 (m, 2H) , 2.60 (s, 3H) , 1.12 -0.99 (m, 1H) , 0.42 -0.28 (m, 4H) .

Step 6 : Preparation of compound 1066-7: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (535 mg, 0.44 mmol, 1.00 eq) in DCM (9 mL) was added 2, 2, 2-trifluoroacetic acid (3 mL) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated, diluted with sodium bicarbonate aqueous solution (60 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=2: 1 to give product (300 mg, 0.38 mmol, 85.4%) as yellow oil liquid.

MS (ESI, pos. ion) m/z: 669.3 [M+1] +, Rt=1.54/2min.

Step 7: Preparation of compound 1066: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (300 mg, 0.38 mmol, 1.00 eq) in a mixture solvent of methanol (5 mL) and tetrahydrofuran (1 mL) in water (1 mL) was added lithium hydroxide (72 mg, 3.01mmol, 7.98 eq) at room temperature. Then the reaction was stirred at 50 ℃ for 2 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 55%to 95%(v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (190 mg, 0.28 mmol, 74.2%) .

MS (ESI, pos. ion) m/z: 655.2 [M+1] ⁺, Rt=1.65/3min.

¹H NMR (400 MHz, DMSO-d₆) δ = 13.79 -13.30 (m, 1H) , 8.62 (d, J = 2.8 Hz, 1H) , 7.95 -7.86 (m, 2H) , 7.86 -7.78 (m, 2H) , 7.72 (t, J = 7.9 Hz, 1H) , 7.59 (d, J = 7.3 Hz, 3H) , 7.45 (s, 1H) , 7.06 -6.88 (m, 3H) , 5.98 (br s, 2H) , 3.35 (br d, J = 7.3 Hz, 2H) , 2.58 (s, 3H) , 1.07 -0.90 (m, 1H) , 0.41 -0.16 (m, 4H) .

Example 90: Synthesis of compound 1067

Step 1: Preparation of compound 1067-2: 1- (p-tolyl) -1H-pyrazole-3-carbaldehyde

To a solution of 4-iodo-1-methylbenzene (1.65 mL, 12.71 mmol, 1.22 eq) and 1H-pyrazole-3-carbaldehyde (1.0 g, 10.41 mmol, 1.0 eq) in DMSO (20 mL) was added copper (1+) iodide (0.83 g, 4.36 mmol, 0.42 eq) , potassium carbonate (2.97 g, 21.49 mmol, 2.07 eq) and L-Proline (0.28 g, 2.43 mmol, 0.23 eq) at room temperature. The reaction was stirred at 105 ℃ under N₂ atmosphere overnight. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2) . The organic layer was washed with brine (200 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography (SiO₂, PE : EA = 4 : 1) , to afford the title product as a yellow solid (200 mg, 1.06 mmol, 10.1%) .

MS (ESI, pos. ion) m/z: 187.0 [M+1] +, Rt=1.23/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 10.01 (s, 1H) , 8.65 (d, J = 2.0 Hz, 1H) , 7.83 (d, J = 8.5 Hz, 2H) , 7.38 (d, J = 8.3 Hz, 2H) , 7.04 (d, J = 2.5 Hz, 1H) , 2.37 (s, 3H) .

Step 2: Preparation of compound 1067-3: 1- (1- (p-tolyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol

A 25 mL three-necked round bottom flask equipped with mechanical stirrer, addition funnel and thermometer were charged with 1- (4-methylphenyl) pyrazole-3-carbaldehyde (200 mg, 1.06 mmol, 1.00 eq) and tetrahydrofuran (2 mL) , and then bromo (ethynyl) magnesium (3.50 mL, 1.75 mmol, 1.66 eq) was added dropwise to the reaction at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was adjusted to pH=6～7 with NH₄Cl aq., diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20) , to afford the title product as a yellow oil liquid (190 mg, 0.76 mmol, 72.1%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.38 (d, J = 2.5 Hz, 1H) , 7.69 (d, J = 8.5 Hz, 2H) , 7.30 (d, J = 8.3 Hz, 2H) , 6.53 (d, J = 2.5 Hz, 1H) , 6.07 (d, J = 6.0 Hz, 1H) , 5.40 (dd, J = 2.4, 6.1 Hz, 1H) , 3.46 (d, J = 2.3 Hz, 1H) , 2.34 (s, 3H) .

Step 3: Preparation of compound 1067-4: methyl (E) -6-methyl-2- (3-oxo-3- (1- (p-tolyl) -1H-pyrazol-3-yl) prop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of methyl 1- [1- (4-methylphenyl) pyrazol-3-yl] prop-2-yn-1-ol (180 mg, 0.72 mmol, 1.00 eq) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (121 mg, 0.65 mmol, 0.90 eq) in dioxane (5 mL) was added Pd (PPh₃) Cl₂ (33 mg, 0.05 mmol, 0.07 eq) , triphenylphosphane (48 mg, 0.18 mmol, 0.25 eq) , copper (1+) iodide (21 mg, 0.11 mmol, 0.15 eq) and Et₃N (0.33 mL, 2.38 mmol, 3.31 eq) at room temperature. The reaction mixture was stirred at 100 ℃ under N₂ atmosphere for 3 h. After the reaction was completed, the reaction mixture was diluted with EA (30 mL) . The organic layer was washed with brine (40 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20) , to afford the title product as a yellow solid (83 mg, 0.22 mmol, 30.8%) .

MS (ESI, pos. ion) m/z: 363.2 [M+1] ⁺, Rt=1.38/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 8.67 (d, J = 2.8 Hz, 1H) , 8.43 (d, J = 15.8 Hz, 1H) , 7.94 (s, 1H) , 7.85 (d, J = 8.5 Hz, 2H) , 7.69 (d, J = 15.8 Hz, 1H) , 7.41 (d, J = 8.3 Hz, 2H) , 7.14 (d, J = 2.5 Hz, 1H) , 3.96 (s, 3H) , 2.67 (s, 3H) , 2.39 (s, 3H) .

Step 4: Preparation of compound 1067-5: methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (1- (p-tolyl) -1H-pyrazol-3-yl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -6-methyl-2- (3-oxo-3- (1- (p-tolyl) -1H-pyrazol-3-yl) prop-1-en-1-yl) pyrimidine-4-carboxylate (80 mg, 0.21 mmol, 1.0 eq) and 2-cyclopropylacetaldehyde (218 mg, 0.44 mmol, 2.06 eq) in mixture solvent of dioxane (3 mL) in ethanol (1 mL) was added 3-Benzyl-5- (2-hydroxyethyl) -4-methylthiazol-3-ium chloride (79 mg, 0.29 mmol, 1.37 eq) and Et₃N (0.1 mL, 0.72 mmol, 3.36 eq) at room temperature. The reaction was stirred at 100 ℃ for 1.5 hr. After the reaction was completed, the reaction mixture was diluted with EA (30 mL) . The organic layer was washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -90: 10 -80: 20) , to afford the title product as a yellow oil liquid (80 mg, 0.14 mmol, 63.6%) .

MS (ESI, pos. ion) m/z: 447.2 [M+1] ⁺, Rt=1.46/2min.

Step 5 : Preparation of compound 1067-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (p-tolyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A solution of methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (1- (p-tolyl) -1H-pyrazol-3-yl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate (75 mg, 0.13 mmol, 1.0 eq) and 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (93 mg, 0.20 mmol, 1.57 eq) in acetic acid (3 mL) was stirred at 100 ℃ for 1.5 h. After the reaction was completed, the reaction mixture was diluted with EA (20 mL) . The organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -70: 30) , to afford the title product as a yellow oil liquid (89 mg, 0.09 mmol, 69.3%) .

¹HNMR (400 MHz, DMSO-d₆) δ = 8.45 (d, J = 2.5 Hz, 1H) , 7.82 (br t, J = 7.9 Hz, 1H) , 7.63 (s, 1H) , 7.56 (d, J = 8.5 Hz, 2H) , 7.35 (s, 1H) , 7.23 (d, J = 8.0 Hz, 2H) , 7.01 (s, 2H) , 6.91 (d, J = 2.5 Hz, 1H) , 6.87 (d, J = 8.8 Hz, 4H) , 6.71 (d, J = 8.5 Hz, 4H) , 6.01 (br s, 2H) , 4.17 (s, 3H) , 3.94 (s, 2H) , 3.67 (s, 6H) , 2.59 (s, 3H) , 2.29 (s, 3H) , 1.08 -0.99 (m, 1H) , 0.42 -0.25 (m, 4H) .

Step 6 : Preparation of compound 1067-7: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (p-tolyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (p-tolyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (84 mg, 0.08 mmol, 1.0 eq) in DCM (3 mL) was added 2, 2, 2-trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with sodium bicarbonate aqueous solution (20 mL) and extracted with EA (20 mL ×3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. After removal of solvent by evaporation, the crude product was purified by silica gel chromatography eluted with PE: EtOAc=2: 1 to give product (47 mg, 0.08 mmol, 91.6%) as yellow oil liquid.

MS (ESI, pos. ion) m/z: 615.4 [M+1] ⁺, Rt=1.52/2min.

Step 7: Preparation of compound 1067: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (p-tolyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (p-tolyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (42 mg, 0.07 mmol, 1.0 eq) in a mixture solvent of methanol (2 mL) and tetrahydrofuran (1 mL) in water (1 mL) was added lithium hydroxide (21 mg, 0.88 mmol, 12.53 eq) at room temperature. The reaction was stirred at 50 ℃ for 2 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (30 mg, 0.05 mmol, 72.7%) .

MS (ESI, pos. ion) m/z: 601.2 [M+1] ⁺, Rt=2.85/5min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.85 -13.36 (m, 1H) , 8.42 (d, J = 2.5 Hz, 1H) , 7.70 (t, J = 7.9 Hz, 1H) , 7.63 -7.52 (m, 5H) , 7.37 (s, 1H) , 7.26 (d, J = 8.3 Hz, 2H) , 7.02 -6.91 (m, 2H) , 6.86 (d, J = 2.5 Hz, 1H) , 5.97 (br s, 2H) , 3.42 -3.34 (m, 2H) , 2.57 (s, 3H) , 2.32 (s, 3H) , 1.03 -0.90 (m, 1H) , 0.39 -0.24 (m, 4H) .

Example 91: Synthesis of compound 1068

Step 1: Preparation of compound 1068-2: 3- (2- (4-fluorophenyl) hydrazineylidene) pentane-2, 4-dione

To a solution of 4-fluoroaniline (5 g, 45.0 mmol, 1.0 eq) in 1 M HCl (100 mL) was added sodium nitrite (3.89 g, 56.38 mmol, 1.25 eq) at 0 ℃. The reaction mixture was stirred for 30 min at 0 ℃, and then a solution of pentane-2, 4-dione (6.91 mL, 66.92 mmol, 1.49 eq) in a mixture solvent of EtOH (15 mL) in H₂O (250 mL) was added at 0 ℃, followed by acetamide to pH=5～6. Then a large amount of yellow solid was separated. The reaction mixture was stirred for 3 hours at 0 ℃. The reaction mixture was extracted with EA (200 mL × 3) . The combined organic layer was washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10 to 1/5) to afford the title product as a yellow oil (6500 mg, 65%) .

MS (ESI, pos. ion) m/z: 223.0 [M+1] ⁺, Rt=0.958/2 min.

Step 2: Preparation of compound 1068-3: 1- (1- (4-fluorophenyl) -4-hydroxy-4-methyl-4, 5-dihydro-1H-pyrazol-3-yl) ethan-1-one

To a solution of iodide methanethiol (3.60 g, 16.28 mmol, 1.2 eq) in DMF (60 mL) was added Cs₂CO₃ (13.6 g, 41.74 mmol, 3.0 eq) . The reaction mixture was stirred for 15 min at 25 ℃, and then the 3- (2- (4-fluorophenyl) hydrazineylidene) pentane-2, 4-dione (3.00 g, 13.50 mmol, 1.0 eq) was added. The reaction mixture was stirred for 2 hours at 60 ℃. The reaction mixture was diluted with H₂O (200 mL) and extracted with EA (100 mL × 3) . The combined organic layer was washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was used for next step directly. (3100 mg, 97%) .

MS (ESI, pos. ion) m/z: 237.0 [M+1] ⁺, Rt=0.800/2 min.

Step 3: Preparation of compound 1068-4: 1- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) ethan-1-one

To a solution of 1- (1- (4-fluorophenyl) -4-hydroxy-4-methyl-4, 5-dihydro-1H-pyrazol-3-yl) ethan-1-one (3100 mg, 13.12 mmol) in DMF (60 mL) was added HCl (1 mL, 12.0 mmol, 0.9 eq) . The reaction mixture was stirred for 0.5 hour at 25 ℃. The reaction mixture was diluted with EA (200 mL) and washed with H₂O (100 mL × 3) . The organic layer was washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10 to 1/5) to afford the title product as a yellow oil (2700 mg, 94%) .

Step 4: Preparation of compound 1068-5: methyl (E) -2- (3- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To a solution of 1- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) ethan-1-one (1000 mg, 4.49 mmol, 1.02 eq) in toluene (30 mL) was added methyl 2-formyl-6-methylpyrimidine-4-carboxylate (830 mg, 4.38 mmol, 1.0 eq) and 4-methylbenzenesulfonic acid hydrate (450 mg, 2.37 mmol, 0.5 eq) . The reaction mixture was stirred for 18 hours at 140 ℃. The reaction mixture was filtered. The filtrate was concentrated and diluted with EA (100 mL) . The organic layer was washed with H₂O (500 mL × 3) and brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/3) to afford the title product as a yellow oil (60 mg, 0.16 mmol, 3%) .

MS (ESI, pos. ion) m/z: 381.4 [M+1] ⁺, Rt=0.158/2 min.

Step 5: Preparation of compound 1068-6: methyl 2- (5-cyclopropyl-1- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (60 mg, 0.16 mmol, 1.0 eq) in a mixture solvent of dioxane (4 mL) in EtOH (1 mL) was added 2-cyclopropylacetaldehyde (260 mg, 0.46 mmol, 2.9 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (53 mg, 0.20 mmol, 1.25 eq) and TEA (0.11 mL, 0.79 mmol, 4.9 eq) . The reaction mixture was stirred for 1 hour at 100 ℃. The reaction mixture was concentrated under vacuum. The residue was diluted with EA. The organic layer was washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10 to 1/5) to afford the title product as a yellow solid (60 mg, 0.13 mmol, 81%) .

MS (ESI, pos. ion) m/z: 465.2 [M+1] ⁺, Rt=1.483 /2 min.

Step 6: Preparation of compound 1068-7: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (60 mg, 0.13 mmol, 1.0 eq) in acetic acid (5 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (85 mg, 0.19 mmol, 1.5 eq) . The reaction mixture was stirred for 18 hours at 100 ℃. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/3) to afford the title product as a yellow oil (60 mg, 0.06 mmol, 45%) .

MS (ESI, pos. ion) m/z: 873.3 [M+1] ⁺, Rt=1.383/2 min.

Step 7: Preparation of compound 1068-8: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (60 mg, 0.06 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL) . The reaction mixture was stirred at 25 ℃ for 24 h. After the reaction was completed, the reaction mixture was concentrated. The crude product was used for next step directly. (35 mg, 0.06 mmol, 95%) .

MS (ESI, pos. ion) m/z: 633.7 [M+1] ⁺, Rt=1.158/2 min.

Step 8: Preparation of compound 1068: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (35 mg, 0.06 mmol, 1.0 eq) in a mixture solvent of THF (2 mL) in MeOH (2 mL) was added a solution of LiOH (10 mg, 0.24 mmol, 4.0 eq) in H₂O (2 mL) . The mixture was stirred at RT for 2 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 30%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (15 mg, 43%) .

MS (ESI, pos. ion) m/z: 619.6 [M+1] ⁺, Rt=1.067/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 8.30 (d, J = 0.8 Hz, 1H) , 7.70 (t, J = 7.8 Hz, 1H) , 7.65 -7.55 (m, 5H) , 7.28 (t, J = 8.8 Hz, 2H) , 7.22 (s, 1H) , 6.94 -6.85 (m, 2H) , 5.81 (br s, 2H) , 2.57 (s, 3H) , 2.21 (s, 3H) , 1.00 -0.92 (m, 1H) , 0.37 -0.25 (m, 4H) .

Example 92: Synthesis of compound 1069

Step 1: Preparation of compound 1069-2: ethyl 1- (4-fluorophenyl) -5-methyl-1H-pyrazole-3-carboxylate

To a solution of (4-fluorophenyl) hydrazine (3000 mg, 18.45 mmol, 1.5 eq) in EtOH (50 mL) was added ethyl 2, 4-dioxopentanoate (2000 mg, 12.65 mmol, 1.0 eq) . The reaction mixture was stirred for 18 hours at 80 ℃. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10 to 1/5) to afford the title product (1300 mg, 41%) .

MS (ESI, pos. ion) m/z: 249.0 [M+1] ⁺, Rt=0.950/2 min.

Step 2: Preparation of compound 1069-3: (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) methanol

To a solution of ethyl 1- (4-fluorophenyl) -5-methyl-1H-pyrazole-3-carboxylate (1200 mg, 4.74 mmol, 1.0 eq) in THF (20 mL) was added LiAlH₄ (550 mg, 14.49 mmol, 3.0 eq) at 0 ℃ under N₂. The reaction mixture was stirred for 2 hours at 0 ℃. After the reaction was completed, the reaction mixture was diluted with THF (30 mL) and quenched with H₂O (0.55 mL) , 15%NaOH (0.55 mL) and H₂O (1.65 mL) . The mixture was dried over Na₂SO₄, filtered and concentrated. The crude product was used for next step directly. (1100 mg, 85%) .

MS (ESI, pos. ion) m/z: 207.1 [M+1] ⁺, Rt=0.633/2 min.

Step 3: Preparation of compound 1069-4: 1- (4-fluorophenyl) -5-methyl-1H-pyrazole-3-carbaldehyde

To a solution of (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) methanol (1100 mg, 4.53 mmol, 1.0 eq) in DCM (50 mL) was added MnO₂ (4000 mg, 45.3 mmol, 10.0 eq) . The reaction mixture was stirred at 25 ℃ for 18 hours. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated. The crude product was used for next step directly. (900 mg, 94%) .

MS (ESI, pos. ion) m/z: 205.0 [M+1] ⁺, Rt=0.825/2 min.

Step 4: Preparation of compound 1069-5: 1- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) prop-2-yn-1-ol

To a solution of 1- (4-fluorophenyl) -5-methyl-1H-pyrazole-3-carbaldehyde (900 mg, 4.28 mmol, 1.0 eq) in THF (20 mL) was added bromo (ethynyl) magnesium (12 mL, 6.00 mmol, 1.5 eq) at 0 ℃ under N₂. The reaction mixture was stirred for 1 hour at 0 ℃. After the reaction was completed, the reaction mixture was poured into saturated NH₄Cl aqueous solution (30 mL) and extracted with EA (50 mL× 2) . The combined organic layer was washed with brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/20 to 1/10) to afford the title product as a yellow oil (1000 mg, 99%) .

Step 5: Preparation of compound 1069-6: methyl (E) -2- (3- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To a solution of 1- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) prop-2-yn-1-ol (1000 mg, 4.26 mmol, 1.0 eq) in dioxane (20 mL) was added methyl 2-chloro-6-methylpyrimidine-4-carboxylate (720 mg, 3.86 mmol, 0.9 eq) , Pd (PPh₃) ₂Cl₂ (300 mg, 0.42 mmol, 0.1 eq) , PPh₃ (220 mg, 0.84 mmol, 0.2 eq) , CuI (85 mg, 0.42 mmol, 01 eq) and TEA (1.80 mL, 12.99 mmol, 3.0 eq) . The reaction mixture was stirred for 18 hours at 100 ℃ under N₂ atmosphere. After the reaction was completed, the reaction mixture was diluted with H₂O (100 mL) and extracted with EA (50 mL × 3) . The combined organic layer was washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a yellow solid (120 mg, 7%) .

MS (ESI, pos. ion) m/z: 381.1 [M+1] ⁺, Rt=0.942 /2 min.

Step 6: Preparation of compound 1069-7: methyl 2- (5-cyclopropyl-1- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (120 mg, 0.30 mmol, 1.0 eq) in a mixture solvent of dioxane (8 mL) in EtOH (2 mL) was added 2-cyclopropylacetaldehyde (500 mg, 0.89 mmol, 3.0 eq, 15%wt. in DCM) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (100 mg, 0.37 mmol, 1.25 eq) and TEA (0.21 mL, 1.51 mmol, 5.0 eq) . The reaction mixture was stirred at 100 ℃ for 1 hour. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was diluted with EA (30 mL) . The organic layer was washed with H₂O (10 mL × 3) and brine (10 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/3) to afford the title product as a yellow solid (60 mg, 81%) .

MS (ESI, pos. ion) m/z: 465.5 [M+1] ⁺, Rt=0.975/2 min.

Step 7: Preparation of compound 1069-8: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (60 mg, 0.13 mmol, 1.0 eq) in Acetic acid (5 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (120 mg, 0.26 mmol, 2.0 eq) . The reaction mixture was stirred for 18 hours at 100 ℃. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a yellow oil (100 mg, 88%) .

MS (ESI, pos. ion) m/z: 873.3 [M+1] ⁺, Rt=1.267/2 min.

Step 8: Preparation of compound 1069-9: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -4-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (100 mg, 0.11 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL) . The reaction mixture was stirred at 25 ℃ for 48 hours. After the reaction was completed, the reaction mixture was concentrated and diluted with DCM (30 mL) . The organic layer was washed with brine (10 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was used for next step directly. (70 mg, 97%) .

MS (ESI, pos. ion) m/z: 633.3 [M+1] ⁺, Rt=1.058/2 min.

Step 9: Preparation of compound 1069: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (70 mg, 0.11 mmol, 1.0 eq) in a mixture solvent of THF (6 mL) in MeOH (2 mL) was added a solution of LiOH (20 mg, 0.44 mmol, 4.0 eq) in H₂O (2 mL) . The mixture was stirred at RT for 2 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (50 mg, 73%) .

MS (ESI, pos. ion) m/z: 619.2 [M+1] ⁺, Rt=0.975/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.72 -13.34 (m, 1H) , 7.69 -7.61 (m, 3H) , 7.57 (s, 1H) , 7.26 -7.17 (m, 4H) , 6.99 (s, 1H) , 6.75 -6.67 (m, 2H) , 6.30 (s, 1H) , 4.97 (s, 2H) , 3.18 (br d, J = 6.8 Hz, 2H) , 2.53 (s, 3H) , 2.22 (s, 3H) , 0.94 -0.82 (m, 1H) , 0.28 -0.14 (m, 4H) .

Example 93: Synthesis of compound 1071

Step 1: Preparation of compound 1071-2: ethyl 5-ethyl-1- (4-fluorophenyl) -1H-pyrazole-3-carboxylate

A 250 mL single-necked round bottom flask equipped with magnetic stirrer was added a solution of ethyl 2, 4-dioxohexanoate (2.0 g, 11.62 mmol, 1.0 eq) in EtOH (40 mL) and (4-fluorophenyl) hydrazine hydrochloride (2.84 g, 17.47 mmol, 1.5 eq) . The reaction mixture was stirred at 100 ℃ for 2 hours. The mixture was filtered, and filtrate was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/50 to 1/10) to afford the title product as a white solid (1000 mg, 32%) .

MS (ESI, pos. ion) m/z: 263.2 [M+1] +, Rt=0.958/2 min.

Step 2: Preparation of compound 1071-3: (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) methanol

A 100 mL three-necked round bottom flask equipped with magnetic stirrer was added ethyl 5-ethyl-1- (4-fluorophenyl) -1H-pyrazole-3-carboxylate (1.0 g, 3.81 mmol, 1.0 eq) and DCM (20 mL) . The resulting was added bis (2-methylpropyl) aluminum hydride (11.44 mL, 11.44 mmol, 1 N, 3.0 eq) dropwise with the temperature was kept at -78 ℃ under N₂. The reaction mixture was stirred at -78 ℃ for 2 hours. The reaction mixture was quenched with 100 mL of saturated aqueous potassium sodium tartrate tetrahydrate. The resulting solution was extracted with DCM (50 mL × 2) . The organic layer was dried over Na₂SO₄, filtered and concentrated to afford the crude product as a colorless oil (700 mg, 75%) .

Step 3: Preparation of compound 1071-4: 5-ethyl-1- (4-fluorophenyl) -1H-pyrazole-3-carbaldehyde

A 100 mL single-necked round bottom flask equipped with magnetic stirrer was added (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) methanol (0.70 g, 3.18 mmol, 1.0 eq) and DCM (20 mL) . The resulting was added MnO₂ (2.0 g, 23.00 mmol, 7.24 eq) . The reaction mixture was stirred at RT overnight. The reaction mixture was filtered, and filtrate was concentrated to afford the crude product as a yellow oil (600 mg, 82%) .

Step 4: Preparation of compound 1071-5: 1- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol

A 100 mL three-necked round bottom flask equipped with magnetic stirrer was added 5-ethyl-1- (4-fluorophenyl) -1H-pyrazole-3-carbaldehyde (600 mg, 2.61 mmol, 1.0 eq) and THF (20 mL) . The resulting was added bromo (ethynyl) magnesium (6.6 mL, 3.30 mmol, 0.5 N, 1.26 eq) dropwise with the temperature was kept at 0 ℃ under N₂. The reaction mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was poured into saturated NH₄Cl aqueous solution (50 mL) and extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/3) to afford the title product as a yellow oil (500 mg, 78%) .

Step 5: Preparation of compound 1071-6: methyl (E) -2- (3- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

A 100 mL single-necked round bottom flask equipped with magnetic stirrer was added 1- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) prop-2-yn-1-ol (500 mg, 2.05 mmol, 1.0 eq) , methyl 2-chloro-6-methylpyrimidine-4-carboxylate (343 mg, 1.84 mmol, 0.9 eq) , CuI (40 mg, 0.21 mmol, 0.1 eq) . PPh₃ (120 mg, 0.46 mmol, 0.22 eq) and dioxane (10 mL) . The suspension was added TEA (0.9 mL, 6.49 mmol, 3.17 eq) and Pd (PPh₃) ₂Cl₂ (144 mg, 0.21 mmol, 0.1 eq) . The reaction mixture was stirred at 100 ℃ overnight under N₂. The reaction mixture was concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the title product as a yellow solid (30 mg, 3.7%) .

MS (ESI, pos. ion) m/z: 395.1 [M+1] +, Rt=1.017/2 min.

Step 6: Preparation of compound 1071-7: methyl 2- (5-cyclopropyl-1- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

A 8 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl (E) -2- (3- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (30 mg, 0.08 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (26 mg, 0.10 mmol, 1.27 eq) , TEA (0.1 mL, 0.72 mmol, 9.48 eq) , EtOH (0.2 mL) and dioxane (1 mL) . The resulting was added 2-cyclopropylacetaldehyde (213 mg, 0.38 mmol, 4.99 eq) . The reaction mixture was stirred at 100 ℃for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the title product as a yellow oil (33 mg, 86%) .

MS (ESI, pos. ion) m/z: 479.6 [M+1] +, Rt=1.050/2 min.

Step 7: Preparation of compound 1071-8: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A 8 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 2- (5-cyclopropyl-1- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (33 mg, 0.07 mmol, 1.0 eq) and AcOH (2 mL) . The mixture was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (50 mg, 0.11 mmol, 1.71 eq) . The reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the title product as a yellow solid (40 mg, 56%) .

MS (ESI, pos. ion) m/z: 887.2 [M+1] +, Rt=1.367/2 min.

Step 8: Preparation of compound 1071-9: methyl 2- (2- (cyclopropylmethyl) -5- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A 25 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 2- (1- (4- (N, N-bis(4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (40 mg, 0.05 mmol, 1.0 eq) and DCM (6 mL) . The mixture was added TFA (2 mL) . The reaction mixture was stirred at rt for 48 h. The reaction mixture was concentrated under vacuum. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the title product as a yellow solid (19 mg, 65%) .

MS (ESI, pos. ion) m/z: 647.6 [M+1] +, Rt=1.117/2 min.

Step 9: Preparation of compound 1071: 2- (2- (cyclopropylmethyl) -5- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- (2- (cyclopropylmethyl) -5- (5-ethyl-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (19 mg, 0.03 mmol, 1.0 eq) , THF (2 mL) and MeOH (2 mL) . A solution of LiOH (10 mg, 0.24 mmol, 8.11 eq) in H₂O (2 mL) was added, and the reaction mixture was stirred at RT for 3 h. The mixture was acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃ and extracted with EA (10 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (12 mg, 63%) .

MS (ESI, pos. ion) m/z: 633.6 [M+1] ⁺, Rt=1.008/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.67 -7.60 (m, 3H) , 7.57 (s, 1H) , 7.24 -7.16 (m, 4H) , 6.98 (s, 1H) , 6.72 -6.65 (m, 2H) , 6.31 (s, 1H) , 4.96 (s, 2H) , 3.20 (br d, J = 6.8 Hz, 2H) , 2.58 (q, J = 7.6 Hz, 2H) , 2.52 (s, 3H) , 1.18 (t, J = 7.4 Hz, 3H) , 0.93 -0.86 (m, 1H) , 0.29 -0.22 (m, 2H) , 0.21 -0.15 (m, 2H) .

Example 94: Synthesis of compound 1072

Step 1: Preparation of compound 1072-3: ethyl 1- (4-fluorophenyl) -5-hydroxy-1H-pyrazole-3-carboxylate

To the solution of (4-fluorophenyl) hydrazine (2.0 g, 12.3 mmol, 1.0 eq) in MeOH (50.0 mL) was added diethyl but-2-ynedioate (2.1 g, 14.7 mmol, 1.2 eq) and TEA (3.4 mL, 24.6 mmol, 2.0 eq) portionwise with the temperature was kept at 0 ℃. The mixture solution was stirred at RT overnight. After the reaction was completed, the mixture was filtered and concentrated under vacuum. The crude product was used for next step directly. (3.7 g, 14.88 mmol) .

MS (ESI, pos. ion) m/z: 237.1 [M+1] ⁺ , Rt= 0.718/2min.

Step 2: Preparation of compound 1072-4: ethyl 1- (4-fluorophenyl) -5-methoxy-1H-pyrazole-3-carboxylate

To the solution of ethyl 1- (4-fluorophenyl) -5-hydroxy-1H-pyrazole-3-carboxylate (3.5 g, 14.08 mmol, 1.0 eq) in DMF (60.0 mL) was added K₂CO₃ (2.3 g, 16.89 mmol, 1.2 eq) . The reaction mixture was stirred at RT for 0.5 hour, and then CH₃I (1.71 mL, 21.12 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at rt overnight. After the reaction was completed, the mixture was diluted with H₂O (500 mL) and extracted with EA (50 mL × 3) . The combined organic phase was washed with NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 33%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (1.1 g, 4.4 mmol, 29.6%) .

MS (ESI, pos. ion) m/z: 251.4 [M+1] ⁺ , Rt= 0.850/2min.

Step 3: Preparation of compound 1072-5: (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) methanol

To the solution of ethyl 1- (4-fluorophenyl) -5-methoxy-1H-pyrazole-3-carboxylate (1.1 g, 4.18 mmol, 1.0 eq) in THF (30 mL) was added LiAlH₄ (475 mg, 12.52 mmol, 3.0 eq) slowly with the temperature was kept at 0 ℃ under N₂. The mixture solution was stirred at 0 ℃ for 1 hour. After the reaction was completed, the mixture was quenched by addition of H₂O (0.5 mL) , 15%aqueous NaOH (0.5 mL) , followed by added H₂O (1.5 mL) . The reaction mixture was dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product. The crude product was used for next step directly. (900 mg, 4.05 mmol) .

MS (ESI, pos. ion) m/z: 223.1 [M+1] ⁺ , Rt= 0.679/2min.

Step 4: Preparation of compound 1072-6: 1- (4-fluorophenyl) -5-methoxy-1H-pyrazole-3-carbaldehyde

To the solution of (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) methanol (900 mg, 4.05 mmol, 1.0 eq) in DCM (20 mL) was added MnO₂ (3521 mg, 40.5 mmol, 10.0 eq) . The reaction mixture was stirred at RT for 18 hours. After the reaction was completed, the mixture was filtered and concentrated under vacuum to afford the crude product. The crude product was used for next step directly. (880 mg, 3.99 mmol) .

MS (ESI, pos. ion) m/z: 221.0 [M+1] ⁺ , Rt= 0.867/2min.

Step 5: Preparation of compound 1072-7: 1- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) prop-2-yn-1-ol

To the solution of 1- (4-fluorophenyl) -5-methoxy-1H-pyrazole-3-carbaldehyde (880 mg, 3.99 mmol, 1.0 eq) in THF (15 mL) was added ethynylmagnesium bromide (10.5 mL, 5.25 mmol, 1.3 eq) dropwise with the temperature was kept at 0 ℃ under N₂. The reaction mixture was stirred at 0 ℃ for 30 minutes. After the reaction was completed, the mixture was quenched by addition of saturated aqueous NH₄Cl (30 mL) and extracted with EA (50 mL × 3) . The combined organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (710 mg, 2.88 mmol, 72.1%) .

MS (ESI, pos. ion) m/z: 247.0 [M+1] ⁺ , Rt= 0.749/2min.

Step 6: Preparation of compound 1072-8: methyl (E) -2- (3- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To the solution of 1- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) prop-2-yn-1-ol (710 mg, 2.88 mmol, 1.0 eq) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (537 mg, 2.88 mmol, 1.0 eq) in dioxane (10 mL) was added TEA (1.2 mL, 8.65 mmol, 3.0 eq) , CuI (55 mg, 0.29 mmol, 0.1 eq) , PPh₃ (152 mg, 0.58 mmol, 0.2 eq) and Pd (PPh₃) ₂Cl₂ (203 mg, 0.29 mmol, 0.1 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 3 hours. After the reaction was completed, the mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (270 mg, 0.67 mmol, 23.5%) .

MS (ESI, pos. ion) m/z: 397.2 [M+1] ⁺ , Rt= 1.012/2min.

Step 7: Preparation of compound 1072-9: methyl 2- (5-cyclopropyl-1- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (270 mg, 0.67 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (228 mg, 0.85 mmol, 1.25 eq) , TEA (615 mg, 6.08 mmol, 9.0 eq) in a mixture solution of EtOH (3 mL) in dioxane (12 mL) was added 2-cyclopropylacetaldehyde (756 mg, 1.35 mmol, 2.0 eq 15%wt. in DCM) . The mixture was stirred at 100 ℃ for 1 hour under N₂. After the reaction was completed, the mixture was concentrated under vacuum. The residue was diluted with H₂O (50 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (260 mg, 0.54 mmol, 79.4%) .

MS (ESI, pos. ion) m/z: 481.6 [M+1] ⁺, Rt=1.055/2min.

Step 8: Preparation of compound 1072-10: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (260 mg, 0.54 mmol, 1.0 eq) in AcOH (10 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (360 mg, 0.80 mmol, 1.5 eq) . The reaction mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum, diluted with H₂O (50 mL) and extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated aqueous NaHCO₃ and NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (220 mg, 0.24 mmol, 45.7%) .

MS (ESI, pos. ion) m/z: 889.3 [M+1] ⁺, Rt=1.354/2min.

Step 9: Preparation of compound 1072-11: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (220 mg, 0.24 mmol, 1.0 eq) in DCM (9 mL) was added TFA (3 mL) . The reaction mixture was stirred at RT for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (120 mg, 0.18 mmol, 74.7%) .

MS (ESI, pos. ion) m/z: 649.6 [M+1] ⁺, Rt=1.144/2min.

Step 10: Preparation of compound 1072: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-fluorophenyl) -5-methoxy-1H-pyrazol-3-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (120 mg, 0.18 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (31 mg, 0.74 mmol, 4.0 eq) in H₂O (4 mL) . The mixture was stirred at RT for 2 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (75.9 mg, 0.12 mmol, 64.6%) .

MS (ESI, pos. ion) m/z: 635.2 [M+1] ⁺ , Rt=1.072/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.74 -13.36 (m, 1H) , 7.72 (t, J = 8.0 Hz, 1H) , 7.59 (d, J = 3.5 Hz, 3H) , 7.54 -7.47 (m, 2H) , 7.37 (s, 1H) , 7.31 -7.23 (m, 2H) , 6.97 -6.89 (m, 2H) , 6.36 (s, 1H) , 5.95 (br s, 2H) , 3.98 (s, 3H) , 3.32 -3.29 (m, 2H) , 2.57 (s, 3H) , 1.00 -0.91 (m, 1H) , 0.39 -0.24 (m, 4H) .

Example 95: Synthesis of compound 1075

Step 1: Preparation of compound 1075-3: 1- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) ethan-1-one

To the solution of 1- (4-chloro-1H-pyrazol-3-yl) ethan-1-one (2.8 g, 16.85 mmol, 1.0 eq) and 1-fluoro-4-iodobenzene (5.6 g, 25.28 mmol, 1.5 eq) in DMSO (30 mL) was added CuI (642 mg, 3.37 mmol, 0.2 eq) , K₂CO₃ (4.7 g, 33.70 mmol, 2.0 eq) and L-Proline (776 mg, 6.74 mmol, 0.4 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was diluted with H₂O (150 mL) , extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (3.2 g, 8.71 mmol, 77.1%) .

MS (ESI, pos. ion) m/z: 239.0 [M+1] ⁺ , Rt= 0.975/2min

Step 2: Preparation of compound 1075-4: methyl (E) -2- (3- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To the solution of 1- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) ethan-1-one (1.0 g, 4.10 mmol, 1.0 eq) and methyl 2-formyl-6-methylpyrimidine-4-carboxylate (820 mg, 4.10 mmol, 1.0 eq) in toluene (20 mL) was added PTSA (156 mg, 0.82 mmol, 0.2 eq) . The reaction mixture was stirred at 140 ℃ overnight. After the reaction was completed, the mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (65 mg, 0.16 mmol, 3.8%) .

MS (ESI, pos. ion) m/z: 401.0 [M+1] ⁺ , Rt= 1.050/2min

Step 3: Preparation of compound 1075-5: methyl 2- (1- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (50 mg, 0.12 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (40 mg, 0.15 mmol, 1.25 eq) , TEA (146 mg, 1.44 mmol, 12.0 eq) in a mixture solvent of EtOH (2 mL) in dioxane (8 mL) was added 2-cyclopropylacetaldehyde (207 mg, 0.37 mmol, 3.0 eq, 15%wt.in DCM) . The reaction mixture was stirred at 100 ℃ for 1 h under N₂. After the reaction was completed, the mixture was concentrated under vacuum, diluted with H₂O (20 mL) and extracted with EA (20 mL ×3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (50 mg, 0.09 mmol, 80.0%) .

MS (ESI, pos. ion) m/z: 485.2 [M+1] ⁺, Rt=1.075/2min

Step 4: Preparation of compound 1075-7: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (50 mg, 0.09 mmol, 1.0 eq) in AcOH (5 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (64 mg, 0.14 mmol, 1.5 eq) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction was completd, the mixture was concentrated under vacuum, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaHCO₃ and NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (60 mg, 0.06 mmol, 65.1%) .

MS (ESI, pos. ion) m/z: 893.2 [M+1] ⁺, Rt=1.383/2min.

Step 5: Preparation of compound 1075-8: methyl 2- (5- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -2-(cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (60 mg, 0.06 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The reaction mixture was stirred at RT for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (40 mg, 0.06 mmol, 96.1%) .

MS (ESI, pos. ion) m/z: 653.1 [M+1] ⁺, Rt=1.192/2min.

Step 6: Preparation of compound 1075: 2- (5- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (4-chloro-1- (4-fluorophenyl) -1H-pyrazol-3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (40 mg, 0.06 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (10 mg, 0.25 mmol, 4.0 eq) in H₂O (2 mL) . The mixture was stirred at RT for 2 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (20 mg, 0.03 mmol, 52.6%) .

MS (ESI, pos. ion) m/z: 639.2 [M+1] ⁺ , Rt=1.092/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.61 (br s, 1H) , 8.83 (s, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.67 -7.62 (m, 2H) , 7.61 (d, J = 4.0 Hz, 3H) , 7.55 (s, 1H) , 7.32 (t, J = 8.8 Hz, 2H) , 7.10 (d, J = 8.5 Hz, 1H) , 6.94 (d, J =11.3 Hz, 1H) , 6.89 (d, J = 8.3 Hz, 1H) , 6.84 (d, J = 8.5 Hz, 1H) , 5.81 (s, 2H) , 3.36 (br d, J = 6.8 Hz, 2H) , 2.58 (s, 3H) , 1.03 -0.91 (m, 1H) , 0.38 -0.32 (m, 2H) , 0.32 -0.26 (m, 2H) .

Example 96: Synthesis of compound 1078

Step 1: Preparation of compound 1078-3: 1- (4-chlorophenyl) -1H-pyrazole-4-carbaldehyde

To the solution of 1H-pyrazole-4-carbaldehyde (2.0 g, 20.81 mmol, 1.0 eq) and 1-chloro-4-iodobenzene (7.4 g, 31.22 mmol, 1.5 eq) in DMSO (30 mL) was added CuI (793 mg, 4.16 mmol, 0.2 eq) , K₂CO₃ (5752 mg, 41.62 mmol, 2.0 eq) and L-Proline (958 mg, 8.32 mmol, 0.4 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was diluted with H₂O (150 mL) and extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (1.8 g, 8.71 mmol, 41.8%) .

MS (ESI, pos. ion) m/z: 207.0 [M+1] ⁺ , Rt= 0.853/2min.

Step 2: Preparation of compound 1078-4: 1- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) prop-2-yn-1-ol

To the solution of 1- (4-chlorophenyl) -1H-pyrazole-4-carbaldehyde (1.0 g, 4.84 mmol, 1.0 eq) in THF (20 mL) was added ethynylmagnesium bromide (13.5 mL, 6.78 mmol, 1.4 eq) dropwise with the temperature was kept at 0 ℃ under N₂. The reaction mixture was stirred at 0 ℃ for 30 minutes. After the reaction was completed, the mixture was quenched by addition of saturated aqueous NH₄Cl (50 mL) and extracted with EA (50 mL× 3) . The combined organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (1.0 g, 4.29 mmol, 88.8%) .

MS (ESI, pos. ion) m/z: 232.9 [M+1] ⁺ , Rt= 0.805/2min.

Step 3: Preparation of compound 1078-5: methyl (E) -2- (3- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To the solution of 1- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) prop-2-yn-1-ol (1.0 g, 4.29 mmol, 1.0 eq) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (795 mg, 4.29 mmol, 1.0 eq) in dioxane (10 mL) was added TEA (1.8 mL, 13.0 mmol, 3.0 eq) , CuI (81 mg, 0.43 mmol, 0.1 eq) , PPh₃ (224 mg, 0.86 mmol, 0.2 eq) and Pd (PPh₃) ₂Cl₂ (300 mg, 0.43 mmol, 0.1 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 3 hours. After the reaction was completed, the mixture was diluted with H₂O (50 mL) , extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (140 mg, 0.36 mmol, 8.5%) .

MS (ESI, pos. ion) m/z: 383.0 [M+1] ⁺ , Rt= 1.001/2min.

Step 4: Preparation of compound 1078-6: methyl 2- (1- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (140 mg, 0.36 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (123 mg, 0.45 mmol, 1.25 eq) , TEA (333 mg, 3.3 mmol, 9.0 eq) in a mixture solvent of EtOH (2 mL) in dioxane (8 mL) was added 2-cyclopropylacetaldehyde (410 mg, 0.72 mmol, 2.0 eq, 15%wt. in DCM) . The mixture was stirred at 100 ℃ for 1 hour under N₂. After the reaction was completed, the mixture was concentrated under vacuum, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (100 mg, 0.21 mmol, 58.5%) .

MS (ESI, pos. ion) m/z: 467.2 [M+1] ⁺, Rt=1.047/2min.

Step 5: Preparation of compound 1078-7: methyl 2- (1- (4- (N, N-bis (4-nitrobenzoyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (100 mg, 0.21 mmol, 1.0 eq) in AcOH (5 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (143 mg, 0.32 mmol, 1.5 eq) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum, diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated aq. NaHCO₃ and NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (65 mg, 0.07 mmol, 34.6%) .

MS (ESI, pos. ion) m/z: 875.2 [M+1] ⁺, Rt=1.358/2min.

Step 6: Preparation of compound 1078-8: methyl 2- (5- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-nitrobenzoyl) sulfamoyl) -3-fluorobenzyl) -5- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (65 mg, 0.07 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The mixture was stirred at RT for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (40 mg, 0.06 mmol, 84.8%) .

MS (ESI, pos. ion) m/z: 635.2 [M+1] ⁺, Rt=1.128/2min.

Step 7: Preparation of compound 1078: 2- (5- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (5- (1- (4-chlorophenyl) -1H-pyrazol-4-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (40 mg, 0.06 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (10 mg, 0.25 mmol, 4.0 eq) in H₂O (2 mL) . The reaction mixture was stirred at RT for 2 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (24.6 mg, 0.04 mmol, 62.8%) .

MS (ESI, pos. ion) m/z: 621.1 [M+1] ⁺ , Rt=1.053/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.62 -13.45 (m, 1H) , 8.71 (s, 1H) , 7.89 -7.84 (m, 2H) , 7.80 (s, 1H) , 7.71 (t, J = 7.9 Hz, 1H) , 7.59 -7.54 (m, 5H) , 7.14 (s, 1H) , 6.92 (d, J = 11.0 Hz, 1H) , 6.86 (d, J = 8.0 Hz, 1H) , 5.57 (s, 2H) , 3.29 (br s, 2H) , 2.55 (s, 3H) , 0.99 -0.90 (m, 1H) , 0.34 -0.30 (m, 2H) , 0.28 (br dd, J = 2.8, 7.8 Hz, 2H) .

Example 97: Synthesis of compound 1079

Step 1: Preparation of compound 1079-2: 1- (4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde

To the solution of 1H-pyrazole-4-carbaldehyde (2.0 g, 20.81 mmol, 1.0 eq) and 1-iodo-4-methoxybenzene (7.3 g, 31.21 mmol, 1.5 eq) in DMSO (30 mL) was added CuI (793 mg, 4.16 mmol, 0.2 eq) , K₂CO₃ (5752 mg, 41.62 mmol, 2.0 eq) and L-Proline (958 mg, 8.32 mmol, 0.4 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was diluted with H₂O (150 mL) , extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (1.62 g, 8.01 mmol, 38.4%) .

MS (ESI, pos. ion) m/z: 203.0 [M+1] ⁺ , Rt= 0.741/2min.

Step 2: Preparation of compound 1079-3: 1- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) prop-2-yn-1-ol

To the solution of 1- (4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde (1.62 g, 8.01 mmol, 1.0 eq) in THF (20 mL) was added ethynylmagnesium bromide (21.0 mL, 10.5 mmol, 1.3 eq) dropwise with the temperature was kept at 0 ℃ under N₂. The reaction mixture was stirred at 0 ℃ for 30 minutes. After the reaction was completed, the mixture was quenched by addition of saturated aqueous NH₄Cl (50 mL) and extracted with EA (50 mL× 3) . The combined organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (1.8 g, 7.8 mmol, 98.4%) .

MS (ESI, pos. ion) m/z: 229.4 [M+1] ⁺ , Rt= 0.763/2min.

Step 3: Preparation of compound 1079-4: methyl (E) -2- (3- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate

To the solution of 1- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) prop-2-yn-1-ol (1.8 g, 7.8 mmol, 1.0 eq) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1471 mg, 7.8 mmol, 1.0 eq) in dioxane (20 mL) was added TEA (3.3 mL, 23.7 mmol, 3.0 eq) , CuI (150 mg, 0.79 mmol, 0.1 eq) , PPh₃ (414 mg, 1.58 mmol, 0.2 eq) and Pd (PPh₃) ₂Cl₂ (554 mg, 0.79 mmol, 0.1 eq) under N₂. The reaction mixture was stirred at 100 ℃ for 3 hours. After the reaction was completed, the mixture was diluted with H₂O (50 mL) , extracted with EA (50 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (660 mg, 1.74 mmol, 22.1%) .

MS (ESI, pos. ion) m/z: 379.2 [M+1] ⁺ , Rt= 0.900/2min.

Step 4: Preparation of compound 1079-5: methyl 2- (5-cyclopropyl-1- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -2- (3- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -3-oxoprop-1-en-1-yl) -6-methylpyrimidine-4-carboxylate (660 mg, 1.74 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (588 mg, 2.18 mmol, 1.25 eq) , TEA (1588 mg, 15.7 mmol, 9.0 eq) in a mixture solvent of EtOH (3 mL) in dioxane (12 mL) was added 2-cyclopropylacetaldehyde (1956 mg, 3.48 mmol, 2.0 eq, 15%wt. in DCM) . The mixture was stirred at 100 ℃ for 1 hour under N₂. After the reaction was completed, the mixture was concentrated under vacuum, diluted with H₂O (30 mL) and extracted with EA (30 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (467 mg, 1.0 mmol, 57.8%) .

MS (ESI, pos. ion) m/z: 463.5 [M+1] ⁺, Rt=0.989/2min.

Step 5: Preparation of compound 1079-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -1, 4-dioxopentan-3-yl) -6-methylpyrimidine-4-carboxylate (467 mg, 1.0 mmol, 1.0 eq) in AcOH (10 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (675 mg, 1.5 mmol, 1.5 eq) . The reaction mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum, diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated aq. NaHCO₃ and NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (400 mg, 0.46 mmol, 45.5%) .

MS (ESI, pos. ion) m/z: 871.4 [M+1] ⁺, Rt=1.359/2min.

Step 6: Preparation of compound 1079-7: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (400 mg, 0.46 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The reaction mixture was stirred at RT for 18 hours. After the reaction was completed, the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (250 mg, 0.39 mmol, 86.2%) .

MS (ESI, pos. ion) m/z: 631.3 [M+1] ⁺, Rt=1.078/2min.

Step 7: Preparation of compound 1079: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (250 mg, 0.39 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (66 mg, 1.58 mmol, 4.0 eq) in H₂O (2 mL) . The mixture was stirred at RT for 2 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 50%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (187.0 mg, 0.3 mmol, 76.5%) .

MS (ESI, pos. ion) m/z: 617.2 [M+1] ⁺ , Rt=0.987/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.70 -13.41 (m, 1H) , 8.55 (s, 1H) , 7.75 -7.70 (m, 4H) , 7.59 (s, 2H) , 7.57 (s, 1H) , 7.12 (s, 1H) , 7.08 -7.00 (m, 2H) , 6.97 -6.91 (m, 1H) , 6.88 (d, J = 8.0 Hz, 1H) , 5.56 (s, 2H) , 3.80 (s, 3H) , 3.29 (br s, 2H) , 2.57 -2.54 (m, 3H) , 1.00 -0.90 (m, 1H) , 0.36 -0.31 (m, 2H) , 0.30 -0.25 (m, 2H) .

Example 98: Synthesis of compound 1082

Step 1: Preparation of compound 1082-2: 1- (p-tolyl) -1H-pyrazole-4-carbaldehyde

To a solution of 1-iodo-4-methylbenzene (5.00 g, 22.93 mmol, 1.0 eq) in DMSO (100 mL) was added 1H-pyrazole-4-carbaldehyde (2.20 g, 22.93 mmol, 1.0 eq) , L-proline (1.06 g, 9.17 mmol, 0.4 eq) , CuI (0.87 g, 4.59 mmol, 0.2 eq) and K₂CO₃ (6.34 g, 45.86 mmol, 2.0 eq) . The reaction mixture was stirred for 18 hours at 100 ℃ under N₂ atmosphere. After the reaction was completed, the reaction mixture was filtered. The filtrate was diluted with EA (100 mL) . The organic layer was washed with H₂O (30 mL × 3) and brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10 to 1/5) to afford the title product (1.50 g, 35%) .

MS (ESI, pos. ion) m/z: 187.0 [M+1] ⁺, Rt=0.817/2 min.

Step 2: Preparation of compound 1082-3: 1- (1- (p-tolyl) -1H-pyrazol-4-yl) prop-2-yn-1-ol

To a solution of 1- (p-tolyl) -1H-pyrazole-4-carbaldehyde (1.50 g, 8.06 mmol, 1.0 eq) in THF (20 mL) was added ethynylmagnesium bromide (21 mL, 10.50 mmol, 1.25 eq) at 0 ℃ under N₂. The reaction mixture was stirred for 2 hours at 0 ℃. After the reaction was completed, the reaction mixture was quenched with NH₄Cl aqueous solution (30 mL) and extracted with EA (50 mL × 2) . The organic layer was washed with brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/10) to afford the title product (1.50 g, 86%) .

MS (ESI, pos. ion) m/z: 213.4 [M+1] ⁺, Rt=0.767/2 min.

Step 3: Preparation of compound 1082-4: methyl (E) -6-methyl-2- (3-oxo-3- (1- (p-tolyl) -1H-pyrazol-4-yl) prop-1-en-1-yl) pyrimidine-4-carboxylate

To a solution of 1- (1- (p-tolyl) -1H-pyrazol-4-yl) prop-2-yn-1-ol (1.50 g, 7.00 mmol, 1.0 eq) in dioxane (30 mL) was added methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.30 g, 6.97 mmol, 0.9 eq) , Pd (PPh₃) ₂Cl₂ (500 mg, 0.71 mmol, 0.1 eq) , PPh₃ (370 mg, 1.41 mmol, 0.2 eq) , CuI (135 mg, 0.71 mmol, 0.1 eq) and TEA (3.0 mL, 21.64 mmol, 3.0 eq) . The reaction mixture was stirred for 18 hours at 100 ℃under N₂ atmosphere. After the reaction was completed, the reaction mixture was filtered. The filtrate was diluted with EA (100 mL) . The organic layer was washed with H₂O (30 mL × 3) and brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product (600 mg, 23%) .

MS (ESI, pos. ion) m/z: 363.4 [M+1] ⁺, Rt=0.967/2 min.

Step 4: Preparation of compound 1082-5: methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (1- (p-tolyl) -1H-pyrazol-4-yl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl (E) -6-methyl-2- (3-oxo-3- (1- (p-tolyl) -1H-pyrazol-4-yl) prop-1-en-1-yl) pyrimidine-4-carboxylate (550 mg, 1.52 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (500 mg, 1.85 mmol, 1.25 eq) and TEA (0.65 mL, 4.69 mmol, 3.08 eq) in a mixture solvent of dioxane (20 mL) in EtOH (5 mL) was added 2-cyclopropylacetaldehyde (2500 mg, 4.46 mmol, 3.0 eq, 15%wt. in DCM) . The resulting was stirred at 100 ℃ for 1 h. After the reaction was completed, the mixture was diluted with H₂O (30 mL) and extracted with EA (50 mL × 3) . The organic layer was washed with brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/3) to afford the title product (340 mg, 47%) .

MS (ESI, pos. ion) m/z: 447.6 [M+1] ⁺, Rt=1.025/2 min.

Step 5: Preparation of compound 1082-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (p-tolyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (5-cyclopropyl-1, 4-dioxo-1- (1- (p-tolyl) -1H-pyrazol-4-yl) pentan-3-yl) -6-methylpyrimidine-4-carboxylate (340 mg, 0.72 mmol, 1.0 eq) in AcOH (20 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (480 mg, 1.03 mmol, 1.43 eq) . The mixture was stirred at 100 ℃ for 18 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was diluted with EA (40 mL) and washed with saturated NaHCO₃ aqueous solution (20 mL × 2) , brine (20 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The mixture was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product (400 mg, 65%) .

MS (ESI, pos. ion) m/z: 855.0 [M+1] ⁺, Rt=1.392/2 min.

Step 6: Preparation of compound 1082-7: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (p-tolyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (1- (p-tolyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (400 mg, 0.47 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL) . The mixture was stirred at 25 ℃ for 48 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was diluted with DCM (30 mL) and washed with brine (20 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was used for next step directly. (280 mg, 83%) .

MS (ESI, pos. ion) m/z: 615.2 [M+1] ⁺, Rt=1.125/2 min.

Step 7: Preparation of compound 1082: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (p-tolyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (1- (p-tolyl) -1H-pyrazol-4-yl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (280 mg, 0.39 mmol, 1.0 eq) in a mixture solvent of THF (6 mL) in MeOH (2 mL) was added a solution of LiOH (80 mg, 1.91 mmol, 4.89 eq) in H₂O (2 mL) . The mixture was stirred at 25 ℃ for 1 h. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (160 mg, 67%) .

MS (ESI, pos. ion) m/z: 601.1 [M+1] ⁺, Rt=1.034/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.76 -13.32 (m, 1H) , 8.61 (s, 1H) , 7.75 -7.66 (m, 4H) , 7.58 (d, J =8.0 Hz, 3H) , 7.29 (d, J = 8.2 Hz, 2H) , 7.13 (s, 1H) , 6.94 (d, J = 11.0 Hz, 1H) , 6.90 -6.84 (m, 1H) , 5.57 (s, 2H) , 3.31 (br d, J = 6.8 Hz, 2H) , 2.56 (s, 3H) , 2.34 (s, 3H) , 1.00 -0.91 (m, 1H) , 0.37 -0.24 (m, 4H) .

Example 99: Synthesis of compound 1083

Step 1: Preparation of compounds 1083-2 and 1083-2a: methyl 1- (4-fluorophenyl) -3-methyl-pyrazole-4-carboxylate and methyl 1- (4-fluorophenyl) -5-methyl-pyrazole-4-carboxylate

methyl 3-methyl-1H-pyrazole-4-carboxylate (2.1 g, 14.99 mmol, 1 eq) was added into Pyridine (22 mL) . (4-fluorophenyl) boronic acid (2.52 g, 17.98 mmol, 1.2 eq) , Cu (OAc) ₂ (4.08 g, 22.48 mmol, 1.5 eq) and 4A MS (2.15 g) was added into the mixture. The mixture was stirred at 40 ℃ for 16 hrs under O₂. The reaction mixture was cooled to 25 ℃, and then diluted with H₂O 60 mL and extracted with EtOAc (10 mL *3) . The combined organic layers were washed with aq. NaCl (10 ml) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (120 gSilica Flash Column, Eluent of 0～10%Ethyl acetate/Petroleum ether gradient @50 mL/min) . Compound 1083-2 (1.62 g, 6.92 mmol, 46.16%yield) was obtained as a white solid. Compound 1083-2a (580 mg, 2.48 mmol, 16.52%yield) was obtained as a white solid.

Compound 1083-2

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.29 (s, 1H) , 7.71 -7.59 (m, 2H) , 7.22 -7.13 (m, 2H) , 3.88 (s, 3H) , 2.57 (s, 3H)

Compound 1083-2a

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.03 (s, 1H) , 7.45 -7.39 (m, 2H) , 7.25 -7.18 (m, 2H) , 3.88 (s, 3H) , 2.58 -2.55 (m, 3H)

Step 2: Preparation of compound 1083-3: 1- (4-fluorophenyl) -3-methyl-pyrazole-4-carboxylic acid methyl 1- (4-fluorophenyl) -3-methyl-pyrazole-4-carboxylate (1.42 g, 6.06 mmol, 1 eq) was added into THF (15 mL) and MeOH (15 mL) . NaOH (1 M, 18.19 mL, 3 eq) was added into the mixture. The mixture was stirred at 25 ℃ for 2 h. The reaction mixture was diluted with H₂O 50 mL, and adjusted with 1N HCl to pH=5～6, and extracted with EtOAc (20 mL *3) . The combined organic layers were washed with aq. NaCl (20 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue.

Compound 1083-3 (1.3 g, crude) was obtained as a white solid.

Step 3: Preparation of compound 1083-4: 1- (4-fluorophenyl) -N-methoxy-N, 3-dimethyl-pyrazole-4-carboxamide

1- (4-fluorophenyl) -3-methyl-pyrazole-4-carboxylic acid (1.3 g, 5.90 mmol, 1 eq) was added into dioxane (15 mL) . N-methoxymethanamine; hydrochloride (691.05 mg, 7.08 mmol, 1.2 eq) , DIEA (2.29 g, 17.71 mmol, 3.08 mL, 3 eq) and T₄P (6.38 g, 8.86 mmol, 50%purity, 1.5 eq) was added into the mixture. The mixture was stirred at 25℃ for 2 hrs. The reaction mixture was diluted with H₂O 30 mL and extracted with EtOAc (10 mL *3) . The combined organic layers were washed with aq. NaCl (10mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0～30%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1083-4 (1.4 g, 5.32 mmol, 90.08%yield) was obtained as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.31 (s, 1H) , 7.69 -7.62 (m, 2H) , 7.18 (t, J = 8.6 Hz, 2H) , 3.71 (s, 3H) , 3.37 (s, 3H) , 2.59 (s, 3H)

Step 4: Preparation of compound 1083-5: 1- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] ethanone

1- (4-fluorophenyl) -N-methoxy-N, 3-dimethyl-pyrazole-4-carboxamide (1.4 g, 5.32 mmol, 1 eq) was added into THF (15 mL) . The mixture was degassed and refilled with N₂ for 3 times. The mixture was cooled to -75℃. MeMgBr (3 M, 3.55 mL, 2 eq) was added into the mixture dropwise under N₂ at -75 --70 ℃. The mixture was stirred at -75 ℃ for 10 mins, and then the mixture was warmed to 20 ℃ naturally. The mixture was stirred at 20 ℃ for 1 h. The reaction mixture was quenched by addition NH₄Cl (aq) 30 mL at 25 ℃, and then diluted with H₂O 20 mL and extracted with EtOAc 45 mL (15 mL *3) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～20%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1083-5 (1.1 g, 5.04 mmol, 94.79%yield) was obtained as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.24 (s, 1H) , 7.69 -7.63 (m, 2H) , 7.18 (t, J = 8.6 Hz, 2H) , 2.57 (s, 3H) , 2.49 (s, 3H)

Step 5: Preparation of compound 1083-6: 2- [ (E) -3- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylic acid

1- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] ethanone (200 mg, 916.48 μmol, 1 eq) was added into MeOH (4 mL) . methyl 2-formyl-6-methyl-pyrimidine-4-carboxylate (247.67 mg, 1.37 mmol, 1.5 eq) and NaOH (6 M, 458.24 μL, 3 eq) was added into the mixture. The mixture was stirred at 25℃ for 3 hrs. The reaction mixture was diluted with H₂O 20 mL, and adjusted with 1N HCl to pH = ～5, and extracted with EtOAc (5 mL *3) . The combined organic layers were washed with aq. NaCl (5 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. Compound 1083-6 (330 mg, crude) was obtained as a white solid.

MS (ESI, pos. ion) m/z: 367.0 [M+H] ⁺, Rt=0.894/1.5min.

Step 6: Preparation of compound 1083-7: methyl 2- [ (E) -3- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylate

2- [ (E) -3- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylic acid (330 mg, 900.79 μmol, 1 eq) was added into MeOH (6 mL) . H₂SO₄ (265.04 mg, 2.70 mmol, 144.05 μL, 3 eq) was added into the mixture. The mixture was stirred at 50 ℃ for 2 h. The reaction was cooled to 25 ℃. The reaction mixture was removed most of solvent in vacuum, and then diluted with H₂O 10 mL and extracted with EtOAc (4 mL *3) . The combined organic layers were washed with aq. NaCl (4 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～50%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1083-7 (180 mg, 473.22 μmol, 52.53%yield) was obtained as a light-yellow solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.50 (s, 1H) , 8.05 (d, J = 15.4 Hz, 1H) , 7.85 -7.79 (m, 2H) , 7.75 -7.68 (m, 2H) , 7.20 (t, J = 8.6 Hz, 2H) , 4.06 (s, 3H) , 2.70 (s, 3H) , 2.66 (s, 3H)

Step 7: Preparation of compound 1083-8: methyl 2- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -2-oxo-ethyl] -2-oxo-propyl] -6-methyl-pyrimidine-4-carboxylate

methyl 2- [ (E) -3- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylate (180 mg, 473.22 μmol, 1 eq) was added into dioxane (5 mL) and EtOH (1 mL) . 2-cyclopropylacetaldehyde (99.51 mg, 1.18 mmol, 2.5 eq) , 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (165.97 mg, 615.19 μmol, 1.3 eq) and TEA (430.96 mg, 4.26 mmol, 592.80 μL, 9 eq) was added into the mixture. The mixture was stirred at 100 ℃ for 16 hrs. The mixture was cooled to 25 ℃. The reaction mixture was diluted with H₂O 20 mL and extracted with EtOAc (5 mL *3) . The combined organic layers were washed with aq. NaCl (5 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0～45%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1083-8 (200 mg, 430.58 μmol, 90.99%yield) was obtained as a white solid.

Step 8: Preparation of compound 1083-9: methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate

4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (206.71 mg, 465.03 μmol, 1.2 eq) and methyl 2- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -2-oxo-ethyl] -2-oxo-propyl] -6-methyl-pyrimidine-4-carboxylate (180 mg, 387.52 μmol, 1 eq) was added into AcOH (4 mL) . The mixture was stirred at 90 ℃ for 16 hrs. The mixture was cooled to 25 ℃. The reaction mixture was diluted with H₂O 20 mL and extracted with EtOAc (5 mL *3) . The combined organic layers were washed with aq. NaCl (5 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～40%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1083-9 (240 mg, 274.92 μmol, 70.94%yield) was obtained as a yellow solid.

Step 9: Preparation of compound 1083-10: methyl 2- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate

methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropyl methyl) -5- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (240 mg, 274.92 μmol, 1 eq) was added into TFA (1 mL) and DCM (3 mL) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was concentrated in vacuum to provide crude product. Compound 1083-10 (200 mg, crude, TFA) was obtained as a brown solid.

MS (ESI, pos. ion) m/z: 633.3 [M+H] ⁺, Rt=0.938/1.5min.

Step 10: Preparation of compound 1083: 2- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylic acid

methyl 2- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-methyl-pyrazol-4-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (200 mg, 267.84 μmol, 1 eq, TFA) was added into MeOH (2 mL) , THF (2 mL) and H₂O (1 mL) . The mixture was added LiOH (32.07 mg, 1.34 mmol, 5 eq) . The mixture was stirred at 25 ℃ for 2 hrs. The reaction mixture was diluted with H₂O 10 mL, and adjusted with 1N HCl to pH=～6, and extracted with EtOAc 9 mL (3 mL *3) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (FA) -MeCN] ; gradient: 47%-67%B over 25 min) . Compound 1083 (60.26 mg, 97.41 μmol, 36.37%yield) was obtained as a yellow solid.

MS (ESI, pos. ion) m/z: 619.3 [M+H] ⁺, Rt=0.870/1.5min.

¹H NMR (400 MHz, DMSO-d6) δ = 8.49 (s, 1H) , 7.83 -7.75 (m, 2H) , 7.67 (t, J = 7.8 Hz, 1H) , 7.58 (d, J = 12.3 Hz, 3H) , 7.32 (t, J = 8.8 Hz, 2H) , 6.95 (s, 1H) , 6.83 -6.73 (m, 2H) , 5.41 (s, 2H) , 3.29 (br d, J = 6.6 Hz, 2H) , 2.55 (s, 3H) , 2.15 (s, 3H) , 0.96 (br s, 1H) , 0.36 -0.25 (m, 4H)

Example 100: Synthesis of compound 1084

Step 1: Preparation of compound 1184-3: 1- (4-fluorophenyl) -5-methyl-pyrazole-4-carboxylic acid

methyl 1- (4-fluorophenyl) -5-methyl-pyrazole-4-carboxylate (0.58 g, 2.48 mmol, 1 eq) was added into MeOH (7 mL) and THF (7 mL) . NaOH (1 M, 7.43 mL, 3 eq) was added into the mixture. The mixture was stirred at 25 ℃ for 16 hrs. The reaction mixture was diluted with H₂O 20 mL, and adjusted with 1N HCl to pH=5～6, and extracted with EtOAc (10 mL *3) . The combined organic layers were washed with aq. NaCl (10 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue.

Compound 1184-3 (0.54 g, crude) was obtained as a white solid.

MS (ESI, pos. ion) m/z: 221.2 [M+H] ⁺, Rt=0.671/1.5min.

Step 2: Preparation of compound 1184-4: 1- (4-fluorophenyl) -N-methoxy-N, 5-dimethyl-pyrazole-4-carboxamide

1- (4-fluorophenyl) -5-methyl-pyrazole-4-carboxylic acid (0.54 g, 2.45 mmol, 1 eq) was added into dioxane (10 mL) . N-methoxymethanamine; hydrochloride (287.05 mg, 2.94 mmol, 1.2 eq) , DIEA (950.81 mg, 7.36 mmol, 1.28 mL, 3 eq) and T₄P (2.65 g, 3.68 mmol, 50%purity, 1.5 eq) was added into the mixture. The mixture was stirred at 25℃ for 2 h. The reaction mixture was diluted with H₂O 20 mL and extracted with EtOAc (10 mL *3) . The combined organic layers were washed with aq. NaCl (10mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～30%Ethyl acetate/Petroleum ether gradient @30 mL/min) . Compound 1184-4 (590 mg, 2.24 mmol, 91.39%yield) was obtained as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.06 (s, 1H) , 7.45 -7.39 (m, 2H) , 7.21 (t, J = 8.6 Hz, 2H) , 3.74 (s, 3H) , 3.37 (s, 3H) , 2.56 (s, 3H) .

Step 3: Preparation of compound 1184-5: 1- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] ethanone

1- (4-fluorophenyl) -N-methoxy-N, 5-dimethyl-pyrazole-4-carboxamide (590 mg, 2.24 mmol, 1 eq) was added into THF (10 mL) . The mixture was degassed and refilled with N2 for 3 times. The mixture was cooled to -75℃. MeMgBr (3 M, 1.49 mL, 2 eq) was added into the mixture dropwise under N₂ at -75--70℃. The mixture was stirred at -75℃ for 10 mins, and then the mixture was warmed to 20℃ naturally. The mixture was stirred at 20 ℃ for 1 h. The reaction mixture was quenched by addition NH₄Cl (aq) 20 mL at 0-10 ℃, and then diluted with H₂O 10 mL and extracted with EtOAc 15 mL (5 mL *3) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～20%Ethyl acetate/Petroleum ether gradient @30 mL/min) . Compound 1184-5 (460 mg, 2.11 mmol, 94.06%yield) was obtained as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.01 (s, 1H) , 7.45 -7.38 (m, 2H) , 7.22 (t, J = 8.5 Hz, 2H) , 2.57 (s, 3H) , 2.51 (s, 3H) .

Step 4: Preparation of compound 1184-6: 2- [ (E) -3- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylic acid

1- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] ethanone (200.00 mg, 916.48 μmol, 1 eq) was added into MeOH (4 mL) . methyl 2-formyl-6-methyl-pyrimidine-4-carboxylate (247.67 mg, 1.37 mmol, 1.5 eq) and NaOH (6 M, 458.24 μL, 3 eq) was added into the mixture. The mixture was stirred at 25 ℃ for 3 hrs. The reaction mixture was diluted with H₂O 20mL, and adjusted with 1N HCl to pH = ～5, and extracted with EtOAc (5 mL *3) . The combined organic layers were washed with aq. NaCl (5 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. Compound 1184-6 (330 mg, crude) was obtained as a white solid.

MS (ESI, pos. ion) m/z: 367.0 [M+H] ⁺, Rt=0.854/1.5min.

Step 5: Preparation of compound 1184-7: methyl 2- [ (E) -3- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylate

2- [ (E) -3- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylic acid (330.00 mg, 900.79 μmol, 1 eq) was added into MeOH (6 mL) . H₂SO₄ (265.04 mg, 2.70 mmol, 144.05 μL, 3 eq) was added into the mixture. The mixture was stirred at 50 ℃ for 2 h. The reaction was cooled to 25 ℃. The reaction mixture was removed most of solvent in vacuum, and then diluted with H₂O 10 mL and extracted with EtOAc (4 mL *3) . The combined organic layers were washed with aq. NaCl (4 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～50%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1184-7 (180 mg, 473.22 μmol, 52.53%yield) was obtained as a light-yellow solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.25 (s, 1H) , 8.11 (d, J = 15.4 Hz, 1H) , 7.87 -7.80 (m, 2H) , 7.45 (dd, J = 4.7, 9.0 Hz, 2H) , 7.24 (d, J = 8.2 Hz, 2H) , 4.06 (s, 3H) , 2.71 (s, 3H) , 2.66 (s, 3H) .

Step 6: Preparation of compound 1184-8: methyl 2- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -2-oxo-ethyl] -2-oxo-propyl] -6-methyl-pyrimidine-4-carboxylate

methyl 2- [ (E) -3- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -3-oxo-prop-1-enyl] -6-methyl-pyrimidine-4-carboxylate (180.00 mg, 473.22 μmol, 1 eq) was added into dioxane (5 mL) and EtOH (1 mL) . 2-cyclopropylacetaldehyde (99.51 mg, 1.18 mmol, 2.5 eq) , 2- (3-benzyl-4-methyl-thiazol-3-ium-5-yl) ethanol; chloride (165.97 mg, 615.19 μmol, 1.3 eq) and TEA (430.96 mg, 4.26 mmol, 592.80 μL, 9 eq) was added into the mixture. The mixture was stirred at 100℃ for 16 hrs. The mixture was cooled to 25℃. The reaction mixture was diluted with H₂O 20 mL and extracted with EtOAc (5 mL *3) . The combined organic layers were washed with aq. NaCl (5 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～45%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1184-8 (200 mg, 430.58 μmol, 90.99%yield) was obtained as a yellow solid.

Step 7: Preparation of compound 1184-9: methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate

4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (206.71 mg, 465.03 μmol, 1.2 eq) and methyl 2- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -2-oxo-ethyl] -2-oxo-propyl] -6-methyl-pyrimidine-4-carboxylate (180 mg, 387.52 μmol, 1 eq) was added into AcOH (4 mL) . The mixture was stirred at 90 ℃ for 16 hrs. The mixture was cooled to 25 ℃. The reaction mixture was diluted with H₂O 20 mL and extracted with EtOAc (5 mL *3) . The combined organic layers were washed with aq. NaCl (5 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0～40%Ethyl acetate/Petroleum ether gradient @35 mL/min) . Compound 1184-9 (200 mg, 229.10 μmol, 59.12%yield) was obtained as a yellow solid.

MS (ESI, pos. ion) m/z: 873.6 [M+H] ⁺, Rt=1.104/1.5min.

Step 8: Preparation of compound 1184-10: methyl 2- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate

methyl 2- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (200 mg, 229.10 μmol, 1 eq) was added into TFA (1 mL) and DCM (3 mL) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was concentrated in vacuum to provide crude product. Compound 1184-10 (170 mg, crude, TFA) was obtained as a brown solid.

Step 9: Preparation of compound 1184: 2- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylic acid

methyl 2- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] -6-methyl-pyrimidine-4-carboxylate (170 mg, 227.67 μmol, 1 eq, TFA) was added into MeOH (1 mL) , THF (2 mL) and H₂O (1 mL) . The mixture was added LiOH (27.26 mg, 1.14 mmol, 5 eq) . The mixture was stirred at 25 ℃ for 2 hrs. The reaction mixture was diluted with H₂O 10 mL, and adjusted with 1N HCl to pH=～6, and extracted with EtOAc 9mL (3 mL *3) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Boston Prime C18 150 *30 mm *5 um; mobile phase: [Water (FA) -MeCN] ; gradient: 46%-66%B over 25 min) . Compound 1184 (57.42 mg, 92.81 μmol, 40.77%yield) was obtained as a yellow solid.

MS (ESI, pos. ion) m/z: 619.3 [M+H] ⁺, Rt=0.850/1.5min.

¹H NMR (400 MHz, DMSO-d6) δ = 7.72 (t, J = 7.8 Hz, 1H) , 7.63 (s, 2H) , 7.57 -7.49 (m, 4H) , 7.36 (t, J =8.8 Hz, 2H) , 6.91 (s, 1H) , 6.90 -6.77 (m, 2H) , 5.34 (s, 2H) , 3.29 (br d, J = 6.6 Hz, 2H) , 2.55 (s, 3H) , 2.17 (s, 3H) , 0.98 (br t, J = 6.9 Hz, 1H) , 0.36 -0.26 (m, 4H) .

Example 101: Synthesis of compound 1140

Step 1: Preparation of compound 1140-1: 3- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (cyclopropylmethyl) -4- (4- (hydroxymethyl) -6-methylpyrimidin-2-yl) -1H-pyrrol-2-yl) phenyl trifluoromethanesulfonate

A 25 mL single-necked round bottom flask equipped with mechanical stirrer was charged with methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (300 mg, 0.33 mmol, 1.00 eq) , lithium chloride (34 mg, 0.81 mmol, 2.50 eq) and DCM (5 mL) . The resulting was added NaBH₄ (49 mg, 1.30 mmol, 4.00 eq) at 0 ℃. The reaction was stirred at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with EA (60 mL) , washed with brine (90 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -70: 30) , to afford the title product as a white solid (273 mg, 0.29 mmol, 89.16 %) .

MS (ESI, pos. ion) m/z: 895.3 [M+1] ⁺, Rt=1.71/2min

Step 2: Preparation of compound 1140-2: 3- (5- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -4- (4- (hydroxymethyl) -6-methylpyrimidin-2-yl) -1H-pyrrol-2-yl) phenyl trifluoromethanesulfonate

A 25 mL single-necked round bottom flask equipped with mechanical stirrer was charged with 3- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (cyclopropylmethyl) -4- (4- (hydroxymethyl) -6-methylpyrimidin-2-yl) -1H-pyrrol-2-yl) phenyl trifluoromethanesulfonate (253 mg, 0.27 mmol, 1.00 eq) and DCM (3 mL) . The resulting was added 2, 2, 2-trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated, and the residue was purified by column chromatography (SiO₂, PE : EA = 100: 0 -90: 10 -80: 20) , to afford the title product as a yellow oil liquid (175 mg, 0.27 mmol, 99.54 %) .

MS (ESI, pos. ion) m/z: 655.1 [M+1] ⁺, Rt=1.56/2min.

Step 3 : Preparation of compound 1140-3: 4- ( (3- (4- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-methylpyrimidin-2-yl) -2- (cyclopropylmethyl) -5- (3- ( (trimethylsilyl) ethynyl) phenyl) -1H-pyrrol-1-yl) methyl) -2-fluorobenzenesulfonamide

To a solution of 3- (5- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -4- (4- (hydroxymethyl) -6-methylpyrimidin-2-yl) -1H-pyrrol-2-yl) phenyl trifluoromethanesulfonate (165 mg, 0.24 mmol, 1.00 eq) and 3H-imidazole (24 mg, 0.36 mmol, 1.50 eq) in DCM (3 mL) was added TBSCl (54 mg, 0.36 mmol, 1.50 eq) . The reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with EA (20 mL) . The organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, PE: EA = 100: 0 -80: 20 -70: 30) , to afford the title product as a yellow solid (160 mg, 0.20 mmol, 82.56 %) .

MS (ESI, pos. ion) m/z: 769.2 [M+1] ⁺, Rt=1.71/2min.

Step 4 : Preparation of compound 1140: 4- ( (2- (cyclopropylmethyl) -3- (4- (hydroxymethyl) -6-methylpyrimidin-2-yl) -5- (3- (prop-1-yn-1-yl) phenyl) -1H-pyrrol-1-yl) methyl) -2-fluorobenzenesulfonamide

A 10 mL drying tube equipped with mechanical stirrer was charged with 4- ( (3- (4- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-methylpyrimidin-2-yl) -2- (cyclopropylmethyl) -5- (3- ( (trimethylsilyl) ethynyl) phenyl) -1H-pyrrol-1-yl) methyl) -2-fluorobenzenesulfonamide (100 mg, 0.12 mmol, 1.00 eq) 、trimethyl (prop-1-ynyl) silane (0.06 mL, 0.38 mmol, 3.10 eq) , 2- [ethyl (2-hydroxyethyl) amino] ethan-1-ol (0.05 mL, 0.39 mmol, 3.16 eq) , copper (1+) iodide (6 mg, 0.03 mmol, 0.25 eq) , Pd (dppf) ₂Cl₂ (12 mg, 0.01 mmol, 0.12 eq) , triphenylphosphane (14 mg, 0.05 mmol, 0.43 eq) , TBAF (0.11 mL, 0.38 mmol, 3.10 eq) and N, N-dimethylmethanamide (2 mL) at room temperature The reaction was stirred at 100 ℃ for 16 h under N₂ atmosphere. After the reaction was completed, the mixture was diluted with H₂O (20 mL) and extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (21 mg, 0.04 mmol, 95.15 %) .

MS (ESI, pos. ion) m/z: 545.2 [M+1] ⁺ , Rt=1.46/3min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.69 (s, 1H) , 7.61 (s, 2H) , 7.40 -7.26 (m, 4H) , 7.14 (s, 1H) , 6.93 (s, 1H) , 6.83 (d, J = 11.0 Hz, 1H) , 6.75 (d, J = 8.3 Hz, 1H) , 5.51 (t, J = 5.9 Hz, 1H) , 5.40 (s, 2H) , 4.51 (d, J =5.8 Hz, 2H) , 3.17 (br d, J = 6.8 Hz, 2H) , 2.46 (s, 3H) , 2.03 (s, 3H) , 0.97 (br s, 1H) , 0.37 -0.18 (m, 4H) .

Example 102: Synthesis of compound 1143

Step 1: Preparation of compound 1143-2: trimethyl (prop-1-yn-1-yl-d3) silane

To a solution of ethynyltrimethylsilane (1.0 g, 10.18 mmol, 1.0 eq) in THF (20 mL) was added n-BuLi (720 mg, 11.25 mmol, 1.1 eq) with the temperature was kept at -78 ℃ under N₂. The reaction mixture was stirred at -78 ℃ for 30 minutes, and then the CD₃I (1.8 g, 12.86 mmol, 1.2 eq) was added. The resulting was stirred at rt for 2 h. The mixture was quenched with saturated NH₄Cl aqueous solution (50 mL) and extracted with DCM (50 mL× 3) . The combined organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was used directly for the next step reaction without purification.

Step 2: Preparation of compound 1143-4: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl-d₃) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (300 mg, 0.44 mmol, 1.0 eq) and trimethyl (prop-1-yn-1-yl-d3) silane (100 mg, 0.88 mmol, 2.0 eq) in THF (10 mL) was added TEA (1.8 mL, 13.0 mmol, 3.0 eq) , CuI (8 mg, 0.04 mmol, 0.1 eq) , TBAF (114 mg, 0.44 mmol, 1.0 eq) and Pd (PPh₃) ₂Cl₂ (31 mg, 0.04 mmol, 0.1 eq) under N₂. The reaction mixture was stirred at 70 ℃ for 18 hours. After the reaction was completed, the mixture was diluted with H₂O (20 mL) , extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (40.0 mg, 0.07 mmol, 15.9%) .

MS (ESI, pos. ion) m/z: 576.3 [M+1] ⁺ , Rt= 1.167/2min

Step 3: Preparation of compound 1143: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl-d3) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl-d3) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (40.0 mg, 0.07 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (7 mg, 0.27 mmol, 4.0 eq) in H₂O (2 mL) . The reaction mixture stirred at RT for 2 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (5 mg, 0.01 mmol, 12.7%) .

MS (ESI, pos. ion) m/z: 562.2 [M+1] ⁺ , Rt=1.058/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 7.70 (t, J = 7.9 Hz, 1H) , 7.61 (s, 2H) , 7.58 (s, 1H) , 7.37 (s, 1H) , 7.36 -7.28 (m, 3H) , 7.03 (s, 1H) , 6.86 (d, J = 11.0 Hz, 1H) , 6.79 -6.73 (m, 1H) , 5.42 (s, 2H) , 3.23 (br d, J = 6.5 Hz, 2H) , 2.55 (s, 3H) , 1.03 -0.91 (m, 1H) , 0.38 -0.22 (m, 4H) .

Example 103: Synthesis of compound 1146

Step 1: Preparation of compound 1146-2: methyl (E) -4-methyl-6- (3-oxo-3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-1-en-1-yl) picolinate

A 250 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 6-chloro-4-methylpicolinate (2.00 g, 10.78 mmol, 1.00 eq) , 1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-2-yn-1-ol (3.76 g, 16.17 mmol, 1.50 eq) , CuI (210 mg, 1.08 mmol, 0.10 eq) and PPh₃ (570 mg, 2.16 mmol, 0.20 eq) and dioxane (50 mL) . The resulting was added TEA (4.48 mL, 32.33 mmol, 3.00 eq) and Pd (PPh₃) ₂Cl₂ (760 mg, 1.08 mmol, 0.10 eq) under N₂ atmosphere. The reaction mixture was stirred at 100 ℃ overnight under N₂. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was diluted with EA (200 mL) , and the organic was washed with brine (200 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/3) to afford the title product as a black solid (1.60 g, 35.44%) .

MS (ESI, pos. ion) m/z: 382.6 [M+1] ⁺, Rt=1.075/2 min.

Step 2: Preparation of compound 1146-3: methyl 6- (5-cyclopropyl-1, 4-dioxo-1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) pentan-3-yl) -4-methylpicolinate

A 250 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl (E) -4-methyl-6- (3-oxo-3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) prop-1-en-1-yl) picolinate (1.60 g, 3.82 mmol, 1.0 eq) , 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1, 3-thiazol-3-ium chloride (1.29 g, 4.78 mmol, 1.25 eq) , TEA (2.65 mL, 19.01 mmol, 5.00 eq) , EtOH (20 mL) and dioxane (5 mL) . The resulting was added 2-cyclopropylacetaldehyde (9.64 g, 11.46 mmol, 3.00 eq, 10%wt. in DCM) . The reaction mixture was stirred at 100 ℃ for 1 hour. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was diluted with EA (50 mL) . The organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a yellow oil (1.45 g, 74.14%) .

MS (ESI, pos. ion) m/z: 466.7 [M+1] ⁺, Rt=1.133/2 min.

Step 3: Preparation of compound 1146-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-hydroxyphenyl) -1H-pyrrol-3-yl) -4-methylpicolinate

A 100 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 6- (5-cyclopropyl-1, 4-dioxo-1- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) phenyl) pentan-3-yl) -4-methylpicolinate (1.45 g, 2.83 mmol, 1.00 eq) , AcOH (20 mL) and 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (1.89 g, 4.25 mmol, 1.50 eq) . The reaction mixture was stirred at 100 ℃overnight. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a yellow solid (1.30 g, 58.10%) .

MS (ESI, pos. ion) m/z: 790.3 [M+1] ⁺, Rt=1.616/2 min.

Step 4: Preparation of compound 1146-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -4-methylpicolinate

A 100 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-hydroxyphenyl) -1H-pyrrol-3-yl) -4-methylpicolinate (1.30 g, 1.65 mmol, 1.00 eq) , DIEA (320 mg, 2.47 mmol, 1.50 eq) and DCM (20 mL) . The resulting was added trifluoromethanesulfonic anhydride (460 mg, 1.65 mmol, 1.00 eq) dropwise with the temperature was kept at 0 ℃. The reaction mixture was stirred at RT for 1 hour. After the reaction was completed, the reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated to afford the crude product as a yellow oil (1.40 g, 89.77%) .

MS (ESI, pos. ion) m/z: 922.2 [M+1] ⁺, Rt=1.733/2 min.

Step 5: Preparation of compound 1146-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -4-methylpicolinate

A 100 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -4-methylpicolinate (1.40 g, 1.48 mmol, 1.00 eq) and DCM (12 mL) . The resulting was added TFA (4 mL) and stirred at rt for 48 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a yellow solid (875 mg, 96.00%) .

MS (ESI, pos. ion) m/z: 682.5 [M+1] ⁺, Rt=1.192/2 min.

Step 6: Preparation of compound 1146-7: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -4-methylpicolinate

A 8 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -4-methylpicolinate (100 mg, 0.15 mmol, 1.00 eq) , CuI (3 mg, 0.02 mmol, 0.11 eq) , K₂CO₃ (21 mg, 0.15 mmol, 1.04 eq) , Pd (PPh₃) ₄ (17 mg, 0.01 mmol, 0.10 eq) , TEA (0.06 mL, 0.44 mmol, 3.05 eq) , trimethyl (prop-1-yn-1-yl) silane (50 mg, 0.45 mmol, 3.06 eq) , MeOH (0.5 mL) and DMF (3 mL) . The reaction mixture was stirred at 100 ℃ overnight under N₂. After the reaction was completed, the mixture was diluted with EA (50 mL) . The organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a yellow oil (49 mg, 58.46%) .

MS (ESI, pos. ion) m/z: 572.3 [M+1] ⁺, Rt=1.183/2 min.

Step 7: Preparation of compound 1146: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -4-methylpicolinic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -4-methylpicolinate (49 mg, 0.09 mmol, 1.00 eq) , THF (2 mL) and MeOH (2 mL) . A solution of LiOH·H₂O (11 mg, 0.26 mmol, 3.08 eq) in H₂O (2 mL) was added to the mixture. The reaction mixture was stirred at RT for 2 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was added H₂O (10 mL) and acidified with 1 N aqueous HCl solution until the pH was ～6 at 0 ℃. The resulting was extracted with EA (10 mL × 2) . The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The mixture was purified by Pre-HPLC (Puningtech-Pntulips-C18-10μm-30*250mm, A: 0.1%FA/H2O B: ACN, eluent: 30%-70% (v/v) , Flow rate 30) to afford the title product as a white solid (26 mg, 54.57%) .

MS (ESI, pos. ion) m/z: 558.2 [M+1] ⁺, Rt=0.975/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 12.85 (br s, 1H) , 7.75 (s, 1H) , 7.70 (t, J = 7.8 Hz, 1H) , 7.64 -7.62 (m, 1H) , 7.62 -7.57 (m, 2H) , 7.40 (s, 1H) , 7.37 -7.27 (m, 3H) , 6.90 (s, 1H) , 6.85 (d, J = 11.0 Hz, 1H) , 6.77 (d, J = 8.2 Hz, 1H) , 5.41 (s, 2H) , 3.20 (br d, J = 6.4 Hz, 2H) , 2.40 (s, 3H) , 2.03 (s, 3H) , 0.99 -0.86 (m, 1H) , 0.31 -0.15 (m, 4H) .

Example 104: Synthesis of compound 1147

Step 1: Preparation of compound 1147-2: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (500 mg, 0.73 mmol, 1.00 eq) , 2- (prop-2-yn-1-yloxy) tetrahydro-2H-pyran (309 mg, 2.20 mmol, 3.01 eq) , CuI (14 mg, 0.07 mmol, 0.10 eq) and Pd (PPh₃) ₄ (85 mg, 0.07 mmol, 0.10 eq) in DMF (10 mL) was added TEA (223 mg, 2.20 mmol, 3.01 eq) . The reaction mixture was stirred at 100 ℃ overnight under N₂. After the reaction was completed, the reaction mixture was diluted with EA (20 mL) . The organic layer was filtered and washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a yellow oil (235 mg, 46.56%) .

MS (ESI, pos. ion) m/z: 673.3 [M+1] ⁺, Rt=1.200/2 min.

Step 2: Preparation of compound 1147-3: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxyprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (220 mg, 0.32 mmol, 1.00 eq) in THF (5 mL) was added 4-methylbenzene-1-sulfonamide (60 mg, 0.35 mmol, 1.10 eq) . The reaction mixture was stirred at RT overnight. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the crude product as a yellow solid (168 mg, 81.72%) .

MS (ESI, pos. ion) m/z: 589.2 [M+1] ⁺, Rt=1.008/2 min.

Step 3: Preparation of compound 1147-4: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-fluoroprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A 25 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxyprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (120 mg, 0.19 mmol, 1.00 eq) and DCM (5 mL) . The resulting was added DAST (92 mg, 0.57 mmol, 3.00 eq) . The reaction mixture was stirred at RT for 3 hours. After the reaction was completed, the mixture was diluted with EA (20 mL) . The organic layer was filtered and washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the title product as a yellow oil (20 mg, 16.64%) .

MS (ESI, pos. ion) m/z: 591.2 [M+1] ⁺, Rt=1.125/2 min.

Step 4: Preparation of compound 1147: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-fluoroprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-fluoroprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (20 mg, 0.03 mmol, 1.00 eq) , THF (1 mL) and MeOH (1 mL) . The resulting was added a solution of LiOH·H₂O (5 mg, 0.12 mmol, 3.87 eq) in H₂O (1 mL) . The reaction mixture was stirred at rt for 3 hours. After the reaction was completed, the mixture was concentrated under vacuum. The residue was added H₂O (10 mL) and adjusted to pH=6 with 1N HCl. The aqueous layer was extracted EA (20 mL × 2) . The combined organic layer was washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was purified by Pre-HPLC (Welch-Xtimate-C18-7um-30*250nm, A: 0.1%FA/H2O B: ACN, eluent: 40%-80% (v/v) , Flow rate 35) to afford the title product as a yellow solid (6 mg, 33.65%) .

MS (ESI, pos. ion) m/z: 577.3 [M+1] ⁺, Rt=1.025/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.53 (br s, 1H) , 7.68 (t, J = 7.8 Hz, 1H) , 7.60 (s, 2H) , 7.57 (s, 1H) , 7.51 (s, 1H) , 7.48 -7.38 (m, 3H) , 7.05 (s, 1H) , 6.85 (d, J = 11.2 Hz, 1H) , 6.75 (d, J = 8.0 Hz, 1H) , 5.44 (s, 2H) , 5.39 (s, 1H) , 5.27 (s, 1H) , 3.23 (br d, J = 6.8 Hz, 2H) , 2.54 (s, 3H) , 1.03 -0.92 (m, 1H) , 0.35 -0.23 (m, 4H) .

Example 105: Synthesis of compound 1148

Step 1: Preparation of compound 1148-1: methyl 2- (2- (cyclopropylmethyl) -5- (3- (3, 3-diethoxyprop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (1000 mg, 1.45 mmol, 1.00 eq) , 3, 3-diethoxyprop-1-yne (930 mg, 7.26 mmol, 5.00 eq) , CuI (60 mg, 0.32 mmol, 0.22 eq) and Pd (PPh₃) ₄ (350 mg, 0.32 mmol, 0.21 eq) in DMF (20 mL) was added TEA (0.62 mL, 4.47 mmol, 3.08 eq) . The reaction mixture was stirred at 100 ℃ for 18 hours under N₂. After the reaction was completed, the reaction mixture was diluted with EA (100 mL) . The organic layer was filtered and washed with brine (100 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/2) to afford the title product as a black oil (690 mg, 71.41%) .

MS (ESI, pos. ion) m/z: 661.6 [M+1] ⁺, Rt=1.192/2 min.

Step 2: Preparation of compound 1148-2: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-oxoprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -5- (3- (3, 3-diethoxyprop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (670 mg, 1.01 mmol, 1.00 eq) in MeCN (10 mL) was added 1N HCl (4 mL) . The reaction mixture was stirred at RT for 2 hours. After the reaction was completed, the mixture was diluted with EA (20 mL) . The organic layer was filtered and washed with brine (20 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the title product as a yellow oil (375 mg, 63.57%) .

MS (ESI, pos. ion) m/z: 587.2 [M+1] ⁺, Rt=1.092/2 min.

Step 3: Preparation of compound 1148-3: methyl 2- (2- (cyclopropylmethyl) -5- (3- (3, 3-difluoroprop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

A 25 mL single-necked round bottom flask equipped with magnetic stirrer was added methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-oxoprop-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (375 mg, 0.64 mmol, 1.00 eq) and DCM (5 mL) . The resulting was added DAST (412 mg, 2.56 mmol, 4.00 eq) dropwise. The reaction mixture was stirred at RT for 3 hours. After the reaction was completed, the reaction mixture was diluted with EA (20 mL) . The organic layer was filtered and washed with brine (20 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography through silica gel (eluting with EA/PE=1/5 to 1/1) to afford the title product as a yellow oil (176 mg, 44.59%) .

MS (ESI, pos. ion) m/z: 609.1 [M+1] ⁺, Rt=1.133/2 min.

Step 4: Preparation of compound 1148: 2- (2- (cyclopropylmethyl) -5- (3- (3, 3-difluoroprop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

Into a round bottom flask equipped with a magnetic stir bar was added methyl 2- (2- (cyclopropylmethyl) -5- (3- (3, 3-difluoroprop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (166 mg, 0.27 mmol, 1.00 eq) , THF (2 mL) and MeOH (2 mL) . The resulting was added a solution of LiOH·H₂O (40 mg, 0.95 mmol, 3.55 eq) in H₂O (2 mL) . The reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated under vacuum. The residue was added H₂O (10 mL) and adjusted to pH=6 with 1N HCl. The aqueous layer was extracted EA (20 mL × 2) . The combined organic layer was washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was purified by Pre-HPLC (Puningtech-Pntulips-C18-10μm-30*250mm, A: 0.1%FA/H2O B: ACN, eluent: 30%-70% (v/v) , Flow rate 30) to afford the title product as a yellow solid (156 mg, 97.58%) .

MS (ESI, pos. ion) m/z: 595.3 [M+1] ⁺, Rt=1.058/2 min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.57 (br s, 1H) , 7.71 -7.64 (m, 2H) , 7.60 (s, 2H) , 7.57 (s, 1H) , 7.55 -7.50 (m, 2H) , 7.49 -7.43 (m, 1H) , 7.10 -6.83 (t, J = 108 Hz, 1H) , 6.96 (s, 1H) , 6.88 -6.82 (m, 1H) , 6.74 (dd, J = 1.2, 8.2 Hz, 1H) , 5.45 (s, 2H) , 3.24 (br d, J = 6.8 Hz, 2H) , 2.54 (s, 3H) , 1.04 -0.92 (m, 1H) , 0.36 -0.24 (m, 4H) .

Example 106: Synthesis of compound 1149

Step 1: Preparation of compound 1149-1: methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (prop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate

To a solution of methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (300 mg, 0.42 mmol, 1.0 eq) and trimethyl (prop-1-yn-1-yl) silane (96 mg, 0.85 mmol, 2.0 eq) in DMF (8 mL) was added TEA (0.18 mL, 1.27 mmol, 3.0 eq) , CuI (8 mg, 0.04 mmol, 0.1 eq) , TBAF (110 mg, 0.42 mmol, 1.0 eq) and Pd (PPh₃) ₂Cl₂ (30 mg, 0.04 mmol, 0.1 eq) under N₂. The reaction mixture was stirred at 60 ℃ overnight. After the reaction was completed, the mixture was diluted with H₂O (40 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to afford the crude product, which was purified by column chromatography through silica gel, eluting with 0%to 30%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (40 mg, 0.07 mmol, 15.9%) .

MS (ESI, pos. ion) m/z: 591.3 [M+1] ⁺ , Rt= 1.125/2min.

Step 2: Preparation of compound 1149: 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (prop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylic acid

To a solution of methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (prop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) -6-methylpyrimidine-4-carboxylate (40 mg, 0.07 mmol, 1.0 eq) in a mixture solvent of MeOH (2 mL) in THF (4 mL) was added a solution of LiOH (6.5 mg, 0.27 mmol, 4.0 eq) in H₂O (2 mL) . The reaction mixture was stirred at RT for 18 hours. After the reaction was completed, the mixture was adjusted to pH=5～6 with 1 M HCl, diluted with H₂O (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a white solid (15 mg, 0.03 mmol, 38.4%) .

MS (ESI, pos. ion) m/z: 577.2 [M+1] ⁺ , Rt=1.050/2min.

¹HNMR (400 MHz, DMSO-d₆) δ = 13.91 -13.11 (m, 1H) , 7.70 (t, J = 7.9 Hz, 1H) , 7.62 (s, 2H) , 7.57 (s, 1H) , 7.44 (dd, J = 2.1, 6.9 Hz, 1H) , 7.39 -7.33 (m, 1H) , 7.30 -7.22 (m, 1H) , 7.01 (s, 1H) , 6.86 (d, J = 11.0 Hz, 1H) , 6.75 (d, J = 8.5 Hz, 1H) , 5.40 (s, 2H) , 3.27 -3.16 (m, 2H) , 2.54 (s, 3H) , 2.08 (s, 3H) , 1.03 -0.91 (m, 1H) , 0.36 -0.23 (m, 4H) .

Example 107: Synthesis of compound 1150

Preparation of compound 1150: 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (prop-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid

A 10 mL drying tube equipped with mechanical stirrer were charged with methyl 2- (2- (cyclopropylmethyl) -5- (4-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate (200 mg, 0.29 mmol, 1.00 eq) , trimethyl (prop-1-ynyl) silane (0.22 mL, 1.46 mmol, 5.00 eq) , 2- [ethyl (2-hydroxyethyl) amino] ethan-1-ol (0.11 mL, 0.87 mmol, 3.04 eq) , copper (1+) iodide (11.09 mg, 0.06 mmol, 0.22 eq) , Pd (PPh₃) ₂Cl₂ (24 mg, 0.03 mmol, 0.11 eq) , triphenylphosphane (31 mg, 0.12 mmol, 0.43 eq) , potassium carbonate (81 mg, 0.58 mmol, 2.04 eq) , methanol (0.5 mL) and N, N-dimethylmethanamide (2 mL) at room temperature under N₂ atmosphere. The reaction was stirred at 100 ℃ for 18 h. After the reaction was completed, the mixture was diluted with H₂O (20 mL) , extracted with EA (10 mL × 3) . The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by Prep-HPLC (Phenomenex Gemini 150 mm *25 mm *10 um column (eluent: 60%to 95% (v/v) CH₃CN and H₂O with 0.025%HCOOH) to afford the title product as a yellow solid (25 mg, 0.04 mmol, 15.26 %) .

MS (ESI, pos. ion) m/z: 563.1 [M+1] ⁺ , Rt=1.49/3min.

¹HNMR (400 MHz, DMSO-d₆) δ = 8.96 (d, J = 5.0 Hz, 1H) , 7.62 (s, 4H) , 7.43 (dd, J = 1.6, 6.6 Hz, 1H) , 7.40 -7.32 (m, 1H) , 7.31 -7.22 (m, 1H) , 7.00 (s, 1H) , 6.87 (br d, J = 11.0 Hz, 1H) , 6.75 (br d, J = 8.3 Hz, 1H) , 5.39 (s, 2H) , 3.22 (br d, J = 6.8 Hz, 2H) , 2.08 (s, 3H) , 1.03 -0.91 (m, 1H) , 0.42 -0.18 (m, 4H) .

Test Example 1. Enzymatic activity assay against LDHA and LDHB

The test compounds with an initial concentration of 2 mM (DMSO) were subjected to a 3-fold gradient dilution using DMSO to obtain 10 concentration gradients, in two duplicate wells. 1 μL of the diluted compound solution was transferred to DMSO (49 μL) to make a 4X compound working solution. After sealing, the plate was shaken on an oscillator for 15 min. 5 μL of 4X compound working solution was added into a 384-well plate (784075, Greiner) . 50nM LDHA or LDHB buffer (200 mM Tris HCl, pH 7.4, 100 μM EDTA, and 0.01%Tween-20) was prepared. 5 μL of LDH A or LDHB solution was added into the 384-well plate. After sealing, the plate was incubated in dark at room temperature for 15 min. Preparation of 4X substrate solution: β-NADH and sodium pyruvate were dissolved in 1X buffer (200 mM Tris HCl, pH 7.4, 100 μM EDTA, and 0.01%Tween-20) . 5 μL of 4X substrate solution was added into the 384-well plate. The 384 plate was centrifuged at 1000 rpm for 1 min, and then incubated at 25 ℃ in an incubator in dark for 30 min. Preparation of 4X test solution: Diaphorase and resazurin were dissolved in 1X buffer (200 mM Tris HCl, pH 7.4, 100 μM EDTA, and 0.01%Tween-20) . 5 μL of the 4X test solution was added into the 384-well plate. The 384 plate was centrifuged at 1000 rpm for 1 min, and then incubated at 25 ℃ in an incubator in dark for 20 min. EX540-EM590 data were read on PHERAstar FSX.

%inhibition rate was calculated as follows:

average FLU of positive control group

average FLU of vehicle control group

IC₅₀ was calculated by nonlinear regression fitting the logarithm of %inhibition rate and compound concentration by using Graphpad 8.0 software. The LDHA IC₅₀ of the compounds were presented in Table 1.

Table 1 The results of enzymatic activity against LDHA and LDHB

In the table above, A<1 nM, 1≤B<10 nM, 10≤C<100 nM, D≥100 nM.

Test Example 2. Cellular activity of LDH inhibitors in Jurkat cells

The test compounds (20 mM in DMSO) were gradient diluted, 10 concentration gradients, 3-fold gradient dilution, two duplicate wells. 100 nL of the diluted compounds was transferred to a 96-well cell culture plate through Echo550. Jurkat-Cells were collected by centrifugation, (only cells with cell viability above 90%were used) . The cells were resuspended and counted, the cell suspension was spread into a 96-well cell culture plate, 100 uL culture medium, 20000 cells/well. The 96-well cell culture plate was placed in a cell incubator for 2 h. The cell supernatant in the 96-well cell culture plate was transfer to a 384-well microplate.

Prepare 1*Reaction Mixture containing lactate buffer &probe &Enzyme mix (ratio 23: 1: 1) for each reaction. The reaction mixture was added to the 384-well microplate, 10 uL/well, after mixing with cell supernatant, incubated in dark at room temperature for 30 min. The absorbance value was read at 570 nm on a multi-function microplate reader BMG.

Calculating inhibition rate as follows:

inhibition rate=100- (Signal_cmpd-Signal_{ave_pc}) / (Signal_{ave_vc}-Signal_{ave_pc}) ×100%

Signal_{ave_pc}: average signal of positive control group

Signal_{ave_vc}: average signal of negative control group

IC₅₀ was calculated by nonlinear regression fitting the logarithm of inhibition rate and compound concentration by using Graphpad 8.0 software. The Jurkat IC₅₀ of the compounds were presented in Table 2.

Table 2 Jurkat IC₅₀ results of the compounds according to the present disclosure

In the table above, A<300 nM, 300≤B<1000 nM, 1000≤C<2000 nM, D≥2000 nM.

Test Example 3. Cellular activity of LDH inhibitors in Human T cells

Cell culture

(a) Isolation of human Pan T cells from human PBMCs according to the Pan T cell isolation Kit, detailed information seen in below:

(b) Re-suspend cell pellet in 40 μL of isolation buffer per 10⁷ total cells (eg. 1 X 10⁷ human PBMCs need 40 μL of buffer, 2 X 10⁷ human PBMCs need 80 μL of buffer) ;

(c) Add 10 μL of Pan T Cell Biotin-Antibody Cocktail per 10⁷ total cells;

(d) Mix well and incubate for 5 minutes at 4 ℃;

(e) Add 30 μL of buffer per 10⁷ total cells;

(f) Add 20 μL of Pan T Cell MicroBead Cocktail per 10⁷ total cells;

(g) Mix well and incubate for 10 minutes at 4 ℃ (mix well per 5 minutes) ;

(h) Proceed to subsequent magnetic cell separation;

(i) Place LS Column in the magnetic field of a suitable MACS Separator;

(j) Prepare column by rinsing with 3 mL of isolation buffer;

(k) Apply cell suspension onto the column. Collect flow-through containing unlabeled cells, representing the enriched T cells;

(l) Wash column with 3 mL of buffer twice. Collect unlabeled cells that pass through, representing the enriched T cells, and combine with the effluent from step k (human Pan T cells) ;

(m) Gently mix the cell suspension and stain cells by Trypan Blue and count the cell density on Countess TM II automatically and determine cell number.

Compounds management

(a) Compounds stock solution: Compounds in DMSO were received following a standard protocol;

(b) Compounds storage: All Compounds in DMSO were store at RT in dessicator for short-term storage (up to 3 months) . Leftover Compounds were store at -20℃ for longer term;

(c) Culture Condition: 37℃ and air, 95%; carbon dioxide (CO2) , 5%.

Cell suspension preparation

(a) Only cells (prepared in step 1.1) with viability greater than 90%are used for assays;

(b) Dispense 100μl of cell suspension at 3w/well into 96 well microplate.

Compound treatment

(a) MTLD-002 was 3-fold serial diluted from 20mM for 10 doses in DMSO.

(b) Add 100nl serial dilution (prepare at step b) into 96 cell plate by Echo.

(d) Cells were incubated for 2h in 37℃, 5%CO2 incubator.

Detection

(a) Set up Reaction wells: Transfer 10ul sample/well into 384 well plate;

(b) Prepare 1*Reaction Mix containing lactate buffer &probe &Enzyme mix (ratio 23: 1: 1) for each reaction. Mix enough reagents for the number of assays to be performed;

(c) Add 10uL of Reaction Mix containing lactate buffer &probe &Enzyme mix into each well;

(d) Mix and incubate at room temperature for 30 minutes protected from light;

(d) Measure output on microplate reader. measure OD 570 nm.

Data analysis

%Inhibition is calculated as follow:

Signal_{ave_pc}: average signal of positive control group

Signal_{ave_vc}: average signal of negative control group

Calculate IC50 and Plot effect-dose curve of Compounds:

Calculate IC50 by fitting %inhibition values and log of compound concentrations to nonlinear regression (dose response –variable slope) with Graphpad 8.0

Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC50-X) *HillSlope) )

X: log of inhibitor concentration; Y: %Inhibition

The Human T Cell IC50 of the compounds were presented in Table 3.

Table 3 Human T Cell IC₅₀ results of the compounds according to the present disclosure

In the table above, A<300 nM, 300≤B<1000 nM, 1000≤C<2000 nM, D≥2000 nM.

Test Example 4. LDH Cellular Assay in Male CD1 Mouse Hepatocytes

All test compounds were 3-fold serial diluted from 20mM (DMSO) for 10 doses in DMSO. 100nl serial dilution was added into 96 cell plate by Echo. Cells were collected, resuspend and counted (Williams Medium E. Only cells with viability greater than 90%were used) .

100μl of cell suspension was dispensed at 2w/well into 96 well microplate. Cells were incubated for 2h in 37℃, 5%CO2 incubator. 10ul sample/well were transferred into 384 well plate.

Prepare 1*Reaction Mixture containing lactate buffer & probe & Enzyme mix (ratio 23: 1: 1) for each reaction.

10uL of Reaction Mixture were added into each well and then mixed and incubated at room temperature for 30 minutes protected from light. Output on microplate reader was measured, at OD 570 nm.

%Inhibition is calculated as follows:

%inhibition =100- (Signal_cmpd-Signal_{Ave_PC}) / (Signal_{Ave_VC}-Signal_{Ave_PC}) ×100

Signal_{ave_pc}: The average signal for the positive controls across the plate.

Signal_{ave_vc}: The average signal for negative controls across the plate.

Calculate IC50 by fitting %inhibition values and log of compound concentrations to nonlinear regression (dose response –variable slope) with Graphpad 8.0. Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC50-X) *HillSlope) ) X: log of inhibitor concentration; Y: %Inhibition. The Primary Mouse Hepatocytes IC₅₀ of the compounds were presented in Table 4.

Table 4 Primary Mouse Hepatocytes IC₅₀ results of the compounds according to the present disclosure

In the table above, A<100 nM, 100≤B<500 nM, 500≤C<1000 nM, D≥1000 nM.

Test Example 5. In vivo pharmacokinetic assay in CD1 mice

In vivo pharmacokinetic assay in CD1 mice of the compounds disclosed herein

Taking CD1 mice as test animals, the pharmacokinetics in plasma of mice of the compounds disclosed herein administered by intravenous injection (iv) or oral administration (p.o. ) was studied.

1. Experimental protocol

1.1 Experimental chemicals

The compounds disclosed herein.

1.2 Experimental animals

CD1 mice (3 mice/group) , male, Shanghai Lingchang Biotechnology Co., Ltd

1.3 Administration

CD1 mice, 6, male; After free feeding, the mice were administered by iv and p.o. respectively. The dose administered by iv was 4 mg/kg, and the volume administered was 5 mL/kg. The dose administered by p.o was 20mg/kg, and the volume administered was 10mL/kg.

1.4 Experimental equipment

Centrifuge (5810R) was purchased from Eppendorf, pipette from Eppendorf, and vortex instrument from Scientific Industries.

1.5 Sample collection

After administration, 0.1 mL of blood was collected from saphenous vein at 0.0833 (iv) , 0.25, 0.5, 1, 2, 4, 8 and 24 hours, placed in EDTA-K2 tube, centrifuged at 4600 rpm at 4 ℃ for 5 min, and the plasma was isolated and stored at -80 ℃.

1.6 Sample handling

1) The plasma sample (50μL) was precipitated by adding methanol/ethyl alcohol (1/1) (200μL) , and centrifuged for 15 minutes after mixing.

2) After the treatment, 50 μ L of the supernatant solution was dissolved in the diluent (methanol/water=1/1 containing 0.1%formic acid) , and the concentration of the compound to be tested was analyzed by LC/MS/MS.

1.7 Liquid chromatography analysis

Liquid chromatography conditions: ShimadzuLC-30AD pump.

Mass spectrometry conditions: ABSciexAPI5500 mass spectrometer.

Chromatographic column: PhenomenexKinetex2.6 um C18 50 3.0 mm.

Mobile phase: Solution A is 0.1%formic acid 50 mmol ammonium acetate solution, and solution B is 0.1%formic acid acetonitrile.

Flow rate: 0.7 mL/min.

Elution time: gradient elution 0-3.0 minutes.

2. Experimental results and analysis

The following pharmacokinetic parameters were calculated by using WinNonlin8.0 software. The pharmacokinetic parameters of oral administration and IV administration in mice are shown in the following table 5. Compared with the known structures comparative compound 1 and comparative compound 2, the compounds of the invention have better pharmacokinetic properties, particularly half-life, bioavailability, AUC_last, CI and Vss,

Table 5 The pharmacokinetic parameters of oral administration and IV administration in mice

Claims

A compound of Formula I,

a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof, wherein:

Z₁ and Z₂ are each independently selected from CH and N;

ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:

X₁, X₂, X₃, X₄, and X₅ are each independently selected from CR₅ and NR₅;

wherein three or four of X₁, X₂, X₃, X₄, and X₅ are CR₅;

wherein each R₅ is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl;

and wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 nitrogen atoms;

wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR_c, -CONR_dR_e, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and SO₂NR_dR_e;

and wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

R₃ is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and substituted or unsubstituted five-to ten-membered heteroaryloxy groups with one or two or three heteroatoms each independently selected from N, O, and S; or R₃ and X₂ together form

wherein the substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups;

L₁ is selected from -CR₁R₂-, -CO-, -O-, -NH-, and -S-;

wherein R₁ and R₂ are each independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and wherein the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R₁ and R₂, together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;

ring B is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic alkyl, substituted or unsubstituted six-to ten-membered aryl, and substituted or unsubstituted five-to ten-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S;

wherein each substituent group is independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

R₄ is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO₂NR_aR_b, -CONR_aR_b, and -N (C1-C6 alkyl) (C1-C6 alkyl) ;

wherein R_a and R_b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups;

and wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH₂, -NH-COOH, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups;

n is an integer selected from 0, 1, 2, 3, and 4;

L₂ is a linker comprising an unsaturated or aromatic moiety, preferably L₂ is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S; optionally wherein each hydrogen in L₂ is each independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;

Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with 1 to 3 hetero atoms each independently selected from N, O and S;

wherein the substituent group is each independently selected from oxo, halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, amino group, -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , and -N (C1-C6 alkyl) (C1-C6 alkyl) ;

with the proviso that ring A is not a pyrazole ring.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 1,

wherein ring A comprises a structure selected from:

*is the position connecting Ar₁.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 1 or 2,

wherein Ar₁ has a structure selected from:

wherein R₆ is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR_c, -CONR_dR_e, and -SO₂NR_dR_e, wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

wherein m is 0, 1 or 2.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 1,

wherein Ar₁ iswherein E₁, E₂, E₃ and E₄ are each independently selected from N and CR_f, and at least one of E₁, E₂, E₃ and E₄ is N; R_f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R_c is hydrogen or C1-C6 alkyl groups.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4,

wherein L₂ is selected from wherein R’ is selected from a halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5,

wherein Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, -CH₃, -CF₃, -CF₂H, -CH₂-CF₃, -O-CH₃, -O-CF₃, -O-CF₂H, -O-CH₂-CF₃, -CD₃, -CN,
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6,

wherein R₃ is selected from substituted C1-C6 alkyl groups, C6-C10 aryloxy, C3-C6 cycloalkoxy and substituted C1-C6 alkoxyl groups, wherein the substituent group is independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, phenyl, and C3-C6 cycloalkyl groups; or R₃ and X₂ together form
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7,

wherein R₃ is selected fromor R₃ and X₂ together form
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 8,

wherein ring B is selected from wherein ring B is optionally substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 8,

wherein R₅ is selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, -CF₃, -CH₂OH, and -NH-COOH.
A compound of Formula II

a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof, wherein:

Z₁ and Z₂ are each independently selected from CH and N;

ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:

X₁, X₂, X₃, X₄, and X₅ are each independently selected from CR₅ and NR₅;

wherein three or four of X₁, X₂, X₃, X₄, and X₅ are CR₅;

wherein each R₅ is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl, wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

Y₁, Y₂, Y₃, and Y₄ of ring B, are each independently selected from CR₇ and NR₇;

Y₅ of ring B is absent, CR₇ or NR₇;

wherein each R₇ is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;

Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 nitrogen atoms;

wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR_c, -CONR_dR_e, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and SO₂NR_dR_e; and wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

R₃ is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and substituted or unsubstituted five-to ten-membered heteroaryloxy groups with one or two or three heteroatoms each independently selected from N, O, and S; or R₃ and X₂ together form

wherein the substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups;

L₁ is selected from -CR₁R₂-, -CO-, -O-, -NH-, and -S-;

wherein R₁ and R₂ are each independently selected from H, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and wherein the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R₁ and R₂, together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;

R₄ is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO₂NR_aR_b, -CONR_aR_b, and -N (C1-C6 alkyl) (C1-C6 alkyl) ;

wherein R_a and R_b are each independently selected from H, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups;

and wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH₂, -NH-COOH, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups;

n is an integer selected from 0, 1, 2, 3, and 4;

L₂ is a linker comprising an unsaturated or aromatic moiety, preferably L₂ is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S; optionally wherein each hydrogen in L₂ is each independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;

Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with 1 to 3 hetero atoms each independently selected from N, O and S;

wherein the substituent group is each independently selected from oxo, halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, amino group, -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , and -N (C1-C6 alkyl) (C1-C6 alkyl) ;

with the proviso that ring A is not a pyrazole ring.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 11, wherein Formula II comprises the following Formula II-1 and II-2:
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 11, wherein Formula II comprises the following Formula II-3, II-4, and II-5
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 13,

wherein ring A comprises a structure selected from:

*is the position connecting Ar₁.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 14,

wherein Ar₁ has a structure selected from:

wherein R₆ is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR_c, -CONR_dR_e, and -SO₂NR_dR_e, wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

wherein m is 0, 1 or 2.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 14,

wherein Ar₁ iswherein E₁, E₂, E₃ and E₄ are each independently selected from N and CR_f, and at least one of E₁, E₂, E₃ and E₄ is N; R_f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R_c is hydrogen or C1-C6 alkyl groups.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 16,

wherein L₂ is selected from wherein R’ is selected from a halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 16,

wherein Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, -CH₃, -CF₃, -CF₂H, -CH₂-CF₃, -O-CH₃, -O-CF₃, -O-CF₂H, -O-CH₂-CF₃, -CD₃, -CN,
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 18,

wherein R₃ is selected from substituted C1-C6 alkyl groups, C6-C10 aryloxy, C3-C6 cycloalkoxy and substituted C1-C6 alkoxyl groups, wherein the substituent group is independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, phenyl, and C3-C6 cycloalkyl groups; or R₃ and X₂ together form
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 19,

wherein R₃ is selected fromor R₃ and X₂ together form
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 20,

wherein ring B is selected from wherein ring B is optionally substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 11 to 21,

wherein R₅ is selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, -CF₃, -CH₂OH, and -NH-COOH.
A compound of Formula III

a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof, wherein,

Z₁ and Z₂ are each independently selected from CH and N;

ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:

X₁, X₂, X₃, X₄, and X₅ are each independently selected from CR₅ and NR₅;

wherein three or four of X₁, X₂, X₃, X₄, and X₅ are CR₅;

wherein each R₅ is independently absent or selected from hydrogen halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl, wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO₂N (C1-C6 alkyl) (C1-C6 alkyl) ;

Y₁, Y₂, Y₃, and Y₄ of ring B, are each independently selected from C (R₇) ₂ and NR₇;

Y₅ and Y₆ of ring B are each independently absent, C (R₇) ₂ or NR₇;

wherein each R₇ is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;

Ar₁ is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 nitrogen atoms;

wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR_c, -CONR_dR_e, -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and SO₂NR_dR_e; and wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

R₃ is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and substituted or unsubstituted five -to ten-membered heteroaryloxy groups with one or two or three heteroatoms each independently selected from N, O, and S; or R₃ and X₂ together form

wherein the substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups;

L₁ is selected from -CR₁R₂-, -CO-, -O-, -NH-, and -S-;

wherein R₁ and R₂ are each independently selected from H, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and wherein the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R₁ and R₂, together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;

R₄ is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO₂NR_aR_b, -CONR_aR_b, and -N (C1-C6 alkyl) (C1-C6 alkyl) ;

wherein R_a and R_b are each independently selected from H, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups;

and wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH₂, -NH-COOH, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups;

n is an integer selected from 0, 1, 2, 3, and 4;

L₂ is a linker comprising an unsaturated or aromatic moiety, preferably L₂ is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S; optionally wherein each hydrogen in L₂ is each independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;

Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with 1 to 3 hetero atoms each independently selected from N, O and S;

wherein the substituent group is each independently selected from oxo, halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, amino group, -C (O) NH₂, -NH-COOH, -NH (C1-C6 alkyl) , and -N (C1-C6 alkyl) (C1-C6 alkyl) ;

with the proviso that ring A is not a pyrazole ring.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 23, wherein Formula III comprises the following Formula III-1 and Formula III-2:
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 23, wherein Formula III comprises the following Formula III-3, Formula III-4, and Formula III-5:
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to claim 23, wherein Formula III comprises the following Formula III-6, Formula III-7, and Formula III-8:
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 26,

wherein ring A comprises a structure selected from: *is the position connecting Ar₁.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 27,

wherein Ar₁ has a structure selected from:

wherein R₆ is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR_c, -CONR_dR_e, and -SO₂NR_dR_e, wherein R_c, R_d, and R_e are each independently selected from hydrogen, and C1-C6 alkyl groups;

wherein m is 0, 1 or 2.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 28,

wherein Ar₁ iswherein E₁, E₂, E₃ and E₄ are each independently selected from N and CR_f, and at least one of E₁, E₂, E₃ and E₄ is N; Rf is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R_c is hydrogen or C1-C6 alkyl groups.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 29,

wherein L₂ is selected from wherein R’ is selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 29,

wherein Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH₂, -C (O) N (CH₃) ₂, -NH-COOH, -CH₃, -CF₃, -CF₂H, -CH₂-CF₃, -O-CH₃, -O-CF₃, -O-CF₂H, -O-CH₂-CF₃, -CD₃, -CN,
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 31,

wherein R₃ is selected from substituted C1-C6 alkyl groups, C6-C10 aryloxy, C3-C6 cycloalkoxy and substituted C1-C6 alkoxyl groups, wherein the substituent group is independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, phenyl, and C3-C6 cycloalkyl groups; or R₃ and X₂ together form
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 32,

wherein R₃ is selected fromor R₃ and X₂ together form
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 33,

wherein ring B is selected from wherein ring B is optionally substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups.
The compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 23 to 34,

wherein R₅ is selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, -CF₃, -CH₂OH, and -NH-COOH.
A compound having a structure selected from:

or a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound, a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36.
A method of inhibiting lactate dehydrogenase A activity in a cell, comprising: administering to a subject an effective amount of a compound a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 or a composition according to claim 37.
A method of treating or preventing a disease associated with lactate dehydrogenase A activity, comprising administering to a subject an effective amount of a compound, a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 or a composition according to claim 37.
The method of claim 39, wherein the disease associated with lactate dehydrogenase A activity is an autoimmune disorder.
The method of claim 40, wherein the autoimmune disorder is selected from: autoimmune disorders of the nervous system, autoimmune disorders of the blood, autoimmune disorders of the blood vessels, autoimmune disorders of the skin, autoimmune disorders of the gastrointestinal system, autoimmune disorders of the endocrine glands, autoimmune disorders of multiple organs including connective tissue and musculoskeletal system diseases, and other immune system mediated diseases including graft-versus-host diseases and allergic disorders.
The method of claim 41, wherein the autoimmune disorders of the nervous system are selected from multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barré, and autoimmune uveitis;

wherein the autoimmune disorders of the blood are selected from autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia;

wherein the autoimmune disorders of the blood vessels are selected from temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener’s granulomatosis, and Behcet’s disease;

wherein the autoimmune disorders of the skin are selected from cutaneous lupus erythematosus, Steven-Johnson syndrome, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo;

wherein the autoimmune disorders of the gastrointestinal system are selected from Crohn’s disease, ulcerative colitis, chronic active hepatitis, idiopathic sprue, autoimmune inflammatory bowel disease, irritable bowel syndrome, alcoholic liver disease, nonalcoholic liver disease, nonalcoholic fatty liver, primary biliary cirrhosis, and autoimmune hepatitis;

wherein the autoimmune disorders of the endocrine glands are selected from Type 1 or immune-mediated diabetes mellitus, Grave’s disease, Hashimoto’s thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland;

wherein the autoimmune disorders of multiple organs are selected from rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies selected from ankylosing spondylitis, polychondritis, celiac disease, periodontitis, hyaline membrane disease, glomerular disease, endocrine opthalmopathy, Lupus nephritis, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, and Sjogren’s syndrome; and

wherein the allergic disorders are selected from allergic rhinitis, sinusitis, rhinosinusitis, chronic or recurrent otitis media, ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma, and food allergies.
The method of claim 41, wherein the autoimmune disorder is a kidney disease selected from hyperoxaluria, chronic kidney disease, end stage renal disease and kidney stone disease; and wherein the hyperoxaluria is selected from primary hyperoxaluria type 1, primary hyperoxaluria type 2, primary hyperoxaluria type 3, and secondary hyperoxaluria.
The method of any one of claims 40-43, wherein the compound, the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt, or the composition is administered once daily, twice daily, or three times daily.
Use of a compound, a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 to manufacture a medicament in treating or preventing a disease associated with lactate dehydrogenase A activity.
The compound, a stereoisomer, a tautomer, an isotope labeled compound, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 for use in treating or preventing a disease associated with lactate dehydrogenase A activity.