Heterocyclic derivatives, compositions thereof and uses thereof

Abstract

The present invention relates to heterocyclic derivatives of formula (I) and pharmaceutical compositions thereof, processes for their preparation, and their use as therapeutic agents.

Description

Technical Field

[0001] This invention relates to heterocyclic derivatives as modulators of PPARγ activity. The invention also relates to methods for preparing heterocyclic derivatives, pharmaceutical compositions, and their use in treating diseases or conditions including diabetes, autoimmune diseases, inflammation, cardiovascular diseases, neurodegenerative diseases, and especially cancers characterized by PPARγ overactivation (gain-of-function mutations, amplification, or overexpression) or RXRα gain-of-function mutations (e.g., S427F / Y). Background Technology

[0002] Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the ligand-dependent nuclear receptor superfamily and is involved in a variety of physiological and pathological processes (Tianchen Peng, 2020). Upon binding to a specific ligand, PPARγ is activated, forming a heterodimer with retinoic acid X receptors (RXRs), which then bind to PPAR response elements (PPREs) in the promoter region, thereby regulating the expression of numerous downstream genes. PPARγ is mainly expressed in adipose tissue, colon, macrophages, and the urothelial layer, but is almost absent in muscle tissue. PPARγ's most well-defined role is as a master regulator of adipogenesis, regulating lipid metabolism, adipocyte differentiation / maintenance, and insulin sensitivity (Andrew Hartley, 2022). Furthermore, PPARγ has been shown to play important roles in immune regulation, tumor angiogenesis and metastasis, anti-tumor cell proliferation, and tumor cell apoptosis.

[0003] Numerous studies have revealed the relationship between PPARγ and various tumors. Evidence suggests that PPARγ influences cancer development and progression by regulating proliferation, apoptosis, metastasis, and reactive oxygen species (ROS) and lipid metabolism (Cheng S, 2019; Cao R, 2018). Recent studies have found overexpression or genetic alterations of PPARγ in the luminal subtype of urothelial carcinoma, which is correlated with the long-term use of PPARγ agonists such as thiazolidinediones (TZDs) (Azoulay L, 2012). Simultaneously, RXRα amplification or genetic alterations have also been found in various tumors. It is speculated that mutations in RXRα, especially enhancing mutations (such as RXRαS427F / Y), may lead to enhanced binding between PPARγ and RXRα proteins, thereby continuously activating downstream gene expression and ultimately promoting cancer development and progression.

[0004] Bladder cancer is one of the most common malignant tumors of the urinary system (Siegel RL, 2016). Approximately 70% of newly diagnosed patients have non-muscle-invasive bladder cancer (NMIBC), of which 10%-20% will progress to muscle-invasive bladder cancer (MIBC) (Yun SJ, 2016). PPARγ gene amplification accounts for approximately 10% of bladder cancer tumor samples, while RXRα mutation accounts for approximately 5%. Studies have shown that drug inhibition or gene knockout of the PPARγ gene can inhibit the growth of various urothelial carcinoma cells. Currently, the main treatments for bladder cancer patients are radical cystectomy and intravesical chemotherapy, but treatment options are limited and overall survival is low. In addition, patients with liver cancer, breast cancer, prostate cancer, follicular thyroid cancer, etc., are also potential candidates for PPARγ modulators. Therefore, there is an urgent need to develop effective PPARγ modulators for cancer treatment. Summary of the Invention

[0005] This invention relates to a compound represented by formula (I).

[0006]

[0007] Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound thereof; wherein the definitions of each variable are as defined in this invention.

[0008] On the other hand, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug or deuterated compound thereof, and at least one pharmaceutically acceptable carrier.

[0009] On the other hand, the present invention also provides a combination, particularly a pharmaceutical combination, comprising the compound of formula (I) as described in the present invention and one or more therapeutic agents.

[0010] On the other hand, the present invention also provides a method for inhibiting PPARγ, comprising: contacting PPARγ with a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug or deuterated compound thereof.

[0011] On the other hand, the present invention also provides the use of the compound shown in formula (I) in the preparation of a therapeutic drug, particularly for treating diseases or conditions that can be treated by inhibiting PPARγ function.

[0012] On the other hand, the present invention also provides the use of the compound shown in formula (I) in the preparation of a treatment for cancer, in particular, the cancer being characterized by PPARγ functional activation (activation mutation, amplification or overexpression) or RXRα activation mutation (e.g. S427F / Y).

[0013] On the other hand, the present invention also provides a method for treating cancer, particularly characterized by PPARγ functional activation (gain-of-function mutation, amplification, or overexpression) or RXRα gain-of-function mutation (e.g., S427F / Y), as well as other diseases, the method comprising administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound thereof.

[0014] Details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will become apparent from the specification and claims. Invention Details

[0016] The invention can be more fully understood by referring to the following description, including the definitions and embodiments. Certain features of the compositions and methods of the invention described in different contexts may also be provided in combination in a single aspect. Alternatively, for the sake of brevity, various features of the compositions and methods of the invention described in the context of a single aspect may also be provided individually or in any sub-combination.

[0017] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein, and it should also be understood that the terminology used in the present invention is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention.

[0018] This invention particularly relates to a compound represented by formula (I):

[0019]

[0020] Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound, wherein:

[0021] X 1 For N or CR 1 ;

[0022] X 2 For N or CR 4 ;

[0023] Y 1 For N or CR 7 ;

[0024] Y 2 For N or CR 8 ;

[0025] Y 3 For N or CR 10 ;

[0026] R 1 Selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a ;

[0027] R 2 Selected from D, NO2, N3, SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups having one heteroatom selected from Si, O-C0-C4 alkyl-Cy, OYZ, C0-C4 alkyl-OCy, C0-C4 alkyl-NR CCy, C0-C4 alkyl-SCy, C0-C4 alkyl-C(O)Cy, C0-C4 alkyl-C(O)OCy, C0-C4 alkyl-C(O)NR C Cy, NR C COCy, NR C CO2Cy, NR C C(S)OCy, NR C C(O)NR C Cy, NR C C(S)NR C Cy, NR C SO2NR C Cy, C(S)Cy, C(S)OCy, C(S)NR C Cy, NR C C(S)Cy, SOCy, SO2Cy, SONR C Cy, SiR G R H R I B(OR) C (OR) D ), P(O)R E R F P(O)OR E OR F OP(O)OR E OR F ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group having one heteroatom selected from Si and optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents of R; and R 2 Not CH3;

[0028] Each R 2A Each of the following is independently selected from H, D, halogen, CN, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclic, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D NRC C(O)R D NR C C(O)NR C R D NR C C(O)OR A SiR G R H R I B(OR) C (OR) D ), C(=NR) C )NR C R D NR D C(=NR C )NR C R D NR D C(=NR C )R B P(O)R E R F P(O)OR E OR F OP(O)OR E OR F S(O)R B S(O)NR C R D S(O)2R B NR C S(O)2R B S(O)2NR C R D NR C S(O)2NR C R D S(O)(=NR) C )R B or NR C S(O)(=NR C )R B ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic group, OR a SR a C(O)R b C(O)NR c R d C(O)ORa OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2;

[0029] Cy is a phenyl group, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic; wherein the phenyl group is C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic groups optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)2NR c R d ;

[0030] Y is a C1-C4 alkyl group or a C3-C6 alkenyl group;

[0031] Z represents CN, N3, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D NR C C(O)R D NR C C(O)NR C R D NR C C(O)OR A SiR G R H R I B(OR) C (OR) D ), C(=NR) C )NR C R D NR D C(=NR C )NRC R D NR D C(=NR C )R B P(O)R E R E P(O)OR E OR F OP(O)OR E OR F S(O)R B S(O)NR C R D S(O)2R B NR C S(O)2R B S(O)2NR C R D NR C S(O)2NR C R D S(O)(=NR) C )R B or NR C S(O)(=NR C )R B ;

[0032] R 3 H, D, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl; or

[0033] R 1 and R 2 Or R 2 and R 3 Together with the atoms attached thereto, it forms a phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group; wherein the phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independently selected substituents from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NRc C(O)NR c R d NR c C(O)OR a ;

[0034] R 4 For H, D, halogen, CN;

[0035] R 5 Selected from H, D, halogens, OH, CH3, CF3, CHF2, CH2F;

[0036] R 6 Selected from halogens, OS(O)2R 6A SR 6A S(O)R 6A S(O)OR 6A S(O)2R 6A S(O)2OR 6A S(O)2NR 6A R 6B S(O)(=NR) 6A )R 6B ;

[0037] R 6A and R 6B Each of the following is independently selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-OC1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-NHC1-C4 alkyl, C1-C4 alkyl-N(C1-C4 alkyl)2, optionally halogenated C3-C4 cycloalkyl, optionally halogenated, C1-C4 alkyl, C1-C4 haloalkyl-substituted phenyl;

[0038] R 7 and R 10 Each is independently selected from H and D;

[0039] R 8 Selected from H, D, halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl;

[0040] R 9 Selected from CF3, SF5, CN, NC, NO2;

[0041] Or R 8 and R 9 Together with the atoms to which it is attached, a 5-membered heteroaryl group is formed, which is optionally oxidized;

[0042] R A and R aEach of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2;

[0043] R B and R b Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2;

[0044] R C R D R c and R d Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2;

[0045] Or R C and RD Or R c and R d Together with the N atom to which it is attached, it forms a 4-6 membered heterocyclic group, which may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, halogen, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;

[0046] R E and R e Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl;

[0047] R F and R f Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl;

[0048] R G R H R I R g R h and R i Each is independently selected from C1-C4 alkyl or phenyl groups.

[0049] In some implementations, X 1 For CR 1 X 2 For CR 4 .

[0050] In some implementations, X 1 For CR 1 X 2 Let N be the number of elements in the array.

[0051] In some implementations, X 1 Let N, X 2 For CR 4 .

[0052] In some implementations, R 1 Selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R BOC(O)NR C R D NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0053] In some implementations, R 1 For H. In some implementations, R 1 The answer is D.

[0054] In some implementations, R 1 It is a halogen. In some embodiments, R 1 It is F, Cl, Br, or I. In some embodiments, R 1 It is F.

[0055] In some implementations, R 1 For CN.

[0056] In some implementations, R 1 The C1-C6 alkyl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R bOC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a In some implementations, R 1 It is CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CH2CH(CH3)2, C(CH3)3.

[0057] In some implementations, R 1 The C2-C6 alkenyl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0058] In some implementations, R 1 The C2-C6 alkynyl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R dNR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0059] In some implementations, R 1 The C3-C6 cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0060] In some implementations, R 1 OR A R A It is H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2. In some embodiments, R 1It is OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3.

[0061] In some implementations, R A For H. In some implementations, R A The answer is D.

[0062] In some implementations, R A The C1-C6 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0063] In some implementations, R A For C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0064] In some implementations, R A It is a 4-6 membered heterocyclic -C0-C4 alkyl group optionally substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0065] In some implementations, R A The phenyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2. In some embodiments, R A It is phenyl, CH2-phenyl; each is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0066] In some implementations, R AIt is a 5-6-membered heteroaryl-C0-C4 alkyl group optionally substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0067] In some implementations, R A It is pyrroloyl, pyrazolyl, thiadiazolyl, pyridyl, pyrimidinyl; each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0068] In some implementations, R 1 For SR A In some implementations, R 1 For C(O)R B In some implementations, R 1 For C(O)NR C R D In some implementations, R 1 C(O)OR A In some implementations, R 1 For OC(O)R B In some implementations, R 1 For OC(O)NR C R D In some implementations, R 1 For NR C R D .

[0069] In some implementations, R 2 Selected from D, NO2, N3, SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups having one heteroatom selected from Si, O-C0-C4 alkyl-Cy, OYZ, C0-C4 alkyl-OCy, C0-C4 alkyl-NR C Cy, C0-C4 alkyl-SCy, C0-C4 alkyl-C(O)Cy, C0-C4 alkyl-C(O)OCy, C0-C4 alkyl-C(O)NR C Cy, NR C COCy, NR C CO2Cy, NR C C(S)OCy, NR C C(O)NR CCy, NR C C(S)NR C Cy, NR C SO2NR C Cy, C(S)Cy, C(S)OCy, C(S)NR C Cy, NR C C(S)Cy, SOCy, SO2Cy, SONR C Cy, SiR G R H R I B(OR) C (OR) D ), P(O)R E R F P(O)OR E OR F OP(O)OR E OR F ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group having one heteroatom selected from Si and optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted.

[0070] In some implementations, R 2 For D. In some implementations, R 2 It is NO2. In some implementations, R 2 For N3. In some implementations, R 2 It is SF5.

[0071] In some implementations, R 2 The C1-C6 alkyl group is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents of R are substituted, and R 1 It is not CH3.

[0072] In some implementations, R 2 The possible values ​​are CH2CN, CH2CH2CN, CH(OH)CF3, and CH(OCH3)CF3.

[0073] In some implementations, R 2 The C2-C6 alkenyl group is optionally surrounded by 1, 2, 3, 4, or 5 independent groups selected from R 2A Substituents are substituted. In some embodiments, R 2 for

[0074] In some implementations, R 2The C2-C6 ynyl group is optionally surrounded by 1, 2, 3, 4, or 5 independent groups selected from R 2A Substituents are substituted.

[0075] In some implementations, R 2 for

[0076] In some implementations, R 2 For C3-C 10 The cycloalkyl group is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted. In some embodiments, R 2 Cyclopropyl or cyclobutyl; each optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted.

[0077] In some implementations, R 2 The 4-10 membered heterocyclic group has one heteroatom selected from Si and optionally surrounded by 1, 2, 3, 4, or 5 independent atoms selected from R. 2A Substituents are substituted.

[0078] In some implementations, R 2 It is an O-C0-C4 alkyl-Cy.

[0079] In some implementations, R 2 for

[0080] In some implementations, R 2 OYZ, where Y is a C1-C4 alkyl group and Z is CN, N3, or OR. A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D NR C C(O)R D NR C C(O)NR C R D NR C C(O)OR A SiR G R H R I B(OR) C)(OR D ), C(=NR C )NR C R D , NR D C(=NR C )NR C R D , NR D C(=NR C )R B , P(O)R E R F , P(O)OR E OR F , OP(O)OR E OR F , S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , NR C S(O)2NR C R D , S(O)(=NR C )R B or NR C S(O)(=NR C )R B .

[0081] In some embodiments, R 2 is O-Y-Z, Y is a C3-C6 alkenyl group, and Z is CN, N3, OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , SiR G R H R I , B(ORC (OR) D ), C(=NR) C )NR C R D NR D C(=NR C )NR C R D NR D C(=NR C )R B P(O)R E R F P(O)OR E OR F OP(O)OR E OR F S(O)R B S(O)NR C R D S(O)2R B NR C S(O)2R B S(O)2NR C R D NR C S(O)2NR C R D S(O)(=NR) C )R B or NR C S(O)(=NR C )R B .

[0082] In some implementations, R 2 It is a C0-C4 alkyl-OCy. In some embodiments, R 2 C0-C4 alkyl-NR C Cy. In some implementations, R 2 It is a C0-C4 alkyl-SCy.

[0083] In some implementations, R 2 It is a C0-C4 alkyl-C(O)Cy. In some embodiments, R 2 It is a C0-C4 alkyl-C(O)OCy. In some embodiments, R 2 C0-C4 alkyl-C(O)NR C Cy.

[0084] In some implementations, R 2 For NR C COCy. In some implementations, R 2 For NR CCO2Cy. In some implementations, R 2 For NR C C(S)OCy. In some implementations, R 2 For NR C C(O)NR C Cy. In some implementations, R 2 For NR C C(S)NR C Cy. In some implementations, R 2 For NR C SO2NR C Cy.

[0085] In some implementations, R 2 For C(S)Cy. In some implementations, R 2 For C(S)OCy. In some implementations, R 2 For C(S)NR C Cy. In some implementations, R 2 For NR C C(S)Cy.

[0086] In some implementations, R 2 For SOCy. In some implementations, R 2 For SO2Cy. In some implementations, R 2 For SONR C Cy.

[0087] In some implementations, each R 2A Each of the following is independently selected from H, D, halogen, CN, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclic, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D NR C C(O)R D NR C C(O)NR C R D NR C C(O)ORA SiR G R H R I B(OR) C (OR) D ), C(=NR) C )NR C R D NR D C(=NR C )NR C R D NR D C(=NR C )R B P(O)R E R F P(O)OR E OR F OP(O)OR E OR F S(O)R B S(O)NR C R D S(O)2R B NR C S(O)2R B S(O)2NR C R D NR C S(O)2NR C R D S(O)(=NR) C )R B or NR C S(O)(=NR C )R B ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic group, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NRc C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0088] In some implementations, each R 2A Each is independently selected from H. In some implementations, each R... 2A Each is independently selected from D. In some implementations, each R 2AEach R is independently selected from halogens (e.g., F, Cl, Br, I). In some embodiments, each R 2A Each is independently selected from CN. In some implementations, each R 2A They were each independently selected from the oxidative process.

[0089] In some implementations, each R 2A Each alkyl group independently selected from C1-C6 is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R bS(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0090] In some implementations, each R 2A Each of the C2-C6 alkenyl groups is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)Re R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0091] In some implementations, each R 2A Each of the C2-C6 alkynyl groups is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R iB(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0092] In some implementations, each R 2A Selected independently from C6-C 10 The aryl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NRc R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0093] In some implementations, each R 2A Selected independently from C3-C10 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NRc )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0094] In some implementations, each R 2A Each of the 5-10 membered heteroaryl groups is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c Rd S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0095] In some implementations, each R 2A Each of the 4-10 membered heterocyclic groups is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c Rd NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0096] In some implementations, each R 2A Selected independently from OR A In some implementations, each R 2A Selected independently from SR A .

[0097] In some implementations, each R 2A Selected independently from C(O)R B In some implementations, each R 2A Selected independently from C(O)NR C R D In some implementations, each R 2A Selected independently from C(O)OR A In some implementations, each R 2A Selected independently from OC(O)R B In some implementations, each R 2A Selected independently from OC(O)NR C RD .

[0098] In some implementations, each R 2A Selected independently from NR C R D In some implementations, each R 2A Selected independently from NR C C(O)R D In some implementations, each R 2A Selected independently from NR C C(O)NR C R D In some implementations, each R 2A Selected independently from NR C C(O)OR A .

[0099] In some implementations, each R 2A Selected independently from SiR G R H R I In some implementations, each R 2A They were each independently selected from Si(CH3)3.

[0100] In some implementations, each R 2A Each independently selected from B(OR) C (OR) D In some implementations, each R 2A Each independently selected from C(=NR) C )NR C R D In some implementations, each R 2A Selected independently from NR D C(=NR C )NR C R D In some implementations, each R 2A Selected independently from NR D C(=NR C )R B .

[0101] In some implementations, each R 2A Selected independently from P(O)R E R F In some implementations, each R 2A Selected independently from P(O)OR E OR F In some implementations, each R 2AEach is independently selected from OP(O)OR E OR F .

[0102] In some implementations, each R 2A Selected independently from S(O)R B In some implementations, each R 2A Selected independently from S(O)NR C R D In some implementations, each R 2A Selected independently from S(O)2R B In some implementations, each R 2A Selected independently from NR C S(O)2R B In some implementations, each R 2A Selected independently from S(O)2NR C R D In some implementations, each R 2A Selected independently from NR C S(O)2NR C R D In some implementations, each R 2A Each is independently selected from S(O)(=NR) C )R B In some implementations, each R 2A Selected independently from NR C S(O)(=NR C )R B .

[0103] In some embodiments, Cy is phenyl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic; wherein the phenyl group is C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic groups optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c Rd NR c C(O)OR a S(O)2NR c R d .

[0104] In some embodiments, Cy is a phenyl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)2NR c R d .

[0105] In some implementations, Cy is C3-C 10 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)2NR c R d .

[0106] In some embodiments, Cy is a 5-10-membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)2NR c R d .

[0107] In some embodiments, Cy is a 4-10 membered heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)2NR c R d .

[0108] In some implementations, R 3 It can be H, D, halogen, CN, C1-C4 alkyl, or C1-C4 haloalkyl.

[0109] In some implementations, R 3 For H. In some implementations, R 3 The answer is D.

[0110] In some implementations, R 3 It is a halogen. In some embodiments, R 3It is F, Cl, Br, or I. In some embodiments, R 3 For F. In some implementations, R 3 It is Cl.

[0111] In some implementations, R 3 For CN. In some implementations, R 3 It is a C1-C4 alkyl group. In some embodiments, R 3 It is a C1-C4 haloalkyl group.

[0112] In some implementations, R 1 and R 2 Together with the atoms attached thereto, it forms a phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group; wherein the phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independently selected substituents from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0113] In some implementations, R 1 and R 2 Together with the atoms attached thereto, a phenyl group is formed, optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NRc R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0114] In some implementations, R 1 and R 2 Together with the atoms attached thereto, a C5-C6 cycloalkyl group is formed, optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0115] In some implementations, R 1 and R 2 Together with the atoms attached thereto, a 5-6 membered heteroaryl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NRc C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0116] In some implementations, R 1 and R 2 Together with the atoms attached thereto, they form pyrroloyl, imidazoyl, or pyrazolyl groups; each optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0117] In some implementations, R 1 and R 2 Together with the atoms attached thereto, a 5-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NRc R d NR c C(O)OR a .

[0118] In some implementations, R 2 and R 3 Together with the atoms attached thereto, it forms a phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group; wherein the phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independently selected substituents from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0119] In some implementations, R 2 and R 3 Together with the atoms attached thereto, a phenyl group is formed, optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c Rd NR c C(O)OR a .

[0120] In some implementations, R 2 and R 3 Together with the atoms attached thereto, a C5-C6 cycloalkyl group is formed, optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0121] In some implementations, R 2 and R 3 Together with the atoms attached thereto, a 5-6 membered heteroaryl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0122] In some implementations, R 2 and R 3 Together with the atoms attached thereto, they form pyrroloyl, imidazoyl, or pyrazolyl groups; each optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a In some implementations, R 2 and R 3 Together with the atoms it is attached to, it forms a 1-methyl-1H-pyrazolyl group.

[0123] In some implementations, R 2 and R 3 Together with the atoms attached thereto, a 5-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

[0124] In some implementations, R 4 For H, D, halogen, CN.

[0125] In some implementations, R 4 For H. In some implementations, R 4 For D. In some implementations, R 4 It is a halogen. In some embodiments, R 4 It is F, Cl, Br, or I. In some embodiments, R 4 For CN.

[0126] In some implementations, R 5 Selected from H, D, halogen, OH, CH3, CF3, CHF2, CH2F.

[0127] In some implementations, R 5 For H. In some implementations, R 5 The answer is D.

[0128] In some implementations, R 5 It is a halogen. In some embodiments, R 5 It can be F, Cl, Br, or I.

[0129] In some implementations, R 5 It is OH. In some embodiments, R 5 It is CH3. In some implementations, R 5 For CF3. In some implementations, R 5 It is CHF2. In some implementations, R 5 It is CH2F.

[0130] In some implementations, R 6 Selected from halogens, OS(O)2R 6A SR 6A S(O)R 6A S(O)OR 6A S(O)2R 6A S(O)2OR 6A S(O)2NR 6A R 6B S(O)(=NR) 6A )R 6B .

[0131] In some implementations, R 6 It is a halogen. In some embodiments, R 6 It is F, Cl, Br, or I. In some embodiments, R 6 It is Cl.

[0132] In some implementations, R 6 OS(O)2R 6A In some implementations, R 6 for OS(O)2CH3, OS(O)2CF3, OTs,

[0133] In some implementations, R 6 For SR 6A In some implementations, R 6 It is SCH3.

[0134] In some implementations, R 6 S(O)R 6A In some implementations, R 6 is S(O)CH3.

[0135] In some implementations, R 6 S(O)OR 6A .

[0136] In some implementations, R 6 is S(O)2R 6A In some implementations, R 6 It is S(O)2CH3, S(O)2CH2CH3, S(O)2CH(CH3)2, S(O)2CH2CH(CH3)2, S(O)2CF3, S(O)2CH2CF3.

[0137] In some implementations, R 6 S(O)2OR 6A In some implementations, R 6 S(O)2NR 6A R 6B .

[0138] In some implementations, R 6 For S(O)(=NR) 6A )R 6B In some implementations, R 6 It is S(O)(=NH)CH3.

[0139] In some implementations, Y 1 Let N be the number of elements in the array.

[0140] In some implementations, Y 1 For CR 7 ;R 7 For H and D. In some implementations, Y 1 For CH.

[0141] In some implementations, Y 2 Let N be the number of elements in the array.

[0142] In some implementations, Y 2 For CR 8 .

[0143] In some implementations, R 8 For H. In some implementations, R 8 The answer is D.

[0144] In some implementations, R 8 It is a halogen. In some embodiments, R 8 The components are F, Cl, Br, and I.

[0145] In some implementations, R 8 It is OH. In some embodiments, R 8 It is a C1-C4 alkyl group. In some embodiments, R 8 It is a C1-C4 haloalkyl group.

[0146] In some implementations, R 9 Selected from CF3, SF5, CN, NC, NO2.

[0147] In some implementations, R 9 For CF3. In some implementations, R 9 It is SF5. In some implementations, R 9 For CN. In some implementations, R 9 For NC. In some implementations, R 9 It is NO2.

[0148] In some implementations, R 8 and R 9 Together with the atoms to which it is attached, a 5-membered heteroaryl group is formed and optionally oxidized.

[0149] In some implementations, R 8 and R 9 Together with the atoms it is attached to, it forms a 5-membered heteroaryl group. In some embodiments, R 8 and R 9 Together with the atoms it is attached to, it forms an oxo-5-membered heteroaryl group.

[0150] In some implementations, R 8 and R 9 It forms together with the atoms it is connected to.

[0151] In some implementations, Y 3 Let N be the number of elements in the array.

[0152] In some implementations, Y 3 For CR 10 ;R 10 For H and D. In some implementations, Y 3 For CH.

[0153] In some implementations, each R A Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0154] In some implementations, each R A Each is independently selected from H. In some implementations, each R... A Each is selected independently from D.

[0155] In some implementations, each R A Each alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0156] In some implementations, each R A Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0157] In some implementations, each R AEach of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0158] In some implementations, each R A Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0159] In some implementations, each R A Each of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0160] In some implementations, each R B Each is independently selected from H. In some implementations, each R... B Each is selected independently from D.

[0161] In some implementations, each R B Each alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0162] In some implementations, each R B Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0163] In some implementations, each R BEach of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0164] In some implementations, each R B Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0165] In some implementations, each R B Each of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0166] In some implementations, each R C Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0167] In some implementations, each R C Each is independently selected from H. In some implementations, each R... C Each is selected independently from D.

[0168] In some implementations, each R CEach alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0169] In some implementations, each R C Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0170] In some implementations, each R C Each of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0171] In some implementations, each R C Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0172] In some implementations, each R C Each of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0173] In some implementations, each R D Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0174] In some implementations, each R D Each is independently selected from H. In some implementations, each R... D Each is selected independently from D.

[0175] In some implementations, each R D Each alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0176] In some implementations, each R D Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0177] In some implementations, each R D Each of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0178] In some implementations, each R D Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0179] In some implementations, each R DEach of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0180] In some implementations, R C and R D Together with the N atom to which it is attached, it forms a 4-6 membered heterocyclic group, which may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, halogen, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.

[0181] In some implementations, each R E Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl.

[0182] In some implementations, each R E Each is independently selected from H. In some implementations, each R... E Each is selected independently from D.

[0183] In some implementations, each R E Each R is independently selected from C1-C4 alkyl groups. In some embodiments, each R E Each R is independently selected from C1-C4 haloalkyl groups. In some embodiments, each R E Each is independently selected from (C1-C4 alkoxy)-C1-C4 alkyl.

[0184] In some implementations, each R F Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl.

[0185] In some implementations, each R F Each is independently selected from H. In some implementations, each R... F Each is selected independently from D.

[0186] In some implementations, each R F Each R is independently selected from C1-C4 alkyl groups. In some embodiments, each R F Each R is independently selected from C1-C4 haloalkyl groups. In some embodiments, each R FEach is independently selected from (C1-C4 alkoxy)-C1-C4 alkyl.

[0187] In some implementations, R G R H and R I Each is independently selected from C1-C4 alkyl or phenyl groups.

[0188] In some implementations, R G Selected from C1-C4 alkyl or phenyl. In some embodiments, R G It is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0189] In some implementations, R H Selected from C1-C4 alkyl or phenyl. In some embodiments, R H It is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0190] In some implementations, R I Selected from C1-C4 alkyl or phenyl. In some embodiments, R I It is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0191] In some implementations, each R a Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0192] In some implementations, each R a Each is independently selected from H. In some implementations, each R... a Each is selected independently from D.

[0193] In some implementations, each R aEach alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0194] In some implementations, each R a Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0195] In some implementations, each R a Each of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0196] In some implementations, each R a Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0197] In some implementations, each R a Each of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0198] In some implementations, each R b Each is independently selected from H. In some implementations, each R... b Each is selected independently from D.

[0199] In some implementations, each R bEach alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0200] In some implementations, each R b Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0201] In some implementations, each R b Each of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0202] In some implementations, each R b Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0203] In some implementations, each R b Each of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0204] In some implementations, each R c Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0205] In some implementations, each R c Each is independently selected from H. In some implementations, each R... c Each is selected independently from D.

[0206] In some implementations, each R c Each alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0207] In some implementations, each R c Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0208] In some implementations, each R c Each of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0209] In some implementations, each R c Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0210] In some implementations, each R cEach of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0211] In some implementations, each R d Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0212] In some implementations, each R d Each is independently selected from H. In some implementations, each R... d Each is selected independently from D.

[0213] In some implementations, each R d Each alkyl group is independently selected from C1-C6 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0214] In some implementations, each R d Selected independently from C3-C 10 The cycloalkyl-C0-C4 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0215] In some implementations, each R dEach of the 4-6 membered heterocyclic -C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0216] In some implementations, each R d Each of the alkyl groups is independently selected from phenyl-C0-C4 and optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0217] In some implementations, each R d Each of the 5-6-membered heteroaryl-C0-C4 alkyl groups is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0218] In some implementations, R c and R d Together with the N atom to which it is attached, it forms a 4-6 membered heterocyclic group, which may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, halogen, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.

[0219] In some implementations, each R e Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl.

[0220] In some implementations, each R e Each is independently selected from H. In some implementations, each R... e Each is selected independently from D.

[0221] In some implementations, each R e Each R is independently selected from C1-C4 alkyl groups. In some embodiments, each R e Each R is independently selected from C1-C4 haloalkyl groups. In some embodiments, each R e Each is independently selected from (C1-C4 alkoxy)-C1-C4 alkyl.

[0222] In some implementations, each R f Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl.

[0223] In some implementations, each R f Each is independently selected from H. In some implementations, each R... f Each is selected independently from D.

[0224] In some implementations, each R f Each R is independently selected from C1-C4 alkyl groups. In some embodiments, each R f Each R is independently selected from C1-C4 haloalkyl groups. In some embodiments, each R f Each is independently selected from (C1-C4 alkoxy)-C1-C4 alkyl.

[0225] In some implementations, R g R h and R i Each is independently selected from C1-C4 alkyl or phenyl groups.

[0226] In some implementations, R g Selected from C1-C4 alkyl or phenyl. In some embodiments, R g It is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0227] In some implementations, R h Selected from C1-C4 alkyl or phenyl. In some embodiments, R h It is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0228] In some implementations, R i Selected from C1-C4 alkyl or phenyl. In some embodiments, R i It is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0229] In some embodiments, the compound represented by formula (I) is represented by formula (II):

[0230]

[0231] Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope variant, prodrug, or deuterated thereof;

[0232] Among them, X 1 X 2 Y 1 Y 2 Y 3 R 2A R 5 R 6 R 3 and R 9 As defined in the present invention (I).

[0233] In some implementations, R 2A Selected from H, D, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic, C(O)R B C(O)NR C R D C(O)OR A S(O)R B S(O)NR C R D S(O)2R B S(O)2NR C R D SiR G R H R 1 ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic group, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)ORa SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0234] In some implementations, R 2A Selected from H, D, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C 10Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic group, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR) c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR cS(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

[0235] In some implementations, R 2A is H, D, CN, CH3, CH2CH3, CH(CH3)2,

[0236] In some embodiments, the compound represented by formula (I) is a pharmaceutically acceptable salt. In some embodiments, the compound represented by formula (I) is a stereoisomer. In some embodiments, the compound represented by formula (I) is a solvate. In some embodiments, the compound represented by formula (I) is an N-oxide of the compound represented by formula (I).

[0237] The present invention also considers, describes, and covers pharmaceutical salts and solvates of the compounds represented by formula (I). The present invention also describes the uses of the compounds represented by formula (I) and pharmaceutical compositions thereof.

[0238] In some embodiments, the present invention provides compounds represented by formula (I) selected from:

[0239]

[0240]

[0241]

[0242]

[0243] Or its pharmaceutically acceptable salt.

[0244] It is obvious that the compounds represented by formula (I) of this invention, including all subgenus described herein, may have multiple stereocenters. Therefore, the compounds represented by formula (I) of this invention (subgenus described herein) exist in multiple stereoisomers (enantiomers and diastereomers). This invention contemplates and covers any stereoisomer of the compounds represented by formula (I) (subgenus described herein), as well as mixtures of said stereoisomers.

[0245] Pharmaceutically acceptable salts and solvates of the compounds represented by formula (I) (subgenus described in this invention) are also included within the scope of this invention.

[0246] Isotopic variants of the compound shown in formula (I) (the subgenus described in this invention) are also included within the scope of this invention.

[0247] The present invention further provides a pharmaceutical composition comprising: the compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0248] The present invention further provides the use of the compounds described herein, or pharmaceutically acceptable salts thereof, in any of the methods described herein. The present invention further provides the use of the compounds of the present invention, or pharmaceutically acceptable salts thereof, in the preparation of therapeutic medicaments, said medicaments being used in any of the methods described herein.

[0249] The present invention further provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0250] The present invention further provides an in vitro method for recruiting co-inhibitory ligands or blocking co-activating ligands from binding to PPARγ protein, wherein the method comprises: contacting PPARγ protein with the compound of the present invention.

[0251] The present invention further provides a method for regulating PPARγ in cells, the method being associated with the activation function of PPARγ (gain-of-function mutation, amplification, or overexpression) or the gain-of-function mutation of RXRα (e.g., S427F / Y), wherein the method comprises: contacting cells with the compound of the present invention.

[0252] The present invention further provides a method for treating a disease, comprising: administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, or a pharmaceutical composition of the present invention.

[0253] In some implementations, the subject suffers from a disease or condition that requires treatment and presents with symptoms of PPARγ amplification, overexpression, gain-of-function mutation, or RXRα gain-of-function mutation.

[0254] In some implementations, the disease or ailment is cancer.

[0255] In some embodiments, the cancer is a cancer with PPARγ activation function (gain-of-function mutation, amplification, or overexpression) or RXRα gain-of-function mutation (such as S427F / Y).

[0256] In some implementations, the cancer is bladder cancer.

[0257] In some implementations, the subject is a human.

[0258] The routes of administration of the compounds described in this invention include, but are not limited to, oral, injection, topical administration, and inhalation.

[0259] definition

[0260] Unless otherwise stated, the following terms have the meanings described below. Other terms are defined elsewhere throughout this specification.

[0261] Unless the context clearly indicates otherwise, as used herein, the singular forms “a,” “an,” and “the” include the plural objects referred to. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a prior basis for the use of such exclusive terms, such as “unique,” ​​“only,” etc., in connection with references to claim elements or the use of the restrictive term “negation.”

[0262] In various places within this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR′R″)- includes -NR(CR′R″)- and -(CR′R″)NR-, with each form intended to be disclosed separately. When a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," then it should be understood that "alkyl" or "aryl" respectively represents the linked alkylene or aryl group.

[0263] The term "substituted" means that one atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substitution," unless otherwise specified, refers to any number of substitutions, such as mono-, di-, tri-, tetra-, or penta-substitution, if such substitution is permitted. Substituents are chosen independently, and substitution can occur at any chemically possible position. It should be understood that substitution at a particular atom is limited by valence. The term "optionally substituted" means either unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms.

[0264] As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms are substituted, independently and separately, by the same or different substituents. Exemplary substituents include, but are not limited to, D, halogen, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C1-C6 alkyl-NR. c R d ,-(CH2CH2O) oC1-C6 alkyl, wherein o is 1-10; C 2-6 alkenyl-NR c R d C 2-6 alkynyl-NR c R d -OC 2-6 Alkyl-NR c R d -CN, -NO2, -N3, -OR a -SR a , -C(O)R b , -C(O)NR c R d -CH2C(O)NR c R d -C(O)OR a , -OC(O)R b , -OC(O)NR c R d -NR c R d -NR c C(O)R b -NR c C(O)NR c R d -NR c C(O)OR a -C(=NR) c )NR c R d -NR c C(=NR c )NR c R d , -P(R f )2, -P(OR e )2,-P(O)R e R f , -P(O)OR e OR f , -S(O)R b -SO(=NR) b );-S(O)NR c R d -S(O)2R b -NR c S(O)2R b -S(O)2NR c R d; aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with a substituent selected from: D, halogen, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c R d C 2-6 alkenyl-NR c R d C 2-6 alkynyl-NR c R d OC 2-6 Alkyl-NR c R d -CN, -NO2, -N3, -OR a -SR a , -C(O)R b , -C(O)NR c R d -CH2C(O)NR c R d -C(O)OR a , -OC(O)R b , -OC(O)NR c R d -NR c R d -NR c C(O)R b -NR c C(O)NR c R d -NR c C(O)OR a -C(=NR) c )NR c R d -NR c C(=NR c )NR c R d , -P(R f )2, -P(OR e )2,-P(O)R e R f , -P(O)OR e OR f , -S(O)R b , -S(O)NR c R d -S(O)2R b -NR c S(O)2Rb -S(O)2NR c R d .

[0265] The term "Cn-Cm" represents a range including the endpoints, where n and m are integers representing the number of carbon atoms. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. "C0 alkyl" refers to a covalent bond or H.

[0266] The compounds of the present invention are stable. As used herein, “stable” means that the compound is sufficiently stable during the separation of the compound from the reaction mixture to obtain useful purity, and preferably means that the compound can be formulated into an effective therapeutic agent.

[0267] It should also be understood that, for clarity, certain features of the invention described in the context of individual embodiments may also be provided in combination with individual embodiments. Conversely, for the sake of brevity, various features of the invention described in the context of individual embodiments may also be provided individually or in any suitable sub-combination.

[0268] As used herein, unless otherwise specified, the term "alkyl," either alone or as part of another substituent, refers to a straight-chain or branched saturated hydrocarbon group. Alkyl groups may contain 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms. Similarly, C 1-8 C 1-8 An alkyl group is defined as having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.

[0269] As used herein, unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, etc.

[0270] As used herein, unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, etc.

[0271] As used herein, unless otherwise specified, “halogenated alkyl” refers to an alkyl group having one or more halogen substituents. Exemplary halogenated alkyl groups include, but are not limited to, CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc.

[0272] As used herein, unless otherwise specified, "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings). In some embodiments, the aryl group has 6 to about 20 carbon atoms. In some embodiments, the aryl group has 6 to about 14 carbon atoms. In some embodiments, the aryl group has 6 to about 10 carbon atoms. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthryl, indene, indenyl, etc.

[0273] As used herein, unless otherwise specified, “cycloalkyl” refers to an unsubstituted or substituted non-aromatic carbon ring, including cyclic alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., bridged bicyclic alkyl rings). In some embodiments, the cycloalkyl group may have 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to about 7 carbon atoms. The cycloalkyl group may also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. The cycloalkyl group may also optionally be oxidized or thiolated (e.g., -C(O)- or -C(S)-). The definition of cycloalkyl also includes groups having one or more aromatic rings fused to (i.e., having bonds shared with the cycloalkyl group) the cycloalkyl group, such as cyclopentyl, cyclopentenyl, cyclohexyl benzo[a] derivatives, etc. A cycloalkyl group having one or more fused aromatic rings can be linked by either an aromatic ring moiety or a non-aromatic ring moiety. One or more cyclic carbon atoms of the cycloalkyl group can be oxidized, for example, to form oxo or thio substituents. In some embodiments, the cycloalkyl group is selected from C3-C7 monocyclic cycloalkyl groups. In some embodiments, the cycloalkyl group is selected from C4-C7 monocyclic cycloalkyl groups. 10 Spirocyclic or bridged cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinel, norcarelyl, cubic, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, etc. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group is a cyclic non-aromatic hydrocarbon group having 3 to 12 carbon atoms (“C3-C4”). 12Preferably, it has 3 to 6 carbon atoms (“C3-C6”). Exemplary cycloalkyl groups include, for example, cyclopropyl (C3; 3-membered), cyclobutyl (C4; 4-membered), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), adamantyl (C6) 10 )wait.

[0274] When used alone or as part of a substituent, the term "spirocycloalkyl" refers to a non-aromatic cycloalkyl group containing two cycloalkyl groups, wherein, typically, the two cycloalkyl groups share a single carbon atom.

[0275] As used herein, unless otherwise specified, “heteroaryl” refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member, such as boron, sulfur, oxygen, or nitrogen. Heteroaryl includes monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Any N atom of a heteroaryl can be oxidized to form an N-oxide. Exemplary heteroaryl includes, but is not limited to, pyridinyl, N-oxopyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indolyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiopheneyl, purine, carbazoleyl, benzimidazolyl, indololinyl, etc. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms; further, in some embodiments, it has from 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group comprises 3 to about 14, 3 to about 7, or 5 to 6 cyclic atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0276] As used herein, unless otherwise specified, "heterocyclic alkyl" refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated) or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated), wherein one or more cyclic carbon atoms of the heterocyclic alkyl group may be replaced by heteroatoms selected from N, O, S, Si, and B; and the cyclic carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be oxidized or thiolated (e.g., C(O), S(O), C(S), or S(O)2, etc.). Heterocyclic alkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocyclic alkyl groups include monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocyclic alkyl groups. Heterocyclic alkyl groups also include spirocyclic and bridged rings (e.g., 5-10 membered bridged biheterocyclic alkyl groups, having one or more of the cyclic carbon atoms replaced independently by heteroatoms selected from N, O, S, and B). The heterocyclic alkyl groups can be linked by cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group comprises 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group comprises 0 to 2 double bonds.

[0277] The heterocyclic alkyl group further includes a group having one or more aromatic rings fused to (i.e., having a shared bond with the heterocyclic alkyl group) the non-aromatic heterocycle, such as piperidine, morpholine, benzo[a] or thieno[b] derivatives of azaheptanes. The heterocyclic alkyl group containing the fused aromatic ring can be linked by any cyclic atoms, including the cyclic atoms of the fused aromatic ring. In some embodiments, the heterocyclic alkyl group contains 3 to 10 cyclic atoms, 4 to 10 cyclic atoms, 3 to 7 cyclic atoms, or 5 to 6 cyclic atoms. In some embodiments, the heterocyclic alkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatomum. In some embodiments, the heterocyclic alkyl group is a monocyclic 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms independently selected from N, O, S, and B, while having one or more oxygenated ring atoms.

[0278] Exemplary heterocyclic alkyl groups include, but are not limited to, pyrrolidine-2-keto, 1,3-isooxazolidine-2-keto, pyranyl, tetrahydropyranyl, oxacyclobutyl, aziridine, morpholinyl, thiomorpholinyl, piperazine, tetrahydrofuranyl, tetrahydrothiophene, piperidinyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, aziridine-heptyl, and benzozapentenyl. ,1,2,3,4-Tetrahydroisoquinolinyl, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1] Octyl, oxabicyclo[2.2.2]octyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, azaadamantyl, diazaadamantyl, oxaadamantyl, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxa-azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxa-azaspiro[3.4]octyl , oxa-azaspiro[3,5]nonyl, azaspiro[2,5]octyl, diazaspiro[2,5]octyl, azaspiro[4,4]nonyl, diazaspiro[4,4]nonyl, oxa-azaspiro[4,4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4,4]nonyl, oxa-diazaspiro[4,4]nonyl, octahydropyrrolo[3,4-c]pyrrol, etc.

[0279] In some embodiments, a heterocyclic alkyl group refers to any 3- to 10-membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from O, N, S, B, and Si. The heterocyclic alkyl group can be linked by any heteroatom or carbon atom, as long as a stable structure can be generated. Exemplary heterocyclic alkyl groups include, but are not limited to, azirheptanyl, azirheptanyl, azirheptanyl, pyrrolidinyl, dioxocyclopentyl, imidazoalkyl, pyrazolyl, piperazinyl, piperidinyl, dioxohexacycloyl, morpholinyl, dithiaalkyl, thiomorpholinyl, oxaazirheptanyl, ethylene oxide, oxacyclobutyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, etc.

[0280] In some embodiments, the term "spirocyclic heterocyclic alkyl" when used alone or as part of a substituent refers to a non-aromatic ring comprising two rings, at least one of which is selected from heterocyclic alkyl groups, the two rings sharing a single carbon atom.

[0281] As used herein, "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0282] As used herein, unless otherwise specified, "alkoxy" refers to -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, etc.

[0283] As used herein, unless otherwise specified, “hydroxyalkyl” refers to an alkyl group substituted with OH.

[0284] As used herein, unless otherwise specified, “cyanoalkyl” refers to an alkyl group substituted with CN.

[0285] As used herein, unless otherwise specified, “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group.

[0286] As used herein, unless otherwise specified, “haloalkoxy” refers to -O- (haloalkyl).

[0287] As used herein, unless otherwise specified, “oxo” refers to an oxygen substituent (i.e., =O) linked by a double bond.

[0288] The compounds described in this invention may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of this invention. The compounds containing asymmetrically substituted carbon atoms described in this invention can be isolated as optical isomers or racemates. Methods for preparing optically active forms of products from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described in this invention, and all stable isomers are also within the scope of this invention. Cis and trans geometric isomers of the compounds described in this invention are also within the scope of this invention and can be isolated as mixtures of isomers or as individual isomers.

[0289] The compounds of this invention also include tautomers. Tautomers arise from the exchange of single bonds with adjacent double bonds and the accompanying migration of protons. Tautomers include proton-transfer tautomers having the same chemical formula and total charge. Exemplary proton-transfer tautomers include keto-enol tautomers, amide-imino tautomers, lactam-lactide tautomers, amide-imino tautomers, and enamine-imino tautomers, in which protons in the cyclic structure can interleave at two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers can be in equilibrium or formed by fixing space through suitable substitutions.

[0290] In some cases, the compounds described in this invention may exist in the form of rotational isomers. The description of the compounds of this invention is intended to cover any single rotational isomer, and any mixture of rotational isomers in any proportion, and does not represent any particular rotational isomer. The description of a particular rotational isomer means that the described rotational isomer substantially free of other rotational isomers.

[0291] This invention further includes isotopic labels of the compounds or intermediates described herein. "Isotope" refers to atoms having the same number of atoms but different molecular weights. For example, isotopes of hydrogen include protium and deuterium.

[0292] In some embodiments, the compounds or salts thereof described in this invention are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it was formed or detected. Partial isolation may include, for example, compositions rich in the compounds of this invention. Substantialtive isolation may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of this invention or salts thereof. Methods for separating the compounds and their salts are conventional in the art.

[0293] This invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compounds described herein, wherein the parent compound is modified by conversion with an existing acid or base to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues such as amines; and basic salts or organic basic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of this invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods. Typically, the salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0294] The term “pharmaceutically acceptable” in this document refers to those compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and have a reasonable benefit / risk ratio.

[0295] "Pharmaceutical-acceptable excipients" refer to substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, and that are added to or otherwise used as a medium, carrier, or diluent to facilitate the administration of a pharmaceutical agent. Exemplary excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0296] "Solvate" refers to a compound represented by Formula I that is physically bonded to one or more solvent molecules.

[0297] "Subject" includes people. The terms "person," "patient," and "subject" are used interchangeably in this document.

[0298] In one implementation, “treating” any disease or disorder means improving the disease or disorder (i.e., preventing or reducing the development of at least one clinical symptom of the disease or its clinical symptoms). In another implementation, “treating” means improving at least one bodily parameter that the subject may not be able to discern. In yet another implementation, “treating” means modulating the disease or disorder at a physical level (e.g., stabilization of discernible symptoms), a physiological level (e.g., stabilization of bodily parameters), or both. In yet another implementation, “treating” means delaying the onset of the disease or disorder.

[0299] As used herein, the term “inhibition” refers to the reduction or suppression of a given condition, symptom, ailment, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0300] The term "modulator" refers to an agent that binds to a receptor binding site as an agonist, antagonist, or inverse agonist to increase or inhibit receptor activity. The term "inverse agonist" refers to an agent that binds to the same receptor binding site as an agonist (e.g., the binding site of a nuclear receptor such as PPARγ), not only antagonizing the agonist's effect but also producing the opposite effect by inhibiting spontaneous receptor signaling (when present). As used herein, "PPARγ inverse agonist" refers to a compound that increases the inhibitory state (recruitment of co-inhibitory ligands) and inhibits the active state (blocking co-activating ligands).

[0301] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body via the bloodstream and lymphatic system. This article describes examples of various cancers, including but not limited to bladder cancer, prostate cancer, stomach cancer, lung cancer, melanoma, endometrial cancer, sarcoma, breast cancer, hepatobiliary cancer, adrenocortical cancer, and colorectal cancer.

[0302] The terms “tumor” and “cancer” are used interchangeably; for example, both terms cover solid tumors and non-solid tumors, such as diffuse or circulating tumors. As used herein, the terms “cancer” or “tumor” include precancerous lesions as well as malignant cancers and tumors.

[0303] The term "PPARγ" refers to the peroxisome proliferator-activated receptor γ protein, which exists in two PPARγ isoforms—γ1 and γ2—originating from different transcription start sites. The only difference between γ1 and γ2 is that PPARγ2 has an additional 30 amino acids at its N-terminus. The term "PPARγ" includes mutants, fragments, variants, isoforms, and homologs of the full-length wild-type PPARγ. In one embodiment, the protein is encoded by the PPARγ gene (Entrez gene ID: 5468; Ensembl ID: ENSG00000132170). Exemplary PPARγ sequences are available in the Uniprot database with accession number P37231.

[0304] The term "RXRα" refers to the retinoic acid X receptor α protein, which is an important therapeutic target affecting a variety of biological processes. In one embodiment, the protein is encoded by the RXRα gene (Entrez gene ID: 6256; Ensembl ID: ENSG00000186350). An exemplary RXRα sequence is available in the Uniprot database with accession number P19793.

[0305] “PPARγ-mediated diseases or conditions” include diseases or conditions such as cancer that are treated by increasing the inhibitory state of PPARγ (e.g., recruiting the co-inhibitory ligand SMRT) to a higher level. Specifically, this can include cancers characterized by PPARγ activation function (gain-of-function mutations, amplification, or overexpression) or RXRα gain-of-function mutations (e.g., S427F / Y).

[0306] The terms “compounds of the present invention” and equivalent expressions are intended to cover the compounds of formula (I) described herein, as well as their respective subgenuses, and, where the context permits, include stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the compounds of formula (I), as well as pharmaceutically acceptable salts.

[0307] As used herein, the term "isotope variant" refers to a compound that contains an isotopic proportion greater than that naturally occurring at one or more atoms in the atoms constituting the compound. For example, an "isotope variant" of a compound may be radiolabeled, i.e., containing one or more radioactive isotopes, or may be made of non-radioactive isotopes such as, for example, deuterium (…). 2 H or D), carbon-13 (H or D), carbon-13 13 C), Nitrogen-15 ( 15 N), etc. It should be understood that in compounds that have undergone such isotopic substitution, if present, the following atoms can be changed such that, for example, any hydrogen atom can be... 2 H / D, any carbon can be 13 C, or any nitrogen, can be 15 N, and the presence and location of such atoms can be determined within the capabilities of those skilled in the art.

[0308] It should also be understood that compounds having the same molecular formula but different atomic bonding properties or sequences or spatial arrangements are called "isomers". Isomers with different spatial arrangements of atoms are called "stereoisomers", such as diastereomers, enantiomers, and rotational isomers. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be a single (R)- or (S)-stereoisomer or a mixture thereof at each asymmetric center. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include all its racemic or other stereoisomers and mixtures. When a structure contains one chiral center but does not show the specific stereochemistry of that center, the structure comprises two enantiomers, individually or as a mixture of enantiomers. When a structure contains more than one chiral center but does not show the specific stereochemistry of that center, the structure comprises all enantiomers and diastereomers, individually or as a mixture. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0309] Pharmaceutical Composition

[0310] The present invention also provides pharmaceutical compositions comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, an N-oxide, a tautomer, an isotope derivative, a prodrug or a deuterated compound, and a pharmaceutically acceptable carrier.

[0311] The pharmaceutical composition may be in a form suitable for oral administration (e.g., tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), may be for injection (e.g., aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar drug carriers), may be for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), may be for inhalation (e.g., fine powders or liquid aerosols), may be for inhalation (e.g., fine powders), or may be for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0312] The composition can be obtained using conventional pharmaceutical excipients well known in the art through routine procedures. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0313] An effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat or prevent the proliferative diseases mentioned in this invention, slow their progression and / or alleviate symptoms associated with the diseases.

[0314] The amount of active ingredient combined with one or more excipients to produce a single dosage form varies depending on the individual being treated and the specific route of administration. For example, formulations for oral administration in humans typically contain, for example, 0.1 mg to 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, along with a suitable and convenient amount of excipients, the amount of which may vary from about 5% to about 98% of the total composition weight.

[0315] The dosage of the compound indicated by formula (I) for therapeutic or preventative purposes varies, according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0316] The following describes non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0317] Administration method

[0318] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such compound may be administered to a subject by any convenient method of administration, whether systemic / peripheral or local (i.e. at the site of desired action).

[0319] Methods of administration include, but are not limited to: oral (e.g., by ingestion); sublingual; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, for example, by aerosols, for example, by mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrathoracic; implantation in a depot or reservoir, for example, subcutaneous or intramuscular.

[0320] How to use

[0321] The method typically involves administering a therapeutically effective amount of the compound of the invention to a subject. The therapeutically effective amount of the combination of target compounds may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the nature of the disease, such as the subject's weight and age, the severity of the disease, the route of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells, such as reduced proliferation or downregulation of target proteins. The specific dose will vary depending on the specific compound selected, the administration regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0322] As used herein, the term "IC" 50 "IC50%" refers to the half-maximal inhibitory concentration (IC50) of an inhibitor in inhibiting a biological activity or biochemical function. This quantitative measure indicates how much of a specific inhibitor is required to inhibit half of a given biological process (or a component of that process, i.e., an enzyme, cell, cell receptor, or microorganism). In other words, it is the half-maximal (50%) inhibitory concentration (IC50) of a substance. 50 ).

[0323] As used in this article, the term "EC" 50 "50% EC" refers to the half-maximum effective concentration (50% EC) of an activator in order to activate a biological or biochemical function. This quantitative indicator shows the amount of a specific activator required to activate half of a particular biological process (or its components, i.e., enzymes, cells, cell receptors, or microorganisms). In other words, it is the half-maximum (50%) effective concentration (50% EC, or EC50) of a substance. 50 ).

[0324] In some embodiments, the method uses a PPARγ inverse agonist / antagonist to EC 50Increase the PPARγ inhibitory state in a manner that is approximately or below a predetermined value (e.g., recruiting the co-inhibitory ligand SMRT), or by using IC50. 50 The PPARγ activation state is reduced in a manner that is approximately or below a predetermined value (e.g., by blocking the co-activating ligand DRIP205), as determined by in vitro assays. In other embodiments, the method uses a PPARγ agonist at an IC50 concentration. 50 The PPARγ inhibitory state is reduced by an EC50 value approximately or below a predetermined value (e.g., recruiting the co-inhibitory ligand SMRT), or the PPARγ activation state is increased by an EC50 value approximately or below a predetermined value (e.g., blocking the co-activating ligand DRIP205), as determined by in vitro assays. In these embodiments, the PPARγ inverse agonist, antagonist, or agonist has an EC50 value approximately or below a predetermined value for PPARγ activity. 50 or IC 50 The values ​​are as follows: 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM Or smaller, 180nM or smaller, 190nM or smaller, 200nM or smaller, 225nM or smaller, 250nM or smaller, 275nM or smaller, 300nM or smaller, 325nM or smaller, 350nM or smaller, 375nM or smaller, 400nM or smaller, 425nM or smaller, 450nM or smaller, 475nM or smaller, 500nM or smaller, 550nM or smaller, 600nM or smaller Small, 650 nm or less, 700 nm or less, 750 nm or less, 800 nm or less, 850 nm or less, 900 nm or less, 950 nm or less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μ M or smaller, 5μM or smaller, 10μM or smaller, 15μM or smaller, 20μM or smaller, 25μM or smaller, 30μM or smaller, 40μM or smaller, 50μM, 60μM, 70μM, 80μM, 90μM, 100μM, 200μM, 300μM, 400μM, or 500μM, or smaller (or a number within the range defined by any two of the above numbers and containing any two of the above numbers).

[0325] In some embodiments, the PPARγ-related disease or condition is cancer. In some embodiments, the cancer is associated with upregulation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In some aspects, the upregulated PPAR signaling pathway is associated with increased expression of one or more genes selected from the following: plaqueprotein 1A (UPK1A), plaqueprotein 1B (UPK1B), plaqueprotein 2 (UPK2), keratin 20 (KRT20), GATA-binding protein 3 (GATA3), nuclear receptor co-repressor 1 (NCOR1), nuclear receptor co-repressor 2 (NCOR2), fatty acid-binding protein 4 (FABP4), forkhead box protein A1 (FOXA1), CD36 molecule (CD36), acyl-CoA. Oxidase 1 (ACOX1), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), acyl-CoA synthase long chain family member 5 (ACSL5), arachidonic acid 5-lipoxygenase (ALOX5), acyl-CoA synthase long chain family member 1 (ACSL1), angiopoietin-like protein 4 (ANGPTL4), liver X receptor α (LXRA), cell death-inducing DFFA-like effector factor C (CIDEC), phosphoenolpyruvate carboxykinase (PEPCK), aquaporin 7 (AQP7), etc.

[0326] In some embodiments, the method is used to treat diseases or cancers selected from those with poor response to chemotherapy or chemotherapy resistance, such as intravesical chemotherapy for bladder cancer. The compounds of the present invention, and pharmaceutical compositions comprising them, can be administered alone or in combination with medical therapies to treat any of the said diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, whole-body radioisotopes).

[0327] In other respects, the compounds and pharmaceutical compositions thereof described in this invention may be administered alone or in combination with one or more other pharmaceutical agents to treat any of the said diseases.

[0328] synthesis

[0329] The compounds described in this invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, such as those described below.

[0330] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent is one that does not substantially react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out; for example, the temperature range can be from the freezing temperature of the solvent to its boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Those skilled in the art can select a solvent suitable for a particular reaction step based on the specific reaction steps described above.

[0331] The preparation of the compounds of the present invention may involve the above-described protection and deprotection of various chemical groups. The need for the above-described protection and deprotection, and the selection of suitable protecting groups, can be readily determined by those skilled in the art. The disclosed chemical protecting groups are as follows, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith el ah, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Ed. (Wiley, 2019); Petrussion et al, "Protecting Groups in Carbohydrate Chemistry" J Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 5th Ed. (Wiley, 2014).

[0332] The reaction can be monitored using any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible light), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin-layer chromatography.

[0333] As used in this invention, “ambient temperature,” “room temperature,” and “rt” generally refer to temperature in the art, such as reaction temperature, which refers to the temperature of the space where the reaction is performed, for example, about 20°C to about 30°C.

[0334] The compounds of the present invention can be prepared according to various preparation routes known in the literature. The following methods provide general guidance related to the preparation of the compounds described in the present invention. Those skilled in the art will understand that the preparation methods in the following methods can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are as follows.

[0335] The following examples are provided to illustrate some of the concepts described herein. While these examples are intended to provide embodiments, they should not be construed as limiting the more general embodiments described herein.

[0336] abbreviations

[0337]

[0338]

[0339]

[0340] Synthesis scheme

[0341] A series of 4-quinolinone derivatives of formula (I) can be prepared according to the method described in Scheme 1. The amide derivative 1-1 is subjected to Camps cyclization under alkaline conditions, such as NaOH, KOH, LiOtBu, or KOtBu, in a suitable solvent, such as 1,4-dioxane, 2-methyltetrahydrofuran, Et2O, or THF, to obtain the 4-quinolinone derivative of formula (I). Similarly, the 2-ketoaniline derivative 1-2 is subjected to Mannich intramolecular oxidation with TEMPO in an alkaline environment, such as NaOtBu or KOtBu, in the presence of DMSO or DMF, to obtain the 4-quinolinone derivative of formula (I).

[0342] Furthermore, aryl acetylaceton derivatives 1-3 can be subjected to gold-catalyzed intramolecular cyclization in MeCN in the presence of catalysts such as PPh3AuNTf2, KAuCl4 or IMes-AuNTf2 to obtain the 4-quinolinone derivative shown in formula (I).

[0343] Furthermore, the 4-quinolinone derivative shown in formula (I) can be prepared by a Conrad-Limpach cyclization reaction of aniline compounds 1-4 with benzoyl acetate compounds 1-5 under acidic conditions such as H3PO4, PPA or H2SO4 in a high-boiling solvent (e.g. xylene, Ph2O, Dowtherm A).

[0344] Option 1

[0345]

[0346] A series of amide derivatives of Formula 2-1 can be prepared according to the method described in Scheme 2. The amide derivatives of Formula 2-1 can be obtained by coupling carboxylic acid 2-2 with 2-ketoaniline 2-4 under the following conditions (e.g., in the presence of an activating agent such as BOP, PyBOP, HATU, HBTU, EDCI, TCFH, or T3P and a base such as Hunig's base, TEA, pyridine, NMI, or DMAP). Furthermore, the carboxylic acid 2-2 can be reacted with the chlorinating agent such as oxaloyl chloride, thionyl chloride, or POCl3 to obtain the corresponding acyl chloride of Formula 2-3, which can be further coupled with 2-ketoaniline 2-4 under basic conditions such as TEA, DIEA, or DMAP to obtain the amide derivatives of Formula 2-1.

[0347] Furthermore, compounds 2-5, wherein W is a halogen (Br, Cl, I) or a pseudohalogen (e.g., OTf or OMs), can also be coupled with suitable benzamide derivatives 2-6 under standard Ullmann coupling conditions (e.g., CuI, K3PO4 and ligands such as proline derivatives, BINAP, etc.) or under standard Buchwald-Hartwig coupling conditions (e.g., Pd2(dba)3, Bippyphos, RockPhos, RuPhos Pd G3, BrettPhos Pd G3, Q-phos, etc. and bases such as t-BuOK, K3PO4, Cs2CO3, or K2CO3) to obtain the amide derivatives shown in Formula 2-1.

[0348] Option 2

[0349]

[0350] A series of N-substituted 2-ketoaniline derivatives of Formula 3-1 can be prepared according to the method described in Scheme 3. The 2-ketoaniline derivatives of Formula 3-1 can be obtained by reductive amination of aldehyde 3-2 with 2-ketoaniline 3-2 under the following conditions (e.g., in the presence of a catalyst such as HOAc, TFA, or H2SO4 and a reducing agent such as NaBH(OAc)3 or NaBH3CN).

[0351] Furthermore, compounds 3-4, wherein W is a halogen (Br, I) or a pseudohalogen (e.g., OTf), coupled with the corresponding benzylamine derivatives 3-5 in the presence of a base (e.g., TEA, DBU, KOtBu, etc.) or under Buchwald-Hartwig coupling conditions (e.g., Pd2(dba)3, Bippyphos, RuPhos Pd G3, BrettPhos Pd G3, RockPhos, Q-phos and a base, such as t-BuOK, K3PO4, Cs2CO3, or K2CO3), can also yield the N-substituted 2-ketoaniline derivatives of formula 3-1.

[0352] Option 3

[0353]

[0354] A series of aryl acetylenes shown in Formula 4-1 can be prepared according to the method described in Scheme 4. 2-Haloaniline compounds 4-2, wherein W is a halogen (Br, I) or pseudohalogen (e.g., OTf), react with aryl acetylenes 4-4 under Sonogashira conditions (e.g., in the presence of a palladium catalyst such as Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd2(dba)3, or Pd(OAc)2 and a ligand, such as dppf or [HP(tBu)3]BF4, and a base such as TEA or NHEt2) to yield N-protected acetylenes shown in Formula 4-7, which can be further converted to compound 4-1 under acidic conditions such as TFA or HCl.

[0355] Furthermore, the N-protected ketal derivatives of Formula 4-7 can be prepared by a coupling reaction of Weinreb amide-6 with arylacetylenes 4-4 under suitable basic conditions (e.g., LiHMDS, NaHMDS, KHMDS, LDA, EtMgBr, or n-BuLi, etc.) via deprotonation of the alkyne hydrogen. Similarly, the coupling of aldehyde 4-3 with arylacetylenes 4-4 under suitable basic conditions (e.g., LiHMDS, NaHMDS, KHMDS, LDA, EtMgBr, or n-BuLi, etc.) yields the propynyl alcohol derivatives of Formula 4-5, which can be further oxidized in the presence of suitable oxidants such as MnO2, PCC, PDC, DMP, or IBX to obtain the N-protected ketal derivatives of Formula 4-7.

[0356] Option 4

[0357]

[0358] A series of 4-quinolinone derivatives of formula 5-1 can be prepared according to the method described in Scheme 5. The amide derivative 5-2 is subjected to Camps cyclization in the presence of a base, such as NaOH, KOH, LiOtBu, or KOtBu, in a suitable solvent, such as 1,4-dioxane, 2-methyltetrahydrofuran, Et2O, or THF, to obtain the 4-quinolinone derivative 5-3. The 4-quinolinone derivative 5-2 is then coupled with the alkyne derivative 5-4 under standard conditions (e.g., in the presence of a co-catalyst such as Pd(PPh3)2Cl2 / CuI and a base, such as TEA or DIEA) to obtain the 4-quinolinone derivative 5-1.

[0359] Furthermore, the amide derivative 5-2 and the alkyne derivative 5-4 can be coupled via Sonogashira under standard conditions (e.g., in the presence of a co-catalyst such as Pd(PPh3)2Cl2 / CuI and a base such as TEA or DIEA) to obtain compound 5-5, which can be further cyclized in the presence of a base such as NaOH, KOH, LiOtBu or KOtBu in a suitable solvent such as 1,4-dioxane, 2-methyltetrahydrofuran, Et2O or THF to obtain the 4-quinolinone derivative 5-1.

[0360] Option 5

[0361]

[0362] A series of 4-quinolinone derivatives as shown in Formula 6-2, wherein R 6 For OSO2R 6A SR 6A or SO2R 6A It can be obtained through 4-quinolinone derivatives 6-1, where R 6 Cl, Br, or I with HOSO2R 6A NaSR 6A or NaSO2R 6A It is prepared by reacting under alkaline conditions, such as NaH, KOtBu, DIEA, or KOH, according to the method described in Scheme 6.

[0363] Option 6

[0364]

[0365] A series of 2-ketoaniline derivatives of formula 7-1 can be prepared according to the method described in Scheme 7. Weinreb amide 7-3 can be prepared by reacting its acid precursor 7-2 with N,O-dimethylhydroxylamine under standard amide coupling conditions (e.g., in the presence of an amide coupling agent such as BOP, PyBOP, HATU, HBTU, or EDCI, and a base such as TEA, Hunig's base, or pyridine). The reaction of Weinreb amide 7-3 with a THF solution of Grignard reagent 7-4 at low temperature yields the corresponding 2-ketoaniline derivative 7-5. Deprotection of compound 7-5 under acidic conditions, such as TFA or HCl, yields the 2-ketoaniline derivative 7-1.

[0366] In addition, 2-ketoaniline derivative 7-1 can be prepared by Friedel-Crafts acylation reaction of aniline compound 7-6 with acyl chloride 7-7 in a suitable acid (e.g., PPA, or AlCl3, etc.).

[0367] Option 7

[0368]

[0369] A series of benzoyl acetate derivatives of formula 8-1 can be prepared according to the method described in Scheme 8. Esters 8-2 and EtOAc undergo Claisen condensation under basic conditions (e.g., NaOEt, NaOMe, or KOtBu, etc.) to obtain the benzoyl acetate derivative 8-1. Furthermore, arylmethyl ketones 8-3 and diethyl carbonate undergo condensation under basic conditions (e.g., NaH, LDA, NaOEt, NaOMe, or KOtBu, etc.) to obtain the benzoyl acetate derivative 8-1.

[0370] Option 8

[0371]

[0372] A series of arylaceyne derivatives of formula 9-1 can be prepared according to the method described in scheme 9. Compound 9-2 is coupled with trimethylsilylacetylene under standard conditions (e.g., in the presence of a co-catalyst such as Pd(PPh3)2Cl2 / CuI, and a base such as TEA or DIEA) to yield compound 9-3, which is further deprotected under basic conditions (e.g., K2CO3, KOH, NaOH, or TBAF) or with an Olah reagent to yield the arylaceyne derivative 9-1. Furthermore, arylaceyne derivative 9-1 can be obtained by reacting with aldehyde 9-4.

[0373] Option 9

[0374]

[0375] A series of benzoxadiazole derivatives of formula 10-1 can be prepared according to the method described in scheme 10. The 2-nitroaniline derivative 10-2 is reacted with KOH and NaClO to give compound 10-3, which is subsequently reduced in the presence of reducing agent P(OEt)3 to give benzoxadiazole derivative 10-1.

[0376] Option 10

[0377]

[0378] A series of benzothiadiazole derivatives of formula 11-1 can be prepared according to the method described in scheme 10. The o-phenylenediamine derivative 11-2 is reacted with SOCl2 to give compound 11-3, which is further hydrolyzed under alkaline conditions (e.g., LiOH, NaOH, or KOH) to give benzothiadiazole derivative 11-1.

[0379] Option 11

[0380] Example

[0381] Example 1: 3-(5,7-difluoro-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0382]

[0383] Step 1: 1-(2-amino-4,6-difluorophenyl) ethyl ketone

[0384]

[0385] A mixture of 1-(2,4,6-trifluorophenyl)ethyl ketone (5 g, 28.7 mmol) and ammonia (14 g, 230 mmol, 28% aqueous solution) in 2-methyltetrahydrofuran (13 mL) was heated to 105 °C overnight in a sealed tube. The reaction mixture was cooled to 25 °C. The aqueous phase was adjusted to pH 8-9 with 2.0 mol / L hydrochloric acid and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was eluted by silica gel column chromatography with ethyl acetate / petroleum ether (5-12%) to give the target compound (2.5 g) as a white solid. LCMS calculated value: C8H8F2NO[M+H] + m / z = 172.1; Measured value: 172.1.

[0386] Step 2: 1-(6-amino-4-difluoro-3-iodophenyl)ethyl ketone

[0387]

[0388] N-iodosuccinimide (1.4 g, 6.4 mmol) was added to a solution of 1-(2-amino-4,6-diethyl ketone (1.0 g, 5.8 mmol) in dichloromethane (10 mL). The mixture was stirred overnight at 20 °C. The reaction mixture was diluted with 10 mL of water and extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (10–30%)) to give the target compound (450 mg) as a white solid. LCMS calculated value: C8H7F2INO[M+H] + m / z = 298.0; Measured value: 298.0.

[0389] Step 3: 5-Cyano-2-(Methanesulfonyl)benzoyl chloride

[0390]

[0391] 5-Cyano-2-(methanesulfonyl)benzoic acid (0.5 g, 2.2 mmol) was dissolved in SOCl2 (5 mL), stirred at 80 °C for 2 hours, and concentrated under reduced pressure to obtain the target compound (0.5 g), which was a colorless oil.

[0392] Step 4: N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0393]

[0394] A mixture of 1-(6-amino-2,4-difluoro-3-iodophenyl)ethyl ketone (0.6 g, 2.2 mmol) and triethylamine (0.4 g, 4.0 mmol) was dissolved in dichloromethane (10 mL), and 5-cyano-2-(methanesulfonyl)benzoyl chloride (0.55 g, 2.2 mmol) was added. The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column with acetonitrile / water (30–48%) to give the target compound (0.58 g) as a white solid. LCMS calculation of C 17 H 12 F2IN2O4S[M+H] + m / z = 505.0; Actual measurement: 504.9.

[0395] Step 5: 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0396]

[0397] A mixture of N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (35 mg, 0.07 mmol) and LiOtBu (6.7 mg, 0.08 mmol) was dissolved in 1 mL of 2-methyltetrahydrofuran and stirred overnight at 75 °C. The reaction was quenched with 0.1 mL of 2.0 mol / L hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column using acetonitrile / water (containing 0.5% trifluoroacetic acid, 45-63%) to give the target compound (7 mg) as an off-white solid. LCMS calculated value: C 17 H 10 F2IN2O3S[M+H] + m / z = 486.9; Measured value: 486.9.

[0398] Step 6: 3-(5,7-difluoro-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0399] A mixture of CuI (0.4 mg, 0.002 mmol), PdCl2(PPh3)2 (1.4 mg, 0.002 mmol), 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (10 mg, 0.02 mmol), and 2-methylbut-3-yn-2-ol (2.6 mg, 0.03 mmol) was dissolved in DMF (0.2 mL) and TEA (0.1 mL), degassed three times with nitrogen, and stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (15-25%), to give the target compound (7 mg) as a white solid. LCMS calculation of C 22 H 17 F2N2O4S[M+H] + m / z = 443.1; Actual measurement: 443.0.

[0400] Example 2: 3-(6-ethynyl-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0401]

[0402] Step 1: N-(2-acetyl-3,5-difluoro-4-((trimethylsilyl)ethynyl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0403]

[0404] A solution of trimethylsilylacetylene (15 mg, 0.15 mmol), N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (50 mg, 0.1 mmol, Example 1, step 4), copper iodide (2 mg, 0.01 mmol), and PdCl2(PPh3)2 (7 mg, 0.01 mmol) in triethylamine (0.5 mL) and N,N-dimethylformamide (0.5 mL) was degassed three times with nitrogen and stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was eluted with acetonitrile / water (20-50%) by rapid C18 column chromatography to give the target compound (25 mg) as an off-white solid. LCMS calculation of C 22 H 21 F2N2O4SSi[M+H] + m / z = 475.1; Actual measurement: 475.1

[0405] Step 2: 3-(6-ethynyl-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0406] A mixture of N-(2-acetyl-3,5-difluoro-4-((trimethylsilyl)ethynyl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide (25 mg, 0.05 mmol) and lithium tert-butoxide (5 mg, 0.06 mmol) in 2-methyltetrahydrofuran (1 mL) was stirred overnight at 75 °C. The reaction was quenched with 2.0 M hydrochloric acid aqueous solution (0.1 mL) and concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (25–46%), to give the target compound (2.1 mg) as an off-white solid. LCMS calculation of C 19 H 11 F2N2O3S[M+H]+: m / z=385.0; Actual measurement: 385.0.

[0407] Example 3: 3-(5,7-difluoro-6-(3-hydroxyprop-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0408]

[0409] Step 1: N-(2-acetyl-3,5-difluoro-4-(3-hydroxyprop-1-ynyl-phenyl)-5-cyano-2-(methanesulfonyl)benzamide)

[0410]

[0411] A solution of trimethyl(2-propynyl-1-oxy)silane (19 mg, 0.15 mmol), N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (50 mg, 0.1 mmol, Example 1, step 4), copper iodide (2 mg, 0.01 mmol), and PdCl2(PPh3)2 (7 mg, 0.01 mmol) in TEA (0.5 mL) and DMF (0.5 mL) was degassed three times with nitrogen and stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was eluted with ACN / H2O (5-14%) on a C18 column by rapid chromatography to give the target compound (15 mg) as an off-white solid. LCMS calculation of C 20 H 15 F2N2O5S[M+H] + m / z = 433.1; Actual measurement: 433.0.

[0412] Step 2: 3-(5,7-difluoro-6-(3-hydroxyprop-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0413] A mixture of N-(2-acetyl-3,5-difluoro-4-(3-hydroxyprop-1-yn-1-yl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide (15 mg, 0.03 mmol) and LiOtBu (4 mg, 0.05 mmol) in 2-methyltetrahydrofuran (1 mL) was stirred overnight at 75 °C. The reaction was quenched with 2.0 M aqueous HCl (0.1 mL) and concentrated under reduced pressure. The residue was eluted on a C18 column with acetonitrile / water (0–8%) to give the target compound (1.5 mg) as a white solid. LCMS calculated value: C 20 H 11 F2N2O4S[MH] - m / z = 413.1; measured value: 413.0.

[0414] Example 4: (R)-3-(5,7-difluoro-6-(3-hydroxybut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0415]

[0416] A mixture of copper iodide (0.4 mg, 0.002 mmol), bis(triphenylphosphine)palladium chloride (2.8 mg, 0.004 mmol), 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (20 mg, 0.04 mmol, Example 1, step 5), and (R)-3-butyn-2-ol (4.2 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (0.4 mL) and triethylamine (0.2 mL), degassed three times with nitrogen, and stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was eluted with acetonitrile / water (10-25%) by rapid C18 column chromatography to give the target compound (5.2 mg) as an off-white solid. LCMS calculated value: C 21 H 15 F2N2O4S[M+H] + m / z = 429.1; Measured value: 429.1.

[0417] Example 5: (S)-3-(5,7-difluoro-6-(3-hydroxy-1-butyn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0418]

[0419] This compound was prepared using a similar procedure to that in Example 4, except that (S)-3-butyn-2-ol was used instead of (R)-3-butyn-2-ol. LCMS calculated value C 21 H 15 F2N2O4S[M+H] + m / z = 429.1; Measured value: 429.1.

[0420] Example 6: 3-(5,7-difluoro-6-(4-hydroxybut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0421]

[0422] This compound was prepared using a method similar to that described in Example 4, with (R)-2-hydroxy-3-butyne replaced by 1-hydroxy-3-butyne. LCMS calculated value: C 21 H 15 F2N2O4S[M+H] + m / z = 429.1; Measured value: 429.1.

[0423] Example 7: 3-(5,7-difluoro-6-((3-hydroxyoxetane-3-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0424]

[0425] This compound was prepared using a similar procedure to that in Example 4, except that (R)-3-butyn-2-ol was replaced with 3-ethynyloxetane-3-ol. LCMS calculations showed C2... 22 H 15 F2N2O5S[M+H] + m / z = 457.1; Measured value: 457.1.

[0426] Example 8: 3-(6-(3-amino-3-methylbut-1-yn-1-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0427]

[0428] This compound was prepared using a similar procedure to that in Example 4, except that (R)-but-3-yn-2-ol was replaced with 2-methylbut-3-yn-2-amine. LCMS calculated value: C 22 H 18 F2N3O3S[M+H] + m / z = 442.1; Measured value: 442.1.

[0429] Example 9: 3-(6-(cyclopropylethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0430]

[0431] Step 1: N-(2-acetyl-4-(cyclopropylethynyl)-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0432]

[0433] A mixture of ethynylcyclopropane (20 mg, 0.3 mmol), N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (100 mg, 0.2 mmol, Example 1, step 4), copper iodide (4 mg, 0.02 mmol), and PdCl2(PPh3)2 (14 mg, 0.02 mmol) in TEA (0.5 mL) and DMF (0.5 mL) was degassed three times with nitrogen and stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by rapid C18 column chromatography, eluting with ACN / H2O (35-50%), to give the target compound (28 mg) as an off-white solid. LCMS calculation of C 22 H 17 F2N2O4S[M+H] + m / z = 443.1; Actual measurement: 433.0.

[0434] Step 2: 3-(6-(cyclopropylethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0435] A mixture of N-(2-acetyl-4-(cyclopropylethynyl)-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide (28 mg, 0.06 mmol) and LiOtBu (8 mg, 0.1 mmol) in 1 mL of 2-methyltetrahydrofuran was stirred overnight at 75 °C. The reaction was quenched with 0.1 mL of 2 M hydrochloric acid aqueous solution and concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (30-50%), to give the target compound (3 mg) as an off-white solid. LCMS calculated value: C 22 H 13 F2N2O3S[MH] - m / z = 425.1; Measured value: 425.1.

[0436] Example 10: 3-(6-(3,3-dimethylbut-1-yn-1-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0437]

[0438] This compound was prepared using a method similar to that described in steps 1-2 of Example 9, except that in step 1, 3,3-dimethylbut-1-yne was used to replace ethynylcyclopropane. LCMS calculated value C 23 H 19 F2N2O3S[M+H] +m / z = 441.1; Measured value: 441.1. Example 11: 3-(5,7-difluoro-4-oxo-6-(phenylethynylynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0439]

[0440] This compound was prepared using a similar method to that described in steps 1-2 of Example 9, in which phenylacetylene was used instead of ethynylcyclopropane in step 1. LCMS calculated value C 25 H 15 F2N2O3S[M+H] +- m / z = 460.1; Measured value: 460.1.

[0441] Example 12: 3-(5,7-difluoro-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0442]

[0443] This compound was prepared by a similar method as described in Example 4, with 4-ethynyl-1-methyl-1H-pyrazole used instead of (R)-3-butyn-2-ol. LCMS calculated value C 23 H 15 F2N4O3S[M+H] + m / z = 465.1; measured value 465.1.

[0444] Example 13: 3-(6-cyclopropyl-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0445]

[0446] Step 1: N-(2-acetyl-4-cyclopropyl-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0447]

[0448] A mixture of cyclopropylboronic acid (26 mg, 0.3 mmol), N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (50 mg, 0.1 mmol, Example 1, step 4), Pd(dppf)Cl2 (7 mg, 0.01 mmol), and K2CO3 (68 mg, 0.5 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was degassed, purged three times with nitrogen, and stirred overnight at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was eluted by preparative thin-layer chromatography (prep-TLC) with ethyl acetate / petroleum ether (20%) to give the target compound (18 mg) as a yellow oil. LCMS calculated value C 20 H 17 F2N2O4S[M+H] + m / z = 419.1; Measured value: 419.1.

[0449] Step 2: 3-(6-cyclopropyl-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0450] A mixture of N-(2-acetyl-4-cyclopropyl-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide (18 mg, 0.04 mmol) and LiOtBu (4 mg, 0.05 mmol) in 0.5 mL of 2-methyltetrahydrofuran was stirred overnight at 75 °C. The reaction was quenched with 0.1 mL of 2 M hydrochloric acid aqueous solution and concentrated under reduced pressure. The residue was eluted by acetonitrile / water (20–40%) through a C18 column to give the target compound (1.4 mg) as a white solid. LCMS calculated value: C 20 H 15 F2N2O3S[M+H] + m / z = 401.1; Measured value: 401.1.

[0451] Example 14. 4-Fluoro-3-(4-fluoro-1-methyl-5-oxo-5,8-dihydro-1H-pyrazolo[4,3-g]quinoline-7-yl)benzonitrile

[0452]

[0453] Step 1: 4-Bromo-3-fluoro-2-methyl-5-nitroaniline

[0454] Potassium nitrate (6 g, 60 mmol) was added to a sulfuric acid (150 mL) solution of 10 g (49.3 mol) of 4-bromo-3-fluoro-2-methyl-5-nitroaniline, and the reaction mixture was stirred at 0–10 °C for 30 minutes. The resulting mixture was poured into crushed ice, filtered, and concentrated under reduced pressure to give the target compound (12 g, 98% yield) as a yellow solid. LCMS calculated value: C7H7BrFN2O2[M+H] + m / z = 248.9; measured values: 248.9, 250.8.

[0455] Step 2: 5-Bromo-4-fluoro-6-nitro-1H-indazole

[0456] To a solution of 4-bromo-3-fluoro-2-methyl-5-nitroaniline (12 g, 48.4 mmol) in acetic acid (500 mL), a solution of sodium nitrite (3.4 g, 48.4 mmol) in water (10 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. 100 mL of water was added to the residue and the mixture was stirred. The solid formed was collected by filtration, washed with water, and dried. The crude product was recrystallized from ethanol and water to give the target compound (10 g, 80% yield) as a yellow solid. LCMS calculated value: C7H4BrFN3O2[M+H] + m / z = 259.9; measured values: 260.1, 262.1.

[0457] Step 3: 5-Bromo-4-fluoro-1-methyl-6-nitro-1H-indazole

[0458] A mixture of 5-bromo-4-fluoro-6-nitro-1H-indazole (10 g, 38.6 mmol), iodomethane (6 g, 42.5 mmol), and K₂CO₃ (16 g, 115.8 mmol) in DMF (300 mL) was stirred overnight at room temperature. The mixture was diluted with water (300 mL) and extracted with dichloromethane (200 mL × 2). The combined organic phases were washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / petroleum ether (50%), to give the target compound (4.2 g, 40% yield) as a yellow solid. LCMS calculated value: C₈H₆BrFN₃O₂[M+H] + m / z = 273.9; Actual values: 274.0, 275.8.

[0459] Step 4: 5-(1-ethoxyvinyl)-4-fluoro-1-methyl-6-nitro-1H-indazole

[0460] A mixture of 5-bromo-4-fluoro-1-methyl-6-nitro-1H-indazole (2 g, 7.3 mmol), tributyl(1-ethoxyvinyl)stanane (2.9 g, 8.1 mmol), and 1,1′-bis(diphenylphosphine)ironcobalt-palladium dichloride (dichloromethane) complex (598 mg, 0.73 mmol) in toluene (25 mL) was stirred at 110 °C for 3 hours. The mixture was ready for the next step without further treatment. LCMS calculated value: C 12 H 13 FN3O3[M+H] + m / z = 266.1; Actual value: 266.3.

[0461] Step 5: 1-(4-fluoro-1-methyl-6-nitro-1H-indazol-5-yl)ethane-1-one

[0462] Add 10 mL of hydrochloric acid (4.0 M dioxane solution) to the above mixture and stir at room temperature for 1 hour. Dilute the mixture with water (100 mL), extract with dichloromethane (20 mL × 3), combine the organic phases, wash with brine (30 mL), dry to sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with dichloromethane / petroleum ether (50%) to give the target compound (1.2 g, 69% yield) as a yellow solid. LCMS calculated Cp 10 H9FN3O3[M+H] + m / z = 238.0; Measured value: 238.0.

[0463] Step 6: 1-(6-amino-4-fluoro-1-methyl-1H-indazol-5-yl)ethane-1-one

[0464] Iron powder (940 mg, 16.8 mmol) was added to acetic acid (20 mL) containing 800 mg (3.4 mmol) of 1-(4-fluoro-1-methyl-6-nitro-1H-indazol-5-yl)ethane-1-one. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to give the target compound (700 mg, 98% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.01 (d, J = 1.0Hz, 1H), 6.91 (s, 2H), 6.40 (d, J = 1.0Hz, 1H), 3.81 (s, 3H), 2.58 (d, J = 8.3Hz, 3H). LCMS calculated C 10 H 11 FN3O[M+H]+ m / z = 208.1; Measured value: 208.0.

[0465] Step 7: 5-Cyano-2-fluorobenzoic acid

[0466] Methyl 5-cyano-2-fluorobenzoate (2 g, 11.17 mol) was mixed with a mixture of LiOH (295 mg, 12.29 mol), THF (25 mL), and water (5 mL) and stirred at room temperature for 2 hours. The solution was acidified with concentrated hydrochloric acid (12 M) and concentrated under reduced pressure to obtain crude 5-cyano-2-fluorobenzoic acid (1.3 g, 7.88 mol, 72% yield), a white solid, which could be used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ13.77 (s, 1H), 8.30 (dd, J=6.7, 2.2Hz, 1H), 8.15 (ddd, J=8.6, 4.4, 2.3Hz, 1H), 7.58 (dd, J=10.3, 8.9Hz, 1H).

[0467] Step 8: 5-Cyano-2-fluorobenzoyl chloride

[0468] A solution of 5-cyano-2-fluorobenzoic acid (500 mg, 3.03 mmol) in thionyl chloride (3606 mg, 30.3 mmol) was heated at 90 °C for 2 hours. After cooling, the solution was concentrated, diluted with toluene, and then concentrated again to obtain 2-fluoro-5-cyanobenzoyl chloride, which could be used directly in the next step without further purification.

[0469] Step 9: N-(5-acetyl-4-fluoro(-1-methyl-1H-indazol-6-yl)-5-cyano-2-fluorobenzamide)

[0470] A solution of 1-(6-amino-4-fluoro-1-methyl-1H-indazol-5-yl)ethane-1-one (500 mg, 2.42 mmol) in tetrahydrofuran (12 mL) was added to sodium hydride (97 mg, 2.42 mmol, 60% purity, mineral oil as suspension medium) at 0 °C. After stirring for 30 min, 5-cyano-2-fluorobenzoyl chloride (487 mg, 2.66 mmol) dissolved in tetrahydrofuran (10 mL) was added in portions to the above mixture. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated ammonia solution (5 mL) at room temperature, diluted with water (10 mL), and filtered. The filter cake was ground with ethyl acetate (20 mL) and filtered to give the target compound (705 mg, 82% yield) as a yellow solid. LCMS calculated value: C 18 H 13 F2N4O2[M+H] +m / z = 355.1; Measured value: 355.1

[0471] Step 10: 4-Fluoro-3-(4-Fluoro-1-methyl-5-oxo-5,8-dihydro-1H-pyrazolol[4,3-g]quinoline-7-yl)benzonitrile

[0472] A mixture of N-(5-acetyl-4-fluoro-1-methyl-1H-indazol-6-yl)-5-cyano-2-fluorobenzamide (600 mg, 1.69 mmol), LiOH (81 mg, 3.38 mmol), and dioxane (7 mL) was stirred at 110 °C for 1.5 h. The reaction mixture was adjusted to pH approximately 5 with 1 M aqueous hydrochloric acid, diluted with water (30 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane (5%) to give the target compound (509 mg, 1.51 mmol, 89% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 11.79 (s, 1H), 8.38 (d, J = 0.9Hz, 1H), 8.33 (dd, J = 6.8, 2.1Hz, 1H), 8.16 (ddd, J = 8.6, 4.7, 2.2Hz, 1H), 7.71 (dd, J = 10.1, 8.7Hz, 1H), 7.38 (s, 1H), 6.05 (s, 1H), 4.05 (s, 3H). LCMS calculated C 18 H 11 F2N4O[M+H] + m / z = 337.1; Measured value: 337.1.

[0473] Example 15: 3-(4-fluoro-1-methyl-5-oxo-5,8-dihydro-1H-pyrazolo[4,3-g]quinolin-7-yl)-4-(methylthio)benzonitrile

[0474]

[0475] A mixture of 4-fluoro-3-(4-fluoro-1-methyl-5-oxo-5,8-dihydro-1H-pyrazolo[4,3-g]quinoline-7-yl)benzonitrile (100 mg, 0.30 mmol, Example 14) and sodium methanethiol (42 mg, 0.60 mmol) in NMP (1 mL) was stirred at room temperature for 3 hours. Ethyl acetate (10 mL) was added to the mixture, and the mixture was washed with water (2 × 10 mL) and saturated saline solution (2 × 10 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column, eluting with MeCN / H₂O (5%–95%, containing 5% FA) to give the target compound (50 mg, 46% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 11.77 (s, 1H), 8.38 (s, 1H), 7.98–7.97 (m, 2H), 7.60 (d, J = 9.1 Hz, 1H), 7.32 (s, 1H), 5.83 (d, J = 1.6 Hz, 1H), 4.03 (s, 3H), 2.54 (s, 3H). LCMS calculated C 19 H 14 FN4OS[M+H] + m / z = 365.4; measured value: 365.3.

[0476] Example 16: 3-(4-fluoro-1-methyl-5-oxo-5,8-dihydro-1H-pyrazolo[4,3-g]quinolin-7-yl)-4-(methanesulfonyl)benzonitrile

[0477]

[0478] A solution of 3-(4-fluoro-1-methyl-5-oxo-5,8-dihydro-1H-pyrazolo[4,3-g]quinolin-7-yl)-4-(methylthio)benzonitrile (50 mg, 0.15 mmol, Example 15) in acetone (0.5 mL), water (0.3 mL), tetrahydrofuran (0.36 mL), and methanol (0.36 mL) was mixed with potassium persulfate (oxone) (461 mg, 0.75 mmol). The mixture was stirred at 50 °C for 3 hours. The reaction mixture was cooled to room temperature and quenched with an aqueous solution of Na₂SO₃. The reaction mixture was diluted with H₂O (2 mL) and filtered. The filtrate was washed with water and dried under reduced pressure. The residue was purified by high performance liquid chromatography (C18 column, with MeCN / H2O (5%-95%, containing 0.05% NH4HCO3)) to obtain the target compound (12.1 mg, 20% yield) as a light red solid. 1¹H NMR (400MHz, DMSO-d⁶) δ 11.91 (s, 1H), 8.35 (m, 4H), 7.26 (s, 1H), 5.95 (d, J = 1.2Hz, 1H), 4.04 (s, 3H), 3.31 (s, 3H). LCMS calculated C 19 H 14 FN4O3S[M+H] + m / z = 397.1; Measured value: 396.8.

[0479] Example 17: 3-(5,7-difluoro-4-oxo-6-(o-methylphenylethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0480]

[0481] Step 1: N-(2-acetyl-3,5-difluoro-4-(o-methylphenylethynyl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0482]

[0483] 1-Ethynyl-2-methylbenzene (35 mg, 0.3 mmol), N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (100 mg, 0.2 mmol, Example 1, step 4), CuI (4 mg, 0.02 mmol), and PdCl2(PPh3)2 (14 mg, 0.02 mmol) in TEA (0.5 mL) and DMF (0.5 mL) were degassed and purged with nitrogen three times, and stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by acetonitrile / water (35-55%) on a C18 column to give the target compound (54 mg) as a white solid. LCMS calculated value: C 26 H 19 F2N2O4S[M+H] + m / z = 493.1; Measured value: 493.1.

[0484] Step 2: 3-(5,7-difluoro-4-oxo-6-(o-tolylethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0485] A mixture of N-(2-acetyl-3,5-difluoro-4-(o-tolylethynyl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide (54 mg, 0.11 mmol) and LiOtBu (17.6 mg, 0.22 mmol) in 2-methyltetrahydrofuran (1 mL) was stirred overnight at 75 °C. The reaction was quenched with 0.1 mL of 2.0 mol / L aqueous hydrochloric acid and concentrated under reduced pressure. The residue was purified by column chromatography on a C18 column with acetonitrile / water (35-55% containing 0.1 g ammonium carbonate) as the eluent to give the target compound (3.2 mg) as a brown solid. LCMS calculated C 26 H 15 F2N2O3S[MH] - m / z = 473.1; Measured value: 473.1.

[0486] Example 18: 3-(6-(benzyloxy)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0487]

[0488] Step 1: 1-(6-amino-3-(benzyloxy)-2,4-difluorophenyl)ethane-1-one

[0489] A mixture of 4-(benzyloxy)-2-bromo-3,5-difluoroaniline (250.0 mg, 0.79 mmol), tributyl(1-ethoxyvinyl)stanane (429 mg, 1.19 mmol), and Pd(PPh3)4 (91 mg, 0.079 mmol) in 1,4-dioxane was degassed and purged with nitrogen, and stirred at 100 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to give a crude intermediate, which was dissolved in acetone (2 mL) and 2 M hydrochloric acid (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA (15%)) to give the target compound (110 mg, 75.6% yield) as a yellow solid. LCMS calculated value: C 15 H 14 F2NO2[M+H] + m / z = 278.0; Measured value: 278.0

[0490] Step 2: N-(2-acetyl-4-(benzyloxy)-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0491] Under N2 conditions, a mixture of 1-(6-amino-3-(benzyloxy)-2,4-difluorophenyl)ethane-1-one (80.0 mg, 0.29 mmol) and isopropyl acetate (1 mL) was added to 5-cyano-2-(methanesulfonyl)benzoyl chloride (91 mg, 0.375 mmol), and the mixture was stirred at 80 °C for 18 hours. The mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic phases were washed with aqueous NaHCO3 solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA (20%)) to give the target compound (80 mg, 57% yield) as a white solid. LCMS calculated value: C 24 H 19 F2N2O5S[M+H] + m / z = 485.1; Measured value: 485.1.

[0492] Step 3: 3-(6-(benzyloxy)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0493] Under nitrogen protection at 0°C, LiOtBu (21 mg, 0.264 mmol) was added to a solution of N-(2-acetyl-4-(benzyloxy)-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide (80 mg, 0.165 mmol) in 1 mL of 2-methyltetrahydrofuran. The mixture was stirred overnight at 75°C. The reaction was quenched with aqueous hydrochloric acid (0.1 mL, 2 M). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (instrument: GILSON-281; ​​column: XBridge C18 250*19.00mm l 10um; temperature: 25℃; mobile phase: A: water (10mMNH4HCO3) B: acetonitrile; flow rate: 20.0mL / min; gradient: 30-60; detection wavelength: 214 / 254nm; retention time: 6-14min) to obtain the target compound (2.16mg, yield 2.8%) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.05 (s, 1H), 8.27 (d, J = 7.8Hz, 3H), 7.62–7.33 (m, 5H), 7.12 (s, 1H), 6.08 (s, 1H), 5.19 (s, 2H), 3.29 (s, 3H). LCMS calculated C 24 H 17 F2N2O4S[M+H] + m / z = 467.1; measured value: 467.3.

[0494] Example 19: 3-(5,7-difluoro-4-oxo-6-(prop-1-yn-1-yl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0495]

[0496] Step 1: 3-(5,7-difluoro-4-oxo-6-(3-(trimethylsilyl)prop-1-yn-1-yl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0497]

[0498] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (100 mg, 0.2 mmol, Example 1, step 5), trimethyl(prop-2-yn-1-yl)silane (35.0 mg, 0.31 mmol), CuI (4.0 mg, 0.02 mmol), and PdCl2(PPh3)2 (15.0 mg, 0.02 mmol) in TEA (0.5 mL) and DMF (2 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH = 20 / 1) to give the target compound (45 mg, 47.8% yield) as a white solid. LCMS C 23 H 21 F2N2O3SSi[M+H] + m / z = 471.1; Measured value: 471.1.

[0499] Step 2: 3-(5,7-difluoro-4-oxo-6-(prop-1-yn-1-yl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0500] To a mixture of 3-(5,7-difluoro-4-oxo-6-(3-(trimethylsilyl)prop-1-yn-1-yl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.06 mmol) in THF / water (3 mL / 0.3 mL), KOH (10.7 g, 0.19 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was separated by prep... -Purification was performed by HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00mml 10um; temperature: 25℃; mobile phase: A: water (10mM NH4HCO3), B: acetonitrile; flow rate: 20.0mL / min; gradient: 30-60; detection wavelength: 214 / 254nm; retention time: 6-14min) to obtain the target compound (3.1mg, yield 12.9%) as a white solid. ¹H NMR (400MHz, DMSO-d6) δ 12.22 (s, 1H), 8.35-8.21 (m, 3H), 7.18 (s, 1H), 6.24 (s, 1H), 3.34 (s, 3H), 2.17 (s, 3H). LCMS calculated value C 20 H 13 F2N2O3S[M+H] + m / z = 399.1; Measured value: 399.1.

[0501] Example 20: 3-(6-(but-1-yn-1-yl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0502]

[0503] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, step 5), 2-pentyneic acid (36 mg, 0.370 mmol), CuI (2.34 mg, 0.0123 mmol), PPh3 (3.2 mg, 0.0123 mmol), and Pd(OAc)2 (2.8 mg, 0.0123 mmol) in TEA (0.1 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 50 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00mml 10um; temperature: 25℃; mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; flow rate: 20.0mL / min; gradient: 30-60; detection wavelength: 214 / 254nm; retention time: 6-14min) to obtain the target compound (18.4mg, 36.3% yield) as a yellow solid. 1¹H NMR (400MHz, DMSO-d⁶) δ 12.22 (s, 1H), 8.42–8.18 (m, 3H), 7.12 (d, J = 9.1 Hz, 1H), 6.16 (s, 1H), 3.30 (s, 3H), 2.58–2.52 (m, 2H), 1.21 (dd, J = 12.8, 5.4 Hz, 3H). LCMS calculated C 21 H 15 F2N2O3S[M+H] + m / z = 413.4; Measured value: 413.4.

[0504] Example 21: 3-(5,7-difluoro-6-(3-methylbut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0505]

[0506] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.103 mol, Example 1, step 5), 3-methylbut-1-yne (10.5 mg, 0.154 mol), CuI (2 mg, 0.0103 mol), and PdCl2(PPh3)2 (7.23 mg, 0.0103 mol) in TEA (0.3 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00mml 10um; temperature: 25℃; mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; flow rate: 20.0mL / min; gradient: 30-60; detection wavelength: 214 / 254nm; retention time: 6-14min) to obtain the target compound (6.3mg, 14.34% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.24 (s, 1H), 8.42–8.18 (m, 3H), 7.11 (d, J = 10.0 Hz, 1H), 6.16 (s, 1H), 3.30 (s, 3H), 3.01–2.86 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H). LCMS calculated C 22 H 17 F2N2O3S[M+H] +m / z = 427.1; Measured value: 427.2.

[0507] Example 22: 3-(5,7-difluoro-4-oxo-6-(pyridin-4-ylethynyl)-1,4-dihydroquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0508]

[0509] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, step 5), 4-ethynylpyridine (19 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged with nitrogen three times, and stirred at 75 °C for 5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM (2%)) to give the crude product. The crude product was washed with MeOH and dried under vacuum to give the target compound (9.4 mg, 17% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.38 (s, 1H), 8.68 (d, J = 5.9Hz, 2H), 8.41–8.23 (m, 3H), 7.58 (d, J = 5.8Hz, 2H), 7.22 (s, 1H), 6.23 (s, 1H), 3.33 (s, 3H). LCMS calculated C 24 H 14 F2N3O3S[M+H] + m / z = 462.1; Measured value: 462.1.

[0510] Example 23: 3-(5,7-difluoro-6-(3-fluoro-3-methylbut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0511]

[0512] Under nitrogen protection at 0°C, DAST (12.4 mg, 0.07 mmol) was added dropwise to a DCM (2.5 mL) solution of 3-(5,7-difluoro-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (17.0 mg, 0.04 mmol, Example 1, step 6). The mixture was stirred at room temperature for 1 hour. The solution was diluted with dichloromethane (5 mL), poured into ice water (10 mL), and extracted with dichloromethane (10 mL × 2). The combined organic phases were dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane / methanol (2%)) to give the target compound (0.61 mg, 3.4% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.32 (s, 1H), 8.45–8.17 (m, 3H), 7.16 (d, J = 9.3 Hz, 1H), 6.19 (s, 1H), 3.29 (s, 3H), 1.77 (s, 3H), 1.72 (s, 3H). LCMS calculated C 22 H 16 F3N2O3S[M+H] + m / z = 445.1; Measured value: 445.1.

[0513] Example 24: 3-(5,7-difluoro-6-(oxetane-3-ylethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0514]

[0515] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (30 mg, 0.062 mmol, Example 1, step 5), 3-ethynyloxetane (7.6 mg, 0.093 mmol), CuI (1.18 mg, 0.0062 mmol), and PdCl2(PPh3)2 (7.6 mg, 0.0062 mmol) in TEA (0.2 mL) and DMF (0.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00mml 10um; temperature: 25℃; mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; flow rate: 20.0mL / min; gradient: 30-60; detection wavelength: 214 / 254nm; retention time: 6-14min) to obtain the target compound (0.5mg, 1.8% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO) δ 12.29 (s, 1H), 8.30 (s, 3H), 7.16 (s, 1H), 6.18 (s, 1H), 4.85 (dd, J = 8.5, 5.5Hz, 2H), 4.66–4.62 (m, 2H), 4.29 (dd, J = 15.5, 7.9Hz, 1H), 3.30 (s, 3H). LCMS calculated C 22 H 15 F2N2O4S[M+H] + m / z = 441.1; Measured value: 441.1.

[0516] Example 25: 3-(5,7-difluoro-4-oxo-6-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,4-dihydroquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0517]

[0518] Step 1: 1-(6-amino-2,4-difluoro-3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)ethane-1-one

[0519] A mixture of 1-(6-amino-2,4-difluoro-3-iodophenyl)ethane-1-one (500.0 mg, 1.68 mmol), 4-ethynyltetrahydro-2H-pyran (278.3 mg, 2.52 mmol), PdCl2(PPh3)2 (117.9 mg, 0.168 mmol), CuI (31.9 mg, 0.168 mmol), and TEA (2 mL) in DMF (8 mL) was stirred at 60 °C for 2 hours under nitrogen protection. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using petroleum ether / ethyl acetate (15%) as eluent) to give the target compound (360 mg, 76.5% yield) as a yellow solid. LCMS calculated value: C 15 H 16 F2NO2[M+H] + m / z = 280.3; Measured value: 280.3.

[0520] Step 2: 1-(6-amino-2,4-difluoro-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)ethane-1-one

[0521] A mixture of 1-(6-amino-2,4-difluoro-3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)ethane-1-one (200.0 mg, 0.72 mmol) and Pd / C (10%, 200.0 mg) in MeOH (15 mL) was stirred at room temperature under H2 for 18 hours. The reaction mixture was diluted with methanol (5 mL) and filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to give the target compound (170.0 mg, 83.4% yield) as a white solid, which could be used directly for the next step without further purification. LCMS calculated value: C 15 H 20 F2NO2[M+H] + m / z = 284.2; measured value 284.2.

[0522] Step 3: N-(2-acetyl-3,5-difluoro-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0523] At room temperature, 5-cyano-2-(methanesulfonyl)benzoyl chloride (175.2 mg, 0.72 mol) was added in portions to a 3 mL solution of 1-(6-amino-2,4-difluoro-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)ethane-1-one (170.0 mg, 175.2 mol) in isopropyl acetate. The mixture was evacuated and purged with N2 for 2 minutes. The resulting mixture was stirred in a sealed tube at 80 °C for 18 hours. The mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine, dried over sodium sulfate, and filtered. The mixture was concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography, eluted with PE / EA (3 / 1), to give the target compound (200 mg, 56.6% yield) as a white solid. LCMS calculated value: C 24 H 25 F2N2O5S[M+H] + m / z = 491.3; measured value 491.3.

[0524] Step 4: 3-(5,7-difluoro-4-oxo-6-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,4-dihydroquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0525] LiOtBu (52.0 mg, 0.65 mmol) was added to a solution of N-(2-acetyl-3,5-difluoro-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide (200.0 mg, 0.41 mmol) in 5 mL of 2-methyltetrahydrofuran at 0 °C under nitrogen protection. The mixture was stirred overnight at 75 °C under nitrogen protection. The reaction mixture was quenched with hydrochloric acid (0.7 mL, 2 M) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography, eluted with DCM / MeOH (40 / 1), to give the target compound (12.3 mg, 6.4% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.06 (s, 1H), 8.38–8.27 (m, 3H), 7.06 (d, J = 10.4 Hz, 1H), 6.10 (d, J = 1.4 Hz, 1H), 3.89–3.81 (m, 2H), 3.31–3.23 (m, 5H), 2.72–2.66 (m, 2H), 1.71–1.62 (m, 2H), 1.55–1.43 (m, 3H), 1.25–1.11 (m, 2H). LCMS calculated C 24 H 23 F2N2O4S[M+H] + m / z = 473.5; Measured value: 473.5.

[0526] Example 26: 3-(6-(cyclobutylmethoxy)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0527]

[0528] Step 1: 2-(cyclobutylmethoxy)-1,3-difluoro-5-nitrobenzene

[0529] Sodium hydride (60 wt.%, 452 mg) was added fractionally to a mixture of 1,2,3-trifluoro-5-nitrobenzene (1.0 g, 5.65 mmol) and cyclobutylmethanol (584.0 mg, 6.78 mmol) in DMF (12 mL) at 0 °C under nitrogen protection. The reaction mixture was stirred at room temperature under nitrogen protection for 18 hours. The reaction mixture was quenched with ice-saturated sodium bicarbonate aqueous solution (10 mL). The resulting mixture was extracted with EA (100 mL × 3). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (100 / 3)) to give the target compound (1.26 g, 76.4% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.23-8.08 (m, 2H), 4.29 (d, J=6.7Hz, 2H), 2.79-2.63 (m, 1H), 2.08-1.99 (m, 2H), 1.96-1.76 (m, 4H).

[0530] Step 2: 4-(cyclobutylmethoxy)-3,5-difluoroaniline

[0531] Zinc powder (3.3 g, 51.0 mmol) was added to a mixture of 2-(cyclobutylmethoxy)-1,3-difluoro-5-nitrobenzene (1.26 g, 5.1 mmol) in methanol (10 mL) and saturated ammonium chloride aqueous solution (4 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (25 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with PE / EA (15 / 1) to give the target compound (960 mg, yield 88.3%) as a yellow oil. 1¹H NMR (400MHz, DMSO-d⁶) δ 6.31–6.11 (m, 2H), 5.37 (s, 2H), 3.83 (d, J = 6.7 Hz, 2H), 2.60 (dt, J = 14.6, 7.4 Hz, 1H), 2.06–1.95 (m, 2H), 1.91–1.70 (m, 4H). LCMS calculated C 11 H 14 F2NO[M+H] + m / z = 214.3; Measured value: 214.3.

[0532] Step 3: 2-Bromo-4-(cyclobutylmethoxy)-3,5-difluoroaniline

[0533] NBS (396.9 mg, 2.34 mmol) was added fractionally to a CH3CN (8 mL) solution of 4-(cyclobutylmethoxy)-3,5-difluoroaniline (500.0 mg, 2.34 mmol). The resulting mixture was stirred at 0 °C for 20 min. The mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The mixed organic phase was washed with sodium bicarbonate aqueous solution and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column using PE / EA (12 / 1) elution to give the target compound (550 mg, yield 81.0%) as a red oil. LCMS calculated value C 11 H 13 BrF₂NO[M+H] + : rm / z = 292.1; Measured value: 292.1.

[0534] Step 4: 1-(6-amino-3-(cyclobutylmethoxy)-2,4-difluorophenyl)ethane-1-one

[0535] A mixture of 2-bromo-4-(cyclobutylmethoxy)-3,5-difluoroaniline (300.0 mg, 1.03 mmol), tributyl(1-ethoxyvinyl)stanane (558.0 mg, 1.55 mmol), and Pd(PPh3)4 (118.9 mg, 0.10 mmol) in 1,4-dioxane (3 mL) was stirred at 100 °C under nitrogen for 18 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in acetone (3 mL) and hydrochloric acid (1.5 mL, 2N) was added. The mixture was stirred at room temperature for 2 hours and adjusted to pH 7-8 with saturated sodium bicarbonate solution at 0 °C. The mixture was extracted with EA (15 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The product was separated by silica gel column chromatography, eluting with PE / EA (100 / 7) to give the target compound (100.0 mg, 38.1% yield) as a yellow oil. LCMS calculated Cp 13 H 16 F2NO2[M+H] + m / z = 256.2; Measured value: 256.2.

[0536] Step 5: N-(2-acetyl-4-(cyclobutylmethoxy)-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0537] At room temperature, 5-cyano-2-(methanesulfonyl)benzoyl chloride (85.7 mg, 0.35 mmol) was added fractionally to a solution of 1-(6-amino-3-(cyclobutylmethoxy)-2,4-difluorophenyl)ethane-1-one (75.0 mg, 0.29 mmol) in isopropyl acetate (1.5 mL). The mixture was degassed and purged with N2 for 2 min. The resulting mixture was stirred at 80 °C for 18 h. The mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5 / 1) to give the target compound (70 mg, 52.2% yield) as a white solid. LCMS calculated value: C 22 H 21 F2N2O5S[M+H] + m / z = 463.2; Measured value: 463.2.

[0538] Step 6: 3-(6-(cyclobutylmethoxy)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0539] A mixture of N-(2-acetyl-4-(cyclobutylmethoxy)-3,5-difluorophenyl)-5-cyano-2-(methanesulfonyl)benzamide (55.0 mg, 0.12 mmol) and LiOtBu (15.2 mg, 0.19 mmol) in 2-methyltetrahydrofuran (2 mL) was stirred overnight at 75 °C. The reaction mixture was quenched with dilute hydrochloric acid (0.3 mL, 2 M) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane / methanol (40 / 1) as eluent to give the target compound (3.6 mg, 6.7% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.09 (s, 1H), 8.41–8.26 (m, 3H), 7.15 (d, J = 11.1 Hz, 1H), 6.08 (s, 1H), 4.07 (d, J = 6.6 Hz, 2H), 3.29 (s, 3H), 2.12–1.98 (m, 3H), 1.92–1.79 (m, 4H). LCMS calculated C 22 H 20 F2N2O4S[M+H] + m / z = 445.1; Measured value: 445.4.

[0540] Example 27: 3-(5,7-difluoro-6-((2-methylpyridin-4-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0541]

[0542] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.103 mol, Example 1, step 5), 4-ethynyl-2-methylpyridine (18.0 mg, 0.154 mol), CuI (2 mg, 0.0103 mol), and PdCl2(PPh3)2 (7.23 mg, 0.0103 mol) in TEA (0.3 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00mml 10um; temperature: 25℃; mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; flow rate: 20.0mL / min; gradient: 30-60; detection wavelength: 214 / 254nm; retention time: 6-14min) to obtain the target compound (3.61mg, 7.4% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) 12.39 (s, 1H), 8.54 (d, J = 5.0Hz, 1H), 8.43–8.17 (m, 3H), 7.47 (s, 1H), 7.37 (d, J = 5.0Hz, 1H), 7.23 (s, 1H), 6.24 (s, 1H), 3.30 (s, 3H), 2.52 (s, 3H). LCMS calculated C 25 H 16 F2N3O3S[M+H] + m / z = 476.1; measured value: 476.4.

[0543] Example 28: 3-(5,7-difluoro-6-((3-methylpyridin-4-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0544]

[0545] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.1 mmol, Example 1, step 5), 4-ethynyl-3-methylpyridine (18.1 mg, 0.15 mmol), CuI (1.9 mg, 0.01 mmol), and PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00mml 10um; temperature: 25℃; mobile phase: A: water (10mmol ammonium bicarbonate) B: acetonitrile; flow rate: 20.0mL / min; gradient: 30-60; detection wavelength: 214 / 254nm; retention time: 6-14min) to obtain the target compound (12.2mg, 25.6% yield) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 12.38 (s, 1H), 8.61 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.41–8.22 (m, 3H), 7.51 (d, J = 5.0 Hz, 1H), 7.23 (s, 1H), 6.24 (s, 1H), 3.34 (s, 3H), 2.47 (s, 3H). LCMS calculated C 25 H 16 F2N3O3S[M+H] + m / z = 476.4; Measured value: 476.4.

[0546] Example 29: 3-(5,7-difluoro-6-((2-methylpyridin-3-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0547]

[0548] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (65 mg, 0.134 mmol, Example 1, step 5), 3-ethynyl-2-methylpyridine (24 mg, 0.2 mmol), Pd(PPh3)2Cl2 (10 mg, 0.013 mmol), CuI (3 mg, 0.013 mmol), and TEA (0.5 mL) in DMF (1 mL) was degassed and purged with nitrogen, and stirred at 75 °C for 8 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / DCM (2%) to obtain a crude product, which was washed with MeOH and dried under vacuum to give the target compound (25.1 mg, 40% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.34 (s, 1H), 8.52 (dd, J = 4.8, 1.3Hz, 1H), 8.41–8.21 (m, 3H), 7.95 (d, J = 7.5Hz, 1H), 7.33 (dd, J = 7.7, 4.9Hz, 1H), 7.21 (d, J = 9.1Hz, 1H), 6.22 (s, 1H), 3.32 (s, 3H), 2.70 (s, 3H). LCMS calculated C 25 H 16 F2N3O3S[M+H] + m / z = 476.0; measured value: 476.1.

[0549] Example 30: 3-(5,7-difluoro-6-((2-methoxyphenyl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0550]

[0551] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.103 mol, Example 1, step 5), 1-ethynyl-2-methoxybenzene (20.3 mg, 0.154 mol), CuI (2 mg, 0.0103 mol), and PdCl2(PPh3)2 (7.23 mg, 0.0103 mol) in TEA (0.3 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (13.32 mg, 26.4% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.31 (s, 1H), 8.43–8.21 (m, 3H), 7.56–7.39 (m, 2H), 7.23–7.09 (m, 2H), 7.02 (t, J = 7.3Hz, 1H), 6.20 (s, 1H), 3.89 (s, 3H). LCMS calculated C 26 H 17 F2N2O4S[M+H] + m / z = 491.4; Measured value: 491.4.

[0552] Example 31: 3-(5,7-difluoro-6-((6-methylpyridin-2-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0553]

[0554] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.103 mol, Example 1, step 5), 2-ethynyl-6-methylpyridine (18.0 mg, 0.154 mol), CuI (2 mg, 0.0103 mol), and PdCl2(PPh3)2 (7.23 mg, 0.0103 mol) in TEA (0.3 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with hydrochloric acid solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (22.1 mg, 45.1% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.38 (s, 1H), 8.49–8.20 (m, 3H), 7.79 (t, J = 7.8Hz, 1H), 7.51 (d, J = 7.6Hz, 1H), 7.35 (d, J = 7.8Hz, 1H), 7.26 (s, 1H), 6.27 (s, 1H), 3.38 (s, 3H), 2.55 (s, 3H). LCMS calculated rC 25 H 16 F2N3O3S[M+H] + m / z = 476.3; Measured value: 476.3.

[0555] Example 32: 3-(6-((3,5-dimethylpyridin-4-yl)ethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0556]

[0557] A mixture of 1.5 mL of DMF in the form of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (65 mg, 0.13 mmol, Example 1, Step 5) and 4-ethynyl-3,5-dimethylpyridine (44 mg, 0.33 mmol) was added under a nitrogen atmosphere to Pd(PPh3)2Cl2 (9.1 mg, 0.013 mmol), CuI (2.5 mg, 0.013 mmol), and TEA (0.6 mL). The mixture was stirred overnight at 75 °C. The mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM (1 / 40)) to give the target compound (11.2 mg, 17.2% yield) as a yellow solid. 1 ¹H NMR (401 MHz, DMSO) δ 12.38 (s, 1H), 8.42 (s, 2H), 8.32 (m, 3H), 7.24 (s, 1H), 6.24 (s, 1H), 3.33 (s, 3H), 2.46 (s, 6H). LCMS calculated C 26 H 18 F2N3O3S[M+H] + m / z = 490.5; Measured value: 490.0.

[0558] Example 33: 3-(6-((2-chlorophenyl)ethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0559]

[0560] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (55 mg, 0.113 mmol, Example 1, Step 5), 1-chloro-2-ethynylbenzene (31 mg, 0.226 mmol), Pd(PPh3)2Cl2 (8 mg, 0.011 mmol), CuI (3 mg, 0.011 mmol), and TEA (0.5 mL) in DMF (1 mL) was degassed and purged with nitrogen, and stirred at 65 °C for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM (2%)) to obtain a crude product, which was washed with MeOH and dried under vacuum to give the target compound (18.7 mg, 33% yield) as a yellow solid.1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.35 (s, 1H), 8.42–8.20 (m, 3H), 7.73 (dd, J = 7.5, 1.5Hz, 1H), 7.65 (dd, J = 8.0, 0.9Hz, 1H), 7.51 (td, J = 7.8, 1.8Hz, 1H), 7.45 (td, J = 7.5, 1.2Hz, 1H), 7.23 (s, 1H), 6.24 (s, 1H), 3.33 (s, 3H). LCMS calculated C 25 H 14 ClF₂N₂O₃S[M+H] + m / z = 495.0; Measured value: 495.0.

[0561] Example 34: 3-(5,7-difluoro-4-oxo-6-((tetrahydrofuran-3-yl)ethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0562]

[0563] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (100 mg, 0.206 mmol, Example 1, step 5), 3-ethynyltetrahydrofuran (29.6 mg, 0.308 mmol), CuI (4.0 mg, 0.020 mmol), and PdCl2(PPh3)2 (14.46 mg, 0.02 mmol) in TEA (1 L) and DMF (3 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (45 mg, 48.1% yield) as a yellow solid. 1¹H NMR (400 MHz, DMSO-d⁶) δ 12.25 (s, 1H), 8.49–8.19 (m, 3H), 7.16 (s, 1H), 6.18 (s, 1H), 4.01 (t, J = 7.7 Hz, 1H), 3.91–3.83 (m, 1H), 3.77 (dd, J = 14.4, 7.8 Hz, 1H), 3.64 (dd, J = 8.0, 6.5 Hz, 1H), 3.47–3.33 (m, 4H), 2.34–2.25 (m, 1H), 2.05–1.89 (m, 1H). LCMS calculated C 23 H 17 F2N2O4S[M+H]+: m / z=455.5; measured value: 455.5.

[0564] Example 35: 3-(6-((3,5-dimethylisoxazol-4-yl)ethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0565]

[0566] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, Step 5), 4-ethynyl-3,5-dimethylisoxazole (23 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged with nitrogen three times, and stirred at 70 °C for 5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM (2%)) to obtain a crude product, which was washed with MeOH and dried under vacuum to give the target compound (16.3 mg, 28% yield) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 12.33 (s, ¹H), 8.41–8.23 (m, ³H), 7.20 (s, ¹H), 6.21 (s, ¹H), 3.33 (s, ³H), 2.54 (s, ³H), 2.32 (s, ³H). LCMS calculated C 24 H 16 F2N3O4S[M+H] + m / z = 480.1; Measured value: 480.1.

[0567] Example 36: 3-(5,7-difluoro-4-oxo-6-((2-(trifluoromethoxy)phenyl)ethynyl)-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile

[0568]

[0569] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, Step 5), 1-ethynyl-2-(trifluoromethoxy)benzene (35 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 65 °C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM (2%)) to obtain a crude product, which was washed with MeOH and dried under vacuum to give the target compound (9.9 mg, 15% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.37 (s, 1H), 8.42–8.25 (m, 3H), 7.78 (dd, J = 7.6, 1.4Hz, 1H), 7.66–7.60 (m, 1H), 7.56 (d, J = 8.3Hz, 1H), 7.54–7.50 (m, 1H), 7.26 (s, 1H), 6.26 (s, 1H), 3.36 (s, 3H). LCMS calculated C 26 H 14 F5N2O4S[M+H] + m / z = 545.0; measured value: 545.1.

[0570] Example 37: 3-(6-((2-(difluoromethoxy)phenyl)ethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0571]

[0572] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, Step 5), 1-(difluoromethoxy)-2-ethynylbenzene (31 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 65 °C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM (2%)) to obtain a crude product, which was washed with MeOH and dried under vacuum to give the target compound (9.3 mg, 14% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.34 (s, 1H), 8.47–8.20 (m, 3H), 7.70 (dd, J = 7.8, 1.2Hz, 1H), 7.58–7.53 (m, 1H), 7.53–7.31 (m, 3H), 7.26–7.12 (m, 1H), 6.21 (s, 1H), 3.33 (s, 3H). LCMS calculated C 26 H 15 F4N2O4S[M+H] + m / z = 527.0; Measured value: 527.0.

[0573] Example 38: 3-(5,7-difluoro-6-((3-methoxypyridin-2-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0574]

[0575] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, Step 5), 4-ethynyl-3-methoxypyridine (25 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 70 °C for 5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using MeOH / DCM (2%)) to obtain a crude product, which was further purified by preparative chromatography (MeCN / water (containing 0.1% NH3·H2O) = 0 / 100 to 100 / 0) to obtain the target compound (12.4 mg, 21% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.34 (s, 1H), 8.53 (s, 1H), 8.39–8.29 (m, 3H), 8.28 (d, J = 4.8Hz, 1H), 7.51 (d, J = 4.8Hz, 1H), 7.26 (s, 1H), 6.28 (s, 1H), 4.01 (s, 3H), 3.35 (s, 3H). LCMS calculated C 25 H 16 F2N3O4S[M+H] + m / z = 492.1; Measured value: 492.1.

[0576] Example 39: 3-(5,7-difluoro-4-oxo-6-(p-methylphenylethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0577]

[0578] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, step 5), 1-ethynyl-4-methylbenzene (22 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 65 °C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using MeOH / DCM (2%)) to obtain a crude product, which was washed with MeOH and dried under vacuum to give the target compound (23 mg, 39% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.30 (s, 1H), 8.41–8.19 (m, 3H), 7.50 (d, J = 7.8Hz, 2H), 7.29 (d, J = 7.9Hz, 2H), 7.18 (d, J = 9.7Hz, 1H), 6.20 (s, 1H), 3.31 (s, 3H), 2.37 (s, 3H). LCMS calculated C 26 H 17 F2N2O3S[M+H] + m / z = 475.1; Measured value: 475.1.

[0579] Example 40: 3-(5,7-difluoro-6-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0580]

[0581] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, Step 5), 3-ethynylimidazo[1,2-b]pyridazine (27 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 75 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM (2%)) to obtain a crude product, which was further purified by prep-HPLC (MeCN / water (containing 0.1% NH3·H2O) = 0 / 100 to 100 / 0) to obtain the target compound (7.2 mg, 12% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.36 (s, 1H), 8.74 (d, J = 3.6Hz, 1H), 8.41–8.24 (m, 5H), 7.43 (dd, J = 9.2, 4.4Hz, 1H), 7.22 (d, J = 9.4Hz, 1H), 6.22 (s, 1H), 3.32 (s, 3H). LCMS calculated C 25 H 14 F2N5O3S[M+H] + m / z = 502.1; Measured value: 502.1.

[0582] Example 41: 3-(5,7-difluoro-6-((3-methoxypyridin-2-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0583]

[0584] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (60 mg, 0.123 mmol, Example 1, Step 5), 2-ethynyl-3-methoxypyridine (25 mg, 0.185 mmol), CuI (3 mg, 0.012 mmol), and PdCl2(PPh3)2 (9 mg, 0.012 mmol) in TEA (0.4 mL) and DMF (1 mL) was degassed, purged three times with nitrogen, and stirred at 75 °C for 5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by elution with MeOH / DCM (2%) on a silica gel column to obtain a crude product, which was washed with MeOH and dried under vacuum to give the target compound (10.9 mg, 18% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.34 (s, 1H), 8.41–8.25 (m, 3H), 8.22 (d, J = 4.1 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 8.5, 4.6 Hz, 1H), 7.20 (d, J = 9.8 Hz, 1H), 6.22 (s, 1H), 3.93 (s, 3H), 3.32 (s, 3H). LCMS calculated C 25 H 16 F2N3O4S[M+H] + m / z = 492.1; measured value: 492.0.

[0585] Example 42: 3-(6-((2-cyanophenyl)ethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0586]

[0587] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.1 mmol, Example 1, Step 5), 2-ethynylbenzonitrile (19.6 mg, 0.15 mmol), CuI (1.9 mg, 0.01 mmol), and PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (23.4 mg, 48.2% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.40 (s, 1H), 8.38–8.25 (m, 3H), 8.04–7.97 (m, 1H), 7.88–7.77 (m, 2H), 7.67 (td, J = 7.6, 1.5Hz, 1H), 7.29 (s, 1H), 6.31 (s, 1H), 3.37 (s, 3H). LCMS calculated C 26 H 14 F2N3O3S[M+H] + m / z = 486.4; Measured value: 486.4.

[0588] Example 43: 3-(5,7-difluoro-6-((3-methoxypyrazin-2-yl)ethynyl)-4-oxo-1,4-dihydroquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0589]

[0590] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (40 mg, 0.08 mmol, Example 1, step 5), 2-ethynyl-3-methoxypyrazine (16.5 mg, 0.12 mmol), CuI (1.5 mg, 0.008 mmol), and PdCl2(PPh3)2 (5.6 mg, 0.008 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (19.2 mg, 48.8% yield) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 12.40 (s, 1H), 8.50–8.07 (m, 5H), 7.25 (s, 1H), 6.30 (s, 1H), 4.03 (s, 3H), 3.38 (s, 3H). LCMS calculated C 24 H 15 F2N4O4S[M+H] + m / z = 493.4; Measured value: 493.4.

[0591] Example 44: 3-(5,7-difluoro-4-oxo-6-((2-(trifluoromethyl)phenyl)ethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0592]

[0593] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.1 mmol, Example 1, step 5), 1-ethynyl-2-(trifluoromethyl)benzene (26.2 mg, 0.15 mmol), CuI (1.9 mg, 0.01 mmol), and PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (6.2 mg, 11.7% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.38 (s, 1H), 8.41–8.24 (m, 3H), 7.93–7.84 (m, 2H), 7.78 (t, J = 7.5Hz, 1H), 7.75–7.64 (m, 1H), 7.22 (s, 1H), 6.24 (s, 1H), 3.31–3.25 (m, 3H). LCMS calculated C 26 H 14 F5N2O3S[M+H] + m / z = 529.4; Measured value: 529.4.

[0594] Example 45: 3-(5,7-difluoro-6-((3-methyloxetane-3-yl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0595]

[0596] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (40 mg, 0.08 mmol, Example 1, step 5), 3-ethynyl-3-methyloxetane (11.5 mg, 0.12 mmol), CuI (1.5 mg, 0.008 mmol), and PdCl2(PPh3)2 (5.6 mg, 0.008 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (18.1 mg, 49.8% yield) as a white solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 12.27 (s, 1H), 8.47–8.17 (m, 3H), 7.15 (s, 1H), 6.18 (s, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.49 (d, J = 5.6 Hz, 2H), 3.30–3.23 (m, 3H), 1.68 (s, 3H). LCMS calculated C 23 H 17 F2N2O4S[M+H] + m / z = 455.4; Measured value: 455.4.

[0597] Example 46: 3-(5,7-difluoro-6-(oxetane-3-ylethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(ethanesulfonyl)benzonitrile

[0598]

[0599] Step 1: 5-Cyano-2-(Ethylthio)benzoic acid

[0600] Sodium ethanethiol (1.8 g, 21.8 mmol) was slowly added to a mixture of 5-cyano-2-fluorobenzoic acid (2.0 g, 12.1 mmol) and DMF (25 mL) at 0 °C under nitrogen protection. The reaction mixture was stirred at 78 °C under nitrogen protection for 1 hour. The reaction mixture was diluted with water (120 mL) and the pH was adjusted to 2–3 with hydrochloric acid solution (2N). The mixture was extracted with ethyl acetate (120 mL × 3). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the target compound (2.4 g, 95.0% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ13.53 (s, 1H), 8.21 (d, J=2.0Hz, 1H), 7.91 (dd, J=8.5, 2 .0Hz, 1H), 7.57 (d, J=8.5Hz, 1H), 3.02 (q, J=7.3Hz, 2H), 1.29 (t, J=7.3Hz, 3H).

[0601] Step 2: 5-Cyano-2-(Ethylthio)benzoyl chloride

[0602] Under nitrogen protection at 0°C, oxalyl chloride (0.96 g, 7.7 mmol) and 1 drop of DMF were added dropwise to a DCM (25 mL) solution of 5-cyano-2-(ethylthio)benzoic acid (800 mg, 3.84 mmol). The reaction mixture was stirred for 1 hour under nitrogen protection at room temperature and then concentrated under nitrogen protection to give a crude product as a yellow solid, which was used for the next step.

[0603] Step 3: N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(ethylthio)aniline

[0604] A mixture of 5-cyano-2-(ethylthio)benzoyl chloride (864.0 mg, 3.84 mmol) and isopropyl acetate (24 mL) of 1-(6-amino-2,4-difluoro-3-iodophenyl)ethane-1-one (808.8 mg, 2.72 mmol) was stirred overnight at 80 °C under nitrogen protection. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was ground with CH3CN (6 mL) to give the target product (500 mg, 37.8% yield) as a white solid. LCMS calculated value: C 18 H 14 F2IN2O2S[M+H] + m / z = 487.3; Measured value: 487.3.

[0605] Step 4: 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(ethylthio)benzonitrile

[0606] A mixture of N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(ethylthio)aniline (400.0 mg, 0.84 mmol) and LiOtBu (78.8 mg, 0.96 mmol) in 2-methyltetrahydrofuran (7 mL) was stirred overnight at 80 °C. The reaction mixture was quenched with dilute hydrochloric acid (0.1 mL, 2N) and extracted with EtOAc (50 mL). The organic phase was concentrated under reduced pressure to give a crude product, which was then ground with CH3CN (5 mL) to give the desired product (340 mg, 68.5% yield) as a green solid.

[0607] LCMS calculated value C 18 H 12 F2IN2OS[M+H]+: m / z = 469.3; measured value is 469.3.

[0608] Step 5: 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(ethanesulfonyl)benzonitrile

[0609] To a mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(ethylthio)benzonitrile (280.0 mg, 0.60 mmol) and acetone / H₂O / THF / MeOH (2.5 mL / 1.8 mL / 2.0 mL / 2.0 mL), potassium persulfate (oxone) (1.8 g, 3.0 mmol) was added. The resulting mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The reaction was quenched with an aqueous solution of Na₂SO₃. The reaction mixture was diluted with water (120 mL) and filtered. The filter cake was washed with water and dried under reduced pressure. The crude product was slurried with MTBE (5 mL × 2) and then with MeOH (5 mL × 2) to give the desired product (170 mg, 56.6% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.22 (s, 1H), 8.45–8.12 (m, 3H), 7.16 (d, J = 8.4Hz, 1H), 6.17 (s, 1H), 3.37–3.34 (m, 2H), 1.12 (t, J = 7.2Hz, 3H). LCMS calculated C 18 H 12 F2IN2O3S[M+H] + m / z = 501.2; the measured value is 501.2.

[0610] Step 6: 3-(5,7-difluoro-6-(oxetane-ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(ethanesulfonyl)benzonitrile

[0611] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(ethanesulfonyl)benzonitrile (50 mg, 0.1 mmol), 3-ethynyloxetane (12.3 mg, 0.15 mmol), CuI (2.0 mg, 0.01 mmol), and PdCl2(PPh3)2 (7.1 mg, 0.01 mmol) in TEA (0.4 mL) and DMF (1.2 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (24.4 mg, 53.7% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶ δ 12.27 (s, 1H), 8.45–8.10 (m, 3H), 7.15 (s, 1H), 6.16 (s, 1H), 4.85 (dd, J = 8.5, 5.5Hz, 2H), 4.64 (dd, J = 6.8, 5.7Hz, 2H), 4.38–4.19 (m, 1H), 3.48–3.34 (m, 2H), 1.13 (t, J = 7.1Hz, 3H). LCMS calculated C 23 H 17 F2N2O4S[M+H] + m / z = 455.4; Measured value: 455.4.

[0612] Example 47: 3-(6-((3-(difluoromethoxy)pyridin-4-yl)ethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0613]

[0614]

[0615] Step 1: 3-(difluoromethoxy)-4-iodopyridine

[0616] To a DMF (10 mL) solution of 4-iodopyridin-3-ol (500 mg, 2.262 mmol), Cs₂CO₃ (885 mg, 2.715 mmol) and sodium 2-chloro-2,2-difluoroacetate (414 mg, 2.715 mmol) were added. The mixture was stirred at 80 °C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (40 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EA / PE (17%)) to give the target compound (63 mg, 10% yield) as a colorless oil. LCMS calculated value: C₆H₅F₂INO[M+H] + m / z = 271.9; Actual value: 271.9.

[0617] Step 2: 3-(5,7-difluoro-4-oxo-6-((trimethylsilyl)ethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0618] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (100 mg, 0.206 mmol, the product from step 5 of Example 1), ethynyltrimethylsilane (202 mg, 2.06 mmol), CuI (4 mg, 0.021 mmol), and PdCl2(PPh3)2 (15 mg, 0.021 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed under nitrogen and circulated three times, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (2%), to give the target compound (62 mg, 66% yield) as a yellow solid. LCMS calculated value C 22 H 19 F2N2O3SSi[M+H] + m / z = 457.1; measured value: 457.0.

[0619] Step 3: 3-(6-ethynyl-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0620] A solution of 3-(5,7-difluoro-4-oxo-6-((trimethylsilyl)ethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (62 mg, 0.136 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added to potassium carbonate (38 mg, 0.272 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with hydrochloric acid, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (2%), to give the target compound (32 mg, 61% yield) as a white solid. LCMS calculated C 19 H 11 F2N2O3S[M+H] + m / z = 385.0; Actual value: 385.0.

[0621] Step 4: 3-(6-((3-(difluoromethoxy)pyridin-4-yl)ethynyl)-5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0622] A mixture of 3-(6-ethynyl-5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (32 mg, 0.083 mmol), 3-(difluoromethoxy)-4-iodopyridine (45 mg, 0.167 mmol), CuI (2 mg, 0.008 mmol), and PdCl2(PPh3)2 (6 mg, 0.008 mmol) in TEA (0.3 mL) and DMF (0.8 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with methanol / dichloromethane (3%) as eluent to obtain a crude product, which was then further purified by Prep-HPLC to obtain the target compound (1.5 mg, yield 3%) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.40 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 4.9Hz, 1H), 8.38–8.27 (m, 3H), 7.71 (d, J = 4.9Hz, 1H), 7.44 (t, J = 72.9Hz, 1H), 7.22 (s, 1H), 6.24 (s, 1H), 3.30 (s, 3H). LCMS calculated C 25 H 14 F4N3O4S[M+H]+ m / z = 528.1; Measured value: 528.1.

[0623] Example 48: 3-(5,7-difluoro-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0624]

[0625] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.1 mmol, Example 1, step 5), 3-methyl-3-(methanesulfonyl)but-1-yne (21.9 mg, 0.15 mmol), CuI (1.9 mg, 0.01 mmol), and PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (17.4 mg, 34.5% yield) as a white solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 12.32 (s, 1H), 8.47–8.10 (m, 3H), 7.16 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 3.31–3.26 (m, 3H), 3.21 (s, 3H), 1.69 (s, 3H). LCMS calculated C 23 H 19 F2N2O5S2[M+H] + m / z = 505.4; Measured value: 505.4.

[0626] Example 49: 3-(5,7-difluoro-6-(4-methoxybut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0627]

[0628] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.1 mmol, Example 1, step 5), 4-methoxybut-1-yne (12.6 mg, 0.15 mmol), CuI (1.9 mg, 0.01 mmol), and PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) in TEA (0.5 mL) and DMF (1.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (17.1 mg, 38.7% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.24 (s, 1H), 8.47–8.15 (m, 3H), 7.12 (d, J = 9.8Hz, 1H), 6.16 (d, J = 1.3Hz, 1H), 3.55 (t, J = 6.5Hz, 2H), 3.32 (s, 3H), 3.30 (s, 3H), 2.79 (t, J = 6.4Hz, 2H). LCMS calculated C 22 H 17 F2N2O4S[M+H] + m / z = 443.1; measured value: 443.4.

[0629] Example 50: 3-(5,7-difluoro-6-(3-methoxy-3-methylbut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0630]

[0631] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (25 mg, 0.051 mmol, Example 1, Step 5), 3-methoxy-3-methylbut-1-yne (7.6 mg, 0.077 mmol), CuI (1.0 mg, 0.0051 mmol), and PdCl2(PPh3)2 (3.6 mg, 0.0051 mmol) in TEA (0.2 mL) and DMF (0.5 mL) was degassed, purged three times with nitrogen, and stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (4.09 mg, 17.6% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.31 (s, 1H), 8.43–8.17 (m, 3H), 7.16 (d, J = 9.6 Hz, 1H), 6.19 (s, 1H), 3.35 (s, 3H), 3.31 (s, 3H), 1.52 (s, 6H). LCMS calculated C 23 H 19 F2N2O4S[M+H] + m / z = 457.1; Measured value: 457.1.

[0632] Example 51: 3-(5,7-difluoro-6-((2-fluorophenyl)ethynyl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0633]

[0634] A mixture of 3-(5,7-difluoro-6-iodo-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (50 mg, 0.103 mol, Example 1, step 5), 1-ethynyl-2-fluorobenzene (19 mg, 0.154 mol), PdCl2(PPh3)2 (7 mg, 0.01 mol), CuI (2 mg, 0.01 mol), and TEA (0.5 mL) in DMF (1 mL) was stirred at 60 °C under nitrogen protection for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column, eluting with MeCN / H2O (0%-100%, containing 0.1% NH3·H2O) to give the target compound (19.7 mg, 40% yield) as a pale yellow solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ: 12.35 (s, 1H), 8.45–8.19 (m, 3H), 7.69 (td, J = 7.5, 1.7Hz, 1H), 7.59–7.52 (m, 1H), 7.43–7.37 (m, 1H), 7.35–7.10 (m, 2H), 6.27 (s, 1H), 3.36 (s, 3H). LCMS calculated C 25 H 14 F3N2O3S[M+H] + m / z = 479.1; measured value 479.1.

[0635] Example 52: 3-(5,7-difluoro-4-oxo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,4-dihydroquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0636]

[0637] Step 1: N-(2-acetyl-3,5-difluoro-4-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide

[0638]

[0639] The solution of 4-ethynyltetrahydro-2H-pyran (16.5 mg, 0.15 mmol), N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (50 mg, 0.1 mmol, step 4 of Example 1), CuI (2 mg, 0.01 mmol), and PdCl2(PPh3)2 (7 mg, 0.01 mmol) in TEA (0.5 mL) and DMF (0.5 mL) was degassed three times with nitrogen and stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with ACN / H2O (5-14%), to give the target compound (38 mg) as an off-white solid. LCMS calculated value C 24 H 21 F2N2O5S[M+H] + : 486.1; Measured value: 486.0.

[0640] Step 2: 3-(5,7-difluoro-4-oxo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,4-dihydroquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0641] A mixture of N-(2-acetyl-3,5-difluoro-4-(3-hydroxyprop-1-yn-1-yl)phenyl)-5-cyano-2-(methanesulfonyl)benzamide (38 mg, 0.08 mmol) and LiOtBu (12.8 mg, 0.16 mmol) in 2-methyltetrahydrofuran (1 mL) was stirred overnight at 75 °C. The reaction was quenched with 0.1 mL of 2.0 mol / L aqueous hydrochloric acid and concentrated under reduced pressure. The residue was purified by rapid chromatographic separation on a C18 column with acetonitrile / water (concentration range 15%-35%, containing 0.1 g ammonium bicarbonate) to give the target compound (3.8 mg), calculated by LCMS C1. 24 H 17 F2N2O4S[MH] - m / z = 467.1; Measured value: 467.0.

[0642] Example 53: (E)-3-(5,7-difluoro-4-oxo-6-styryl-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile

[0643]

[0644] Step 1: (E)-N-(2-acetyl-3,5-difluoro-4-styryl)-5-cyano-2-(methanesulfonyl)benzamide

[0645]

[0646] A mixture of (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborhexacyclopentane (26 mg, 0.3 mmol), Pd(dppf)Cl2 (14 mg, 0.02 mmol), K2CO3 (68 mg, 0.5 mmol), and N-(2-acetyl-3,5-difluoro-4-iodophenyl)-5-cyano-2-(methanesulfonyl)benzamide (100 mg, 0.2 mmol, step 4 of Example 1) in 1,4-dioxane (1 mL) and water (0.1 mL) was degassed, purged three times with nitrogen, and stirred overnight at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (prep-TLC) on silica gel, eluting with ethyl acetate / petroleum ether (30%) to give the target compound (18 mg) as a yellow solid. LCMS calculated value C 25 H 19 F2N2O4S[M+H] + m / z = 481.1; Actual value: 481.1.

[0647] Step 2: (E)-3-(5,7-difluoro-4-oxo-6-styryl-1,4-dihydroquinolin-2-yl)-4-(methylsulfonyl)benzonitrile

[0648] A mixture of (E)-N-(2-acetyl-3,5-difluoro-4-styryl)-5-cyano-2-(methanesulfonyl)aniline (52 mg, 0.11 mmol) and LiOtBu (17.6 mg, 0.22 mmol) in 2-methyltetrahydrofuran (1 mL) was stirred overnight at 75 °C. The reaction was quenched with dilute hydrochloric acid (0.1 mL, 2.0 mol / L) and concentrated under reduced pressure. The residue was purified by rapid chromatographic separation on a C18 column with methanol / water (50-55%, containing 0.1 NH4CO3) as eluent to give the target compound (6.5 mg) as a white solid. LCMS calculated C 25 H 15 F2N2O3S[MH] - m / z = 461.1; Measured value: 461.1

[0649] Example 54: 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((1-methyl-1H-tetrazol-5-yl)thio)benzonitrile

[0650]

[0651] Step 1: 5-Cyano-2-fluorobenzoic acid

[0652] A mixture of methyl 5-cyano-2-fluorobenzoate (2.0 g, 11.2 mmol) and LiOH·H₂O (936.6 mg, 22.4 mmol) in THF / H₂O (15 mL / 3 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (8 mL) and the pH was adjusted to 2–3 with 2 N hydrochloric acid solution. The mixture was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the target compound (1.3 g, 70.3% yield) as a white solid. LCMS calculated C 18 H 22 N2O5[MH] - m / z = 163.9; Measured value: 163.9.

[0653] Step 2: 5-Cyano-2-fluorobenzoyl chloride

[0654] A mixture of 5-cyano-2-fluorobenzoic acid (600 mg, 3.64 mmol) and SOCl2 (10 mL) was degassed and purged three times with nitrogen. The mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude product as a white solid, which was used directly in the next step.

[0655] Step 3: N-(2-acetyl-3,5-difluorophenyl)-5-cyano-2-fluorobenzamide

[0656] A mixture of 5-cyano-2-fluorobenzoyl chloride (880 mg, 4.87 mmol) and 1-(2-amino-4,6-difluorophenyl)ethane-1-one (500 mg, 2.92 mmol) in isopropyl acetate (5 mL) was stirred overnight at 80 °C under N2. The reaction mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from an acetic acid / petroleum ether (1:4) mixture to give the target compound (326 mg, 35% yield) as a white solid. LCMS calculated value C 16 H 10 F3N2O2[M+H] + m / z = 319.1; Actual value: 319.1.

[0657] Step 4: 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-fluorobenzonitrile

[0658] A mixture of N-(2-acetyl-3,5-difluorophenyl)-5-cyano-2-fluorobenzamide (325 mg, 1.02 mmol) and LiOtBu (130.8 mg, 1.635 mmol) in 10 mL of 2-methyltetrahydrofuran was stirred overnight at 75 °C. The reaction mixture was quenched with dilute hydrochloric acid (0.1 mL, 2 mol) and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL). The organic phase was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from EA / PE = 1:4 to give the target compound (196 mg, 64% yield) as a yellow solid. LCMS calculated C 16 H8F3N2O[M+H] + m / z = 301.2; Measured value: 301.2.

[0659] Step 5: 3-(5,7-difluoro-4-oxo-1,4-dihydroquinoline-2-yl)-4-((1-methyl-1H-tetrazol-5-yl)thio)benzonitrile

[0660] A mixture of 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-fluorobenzonitrile (140.0 mg, 0.47 mmol) and potassium 1-methyl-1H-tetrazole-5-thiol (86.8 mg, 0.56 mmol) in NMP (3 mL) was stirred overnight at 100 °C under nitrogen protection. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 2). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm × 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (17.2 mg, 9.2% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) 1 ¹H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 8.23 ​​(d, J = 1.7 Hz, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 7.19 (s, 2H), 6.14 (s, 1H), 3.95 (s, 3H). LCMS calculated C 18 H 11 F2N6OS[M+H] + m / z = 397.1; measured value: 397.4.

[0661] Example 55: 3-(5,7-difluoro-6-(3-fluoro-3-methylbut-1-yn-1-yl)-4-methoxyquinoline-2-yl)-4-(methanesulfonyl)benzonitrile

[0662]

[0663] Under nitrogen protection at 0 °C, DAST (21.9 mg, 0.14 mmol) was added dropwise to a DCM solution (3.5 mL) of 3-(5,7-difluoro-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (30.0 mg, 0.07 mmol, Example 1, step 6). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (5 mL) and poured into an ice-cold saturated sodium bicarbonate solution (10 mL). The mixture was extracted with DCM (10 mL × 2). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (instrument: GILSON-281; ​​column: XBridge C18 250*19.00 mm 10 μm; temperature: 25℃; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; flow rate: 20.0 mL / min; gradient: 30-60; detection wavelength: 214 / 254 nm; retention time: 6-14 min) to obtain the target compound (1.0 mg, 3.9% yield) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.35–8.24 (m, 3H), 7.81 (d, J = 10.3 Hz, 1H), 7.43 (s, 1H), 4.12 (s, 3H), 3.65 (s, 3H), 1.80 (s, 3H), 1.75 (s, 3H). LCMS calculated C 23 H 18 F3N2O3S[M+H] + m / z = 459.1; measured value: 459.3.

[0664] Example 56: 5,7-Difluoro-2-(5-methyl-2-(methanesulfonyl)phenyl)-6-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinoline-4(1H)-one

[0665]

[0666] A mixture of 3-(5,7-difluoro-4-oxo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile (25.0 mg, 0.05 mol, Example 52, step 2) and 10% Pd / C (70.0 mg) in methanol (4 mL) was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was diluted with methanol (5 mL) and filtered through silica gel filter paper. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography, eluting with dichloromethane / methanol (5%), to give the target compound (3.93 mg, 17.0% yield) as a white solid. 1 ¹H NMR (400MHz, CDCl₃) δ 7.95 (d, J = 7.9Hz, 1H), 7.50–7.37 (m, 2H), 7.03 (s, 1H), 6.25 (s, 1H), 3.97 (d, J = 8.8Hz, 2H), 3.38 (t, J = 11.4Hz, 2H), 3.00 (s, 3H), 2.76 (s, 2H), 2.49 (s, 3H), 1.69 (d, J = 12.7Hz, 2H), 1.62–1.46 (m, 3H), 1.43–1.29 (m, 2H). LCMS calculated C 24 H 26 F2NO4S[M+H] + m / z = 462.1; Measured value: 462.3.

[0667] Example A: PPARγ-SMRT recruitment experiment

[0668] The PPARγTR-FRET assay was used to evaluate the potential ability of the compounds of this invention to recruit SMRT ligands to the PPARγ protein. PPARγ-LBD (UniProt ID: P37231-2) was expressed and purified in an insect system, aliquoted, and stored at -80°C. A biotinylated SMRT peptide (biotin-HASTNMGLEAIIRKALMGKYDQW) was synthesized. 5 μL of protein solution mixture (composed of 10 nM PARγ-LBD and 2 nM Anti-His Eu (Cisbio, 61HISKLA) dissolved in buffer (25 mM HEPES pH 7.4, 25 mM KCl, 1 mM EDTA, 0.01% BSA, 0.01% Tween-20, 1 mM TCEP)) was added to a 384-well plate (pre-added with 5 μL of compound solution (10 concentration gradients, replicates for each concentration, final DMSO concentration 1%)). After pre-incubation at room temperature for 120 minutes, 5 μL of short peptide mixture (containing 50 nM biotinylated SMRT short peptide and 25 nM Streptavidin-XL665 (Cisbio, catalog number 610SAXLA)) was added to each well. The plate was incubated for another 60 minutes, followed by CLARIOstar. Readings were taken using a Plus microplate reader, with Ex / Em at 620 nm / 665 nm. The average TR-FRET ratio of wells containing 10 μM of the control compound was used as the high control value (HC), and the average TR-FRET ratio of wells containing 1% DMSO was used as the low control value (LC). For a single compound, top% represents its maximum recruitment percentage (%Activation).

[0669] %Activation = 100 * (Ratio) cmpd -Ratio Ave_LC ) / (Ratio Ave_HC -Ratio Ave_LC ).

[0670] Using GraphPad Prism software, the data was fitted to a standard four-parameter model including Hill Slope, and EC was calculated accordingly. 50 Value. EC 50 The data is shown below: "+" indicates EC 50 Value > 1 μM, "++" indicates EC 50 Value 0.1 μM < EC 50 <= 1μM, "+++" indicates EC 50 Value <= 0.1 μM. ND: Not detected.

[0671] Table 1 PPARγ test

[0672]

[0673]

[0674] Example B: PPARγ-DRIP205 Blockade Experiment

[0675] The PPARγ TR-FRET assay was used to evaluate the potential blocking effect of the compounds described in this invention on the binding of DRIP205 to PPARγ protein. PPARγ-LBD (UniProt ID: P37231-2) was expressed and purified in an insect expression system, aliquoted, and stored at -80°C. A biotin-labeled short peptide of DRIP205 was synthesized (sequence: Biotin-GNTKNHPMLMNLLKDNPADQF). 5 μL of protein mixture (composed of 10 nM PPARγ-LBD and 2 nM Anti-His Eu (Cisbio, 61HISKLA) dissolved in (25 mM HEPES pH 7.4, 25 mM KCl, 1 mM EDTA, 0.01% BSA, 0.01% Tween-20, 1 mM TCEP)) was added to a 384-well plate. The plate was pre-filled with: 2.5 μL of a compound prepared with detection buffer (replicas, 10 concentration gradients, DMSO final concentration 1%, v / v), and 2.5 μL of 500 nM rosiglitazone prepared with detection buffer. After pre-incubation at room temperature for 120 minutes, 5 μL of a short peptide mixture containing 50 nM biotin-labeled DRIP205 short peptide and 25 nM Streptavidin-XL665 (Cisbio, catalog number 610SAXLA) was added to the detection plate. The experimental plates were incubated for another 60 minutes, and then read using a CLARIOstar Plus microplate reader, with Ex / Em values ​​of 620 nm / 665 nm. The average TR-FRET ratio of the wells containing 500 nM rosiglitazone was used as the high control value (HC), and the average TR-FRET ratio of the wells containing 1% DMSO was used as the low control value (LC).

[0676] %Inhibition=100-100*(Ratio cmpd -Ratio Ave_LC ) / (Ratio Ave_HC -Ratio Ave_LC ).

[0677] Using GraphPad Prism software, the data was fitted to a standard four-parameter model containing Hill Slope, and the IC was calculated. 50 Value. IC 50 The data is shown below: "+" indicates IC 50 Value > 5μM, "++" indicates IC50 Value 0.5μM < IC 50 <= 5μM, "+++" indicates IC 50 Value <= 0.5 μM.

[0678] Example C: Cell-based PPARγ reporterer experiment

[0679] The PPARγreporter assay was used to evaluate the potential inhibitory effect of the compounds of this invention on nuclear receptor activation. HEK293T cells were cultured at 2.5 × 10⁻⁶ cells / year. 4 Cells were seeded at a density of cells / well in 96-well plates, with 100 μL of RPMI 1640 medium containing 10% fetal bovine serum added to each well. Cells were transiently transfected with the GAL4-UAS-Luciferase (Addgene) reporter plasmid (50 ng / well) and the pcDNA3.1-Gal4 DBD-PPARγLBD (BGI) expression plasmid using FuGENE HD transfection reagent (Promega, 0.3 μL / well). After 18 hours of incubation, the medium was replaced with fresh medium: 300 nM rosiglitazone as a positive control and 0.1% DMSO as a negative control. The test compound dissolved in DMSO was added in replicates, at 9 concentration points, and in 3-fold serial dilutions. The final concentration of DMSO in all wells was 0.2%. After 24 hours of compound treatment, luciferase activity was measured using a luciferase assay kit (Promega).

[0680] The average luminescence signal value of the well containing 300 nM rosiglitazone was used as the high control value (HC), and the average luminescence signal value of the well containing 0.1% DMSO was used as the low control value (LC).

[0681] %Inhibition=100-100*(Signal cmpd -Signal Ave_LC ) / (Signal Ave_HC -Signal Ave_LC ).

[0682] Example D: Cell viability test

[0683] Cell viability was assessed in the PPARγ-amplified bladder cancer cell line 5637, with the PPARγ-low-expressing cell line SW1710 serving as a control. Cells were cultured in RPMI 1640 medium supplemented with 10% FBS and 1% penicillin-streptomycin (Gibco, catalog number 15140122). Cells were seeded in 96-well cell culture plates (PerkinElco, 6005680): 400 cells / well for 5637 and 600 cells / well for SW1710. The compound of this invention (dissolved in DMSO) was serially diluted 3-fold at 9 concentration points, and added to the cell culture plates in replicates using a multichannel pipette. The final concentration of DMSO in all wells was 0.2%. Cells were incubated at 37°C and 5% CO2 for 6 days. Cell viability was assessed using the Cell Titer-Glo kit (Promega, catalog number G7573) according to the kit instructions, and the luminescence signal was read using a multi-functional microplate reader (BMG CLARIO star plus). The average value of the wells treated with 0.2% DMSO on each plate was recorded as the high control (HC), and the average value of the wells containing only culture medium was recorded as the low control (LC).

[0684] Calculate the inhibition percentage using the following formula: %Inhibition = 100 - 100 * (Signal) cmpd -Signal Ave_LC ) / (Signal Ave_HC -Signal Ave_LC ).

[0685] Although the invention has been fully described by way of examples, it is worth noting that various changes and modifications will be apparent to those skilled in the art. These changes and modifications should be included within the scope of the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound thereof, characterized in that: Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound, wherein: X 1 For N or CR 1 ; X 2 For N or CR 4 ; Y 1 For N or CR 7 ; Y 2 For N or CR 8 ; Y 3 For N or CR 10 ; R 1 Selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a ; R 2 Selected from D, NO2, N3, SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups having one heteroatom selected from Si, O-C0-C4 alkyl-Cy, OYZ, C0-C4 alkyl-OCy, C0-C4 alkyl-NR C Cy, C0-C4 alkyl-SCy, C0-C4 alkyl-C(O)Cy, C0-C4 alkyl-C(O)OCy, C0-C4 alkyl-C(O)NR C Cy, NR C COCy, NR C CO2Cy, NR C C(S)OCy, NR C C(O)NR C Cy, NR C C(S)NR C Cy, NR C SO2NR C Cy, C(S)Cy, C(S)OCy, C(S)NR C Cy, NR C C(S)Cy, SOCy, SO2Cy, SONR C Cy, SiR G R H R 1 B(OR) C (OR) D ), P(O)R E R F P(O)OR E OR F OP(O)OR E OR F ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group having one heteroatom selected from Si and optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents; R 2 Not CH3; Each R 2A Each of the following is independently selected from H, D, halogen, CN, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclic, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D NR C C(O)R D NR C C(O)NR C R D NR C C(O)OR A SiR G R H R I B(OR) C (OR) D ), C(=NR C )NR C R D NR D C(=NR C )NR C R D NR D C(=NR C )R B P(O)R E R F P(O)OR E OR F OP(O)OR E OR F S(O)R B S(O)NR C R D S(O)2R B NR C S(O)2R B S(O)2NR C R D NR C S(O)2NR C R D S(O)(=NR) C )R B or NR C S(O)(=NR C )R B ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic group, OR a SR - C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2; Cy is a phenyl group, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic; wherein the phenyl group is C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic groups optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)2NR c R d ; Y is a C1-C4 alkyl group or a C3-C6 alkenyl group; Z is CN, N3, OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , SiR G R H R I , B(OR C )(OR D ), C(=NR C )NR C R D , NR D C(=NR C )NR C R D , NR D C(=NR C )R B , P(O)RER F , P(O)OR E OR F , OP(O)OR E OR F , S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , NR C S(O)2NR C R D , S(O)(=NR C )R B or NR C S(O)(=NR C )R B ; R 3 H, D, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl; or R 1 and R 2 or R 2 and R 3 Together with the atoms attached thereto, it forms a phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group; wherein the phenyl, C5-C6 cycloalkyl, 5-6-membered heteroaryl, or 5-6-membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a ; R 4 For H, D, halogen, CN; R 5 Selected from H, D, halogens, OH, CH3, CF3, CHF2, CH2F; R 6 Selected from halogens, OS(O)2R 6A SR 6A S(O)R 6A S(O)OR 6A S(O)2R 6A S(O)2OR 6A S(O)2NR 6A R 6B S(O)(=NR) 6A )R 6B ; R 6A and R 6B Each of the following is independently selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-OC1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-NHC1-C4 alkyl, C1-C4 alkyl-N(C1-C4 alkyl)2, optionally halogenated C3-C4 cycloalkyl, optionally substituted C1-C4 alkyl, C1-C4 haloalkyl-substituted phenyl; R 7 and R 10 Each is independently selected from H and D; R 8 Selected from H, D, halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl; R 9 Selected from CF3, SF5, CN, NC, NO2; or R 8 and R 9 Together with the atoms to which it is attached, a 5-membered heteroaryl group is optionally oxidized; R A and R a Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2; R B and R b Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2; R C R D R c and R d Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl; wherein, the C1-C6 alkyl, C3-C 10 Cycloalkyl-C0-C4 alkyl, 4-6 membered heterocyclic-C0-C4 alkyl, phenyl-C0-C4 alkyl, or 5-6 membered heteroaryl-C0-C4 alkyl may optionally be substituted by 1, 2, 3, 4 or 5 independent substituents selected from the following: D, CN, halogen, oxo, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2; or R C and R D or R c and R d Together with the N atom to which it is attached, it forms a 4-6 membered heterocyclic group, which may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, halogen, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl; R E and R e Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl; R F and R f Each is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, or (C1-C4 alkoxy)-C1-C4 alkyl; R G R H R I R g R h and R i Each is independently selected from C1-C4 alkyl or phenyl groups.

2. The compound according to claim 1, characterized in that, X 1 For CR 1 and X 2 For CR 4 ;X 1 For CR 1 and X 2 For N; X 1 For N and X 2 For CR 4 .

3. The compound according to claim 1 or 2, characterized in that, R 1 Selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

4. The compound according to claims 1-3, characterized in that, R 2 Selected from D, NO2, N3, SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups having one heteroatom selected from Si, O-C0-C4 alkyl-Cy, OYZ, C0-C4 alkyl-OCy, C0-C4 alkyl-NR C Cy, C0-C4 alkyl-SCy, C0-C4 alkyl-C(O)Cy, C0-C4 alkyl-C(O)OCy, C0-C4 alkyl-C(O)NR C Cy, NR C COCy, NR C CO2Cy, NR C C(S)OCy, NR C C(O)NR C Cy, NR C C(S)NR C Cy, NR C SO2NR C Cy, C(S)Cy, C(S)OCy, C(S)NR C Cy, NR C C(S)Cy, SOCy, SO2Cy, SONR C Cy, SiR G R H R I B(OR) C (OR) D ), P(O)R E R F P(O)OR E OR F OP(O)OR E OR F ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group having one heteroatom selected from Si and optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents; preferably, R 2 Selected from D, NO2, N3, SF5, CH2CN, CH2CH2CN, CH(OH)CF3, CH(OCH3)CF3, cyclopropyl.

5. The compound according to claim 4, characterized in that, Each R2A is independently selected from H, D, halogen, CN, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclic, OR A SR A C(O)R B C(O)NR C R D C(O)OR A OC(O)R B OC(O)NR C R D NR C R D NR C C(O)R D NR C C(O)NR C R D NR C C(O)OR A SiR G R H R I B(OR) C (OR) D ), C(=NR C )NR C R D NR D C(=NR C )NR C R D NR D C(=NR C )R B P(O)R E R F P(O)OR E OR F OP(O)OR E OR F S(O)R B S(O)NR C R D S(O)2R B NR C S(O)2R B S(O)2NR C R D NR C S(O)2NR C R D S(O)(=NR) C )R B or NR C S(O)(=NR C )R B ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic group, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

6. The compound according to claims 1-5, characterized in that, R 3 It can be H, D, halogen, CN, C1-C4 alkyl, or C1-C4 haloalkyl.

7. The compound according to claims 1-2, 6, characterized in that, R 2 and R 3 Together with the atoms attached thereto, a phenyl, 5-6-membered heteroaryl group is formed; wherein the phenyl, 5-6-membered heteroaryl group is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a Preferably, R 2 and R 3 Together with the atoms attached thereto, they form phenyl, pyrrolyl, imidazolyl, or pyrazolyl groups; each optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from the following: D, halogen, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-NH2, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a .

8. The compound according to claims 1-3, characterized in that, R 2 and R 3 Together with the atoms it is attached to, it forms a phenyl, 1-methyl-1H-pyrazolyl group.

9. The compound according to claims 1-8, characterized in that, R 4 For H, D, halogen, CN.

10. The compound according to claims 1-9, characterized in that, R 5 Selected from H, D, halogen, OH, CH3, CF3, CHF2, CH2F.

11. The compound according to claims 1-10, characterized in that, R 6 Selected from halogens, OS(O)2R 6A SR 6A S(O)R 6A S(O)OR 6A S(O)2R 6A S(O)2OR 6A S(O)2NR 6A R 6B S(O)(=NR) 6A )R 6B .

12. The compound according to claims 1-2, characterized in that, R 6 is F, Cl, Br, I, SCH3, S(O)CH3, S(O)2CH3, S(O)2CH2CH3, S(O)2CH(CH3)2, S(O)2CH2CH(CH3)2, S(O)2CF3, S(O)2CH2CF3, OS(O)2CH3, OS(O)2CF3, OTs, 13. The compound according to claims 1-12, characterized in that, Y 1 Let N be the number of elements in the array.

14. The compound according to claims 1-12, characterized in that, Y 1 For CR 7 ; and R 7 H, D; preferably, Y 1 For CH.

15. The compound according to claims 1-14, characterized in that, Y 2 Let N be the number of elements in the array.

16. The compound according to claims 1-14, characterized in that, Y 2 For CR 8 ;R 8 It can be H, D, halogen, OH, C1-C4 alkyl, or C1-C4 haloalkyl.

17. The compound according to claims 1-16, characterized in that, R 9 Selected from CF3, SF5, CN, NC, NO2.

18. The compound according to claims 1-16, characterized in that, R 8 and R 9 Together with the atoms it is attached to, it forms an oxo-5-membered heteroaryl group; preferably, R 8 and R 9 It forms together with the atoms it is connected to.

19. The compound according to claims 1-18, characterized in that, Y 3 Let N be the number of elements in the array.

20. The compound according to claims 1-18, characterized in that, Y 3 For CR 10 ;R 10 H, D; preferably, Y 3 For CH.

21. The compound according to claims 1-20, characterized in that, The compound represented by formula (I) is shown as shown by formula (II): Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope variant, prodrug, or deuterated thereof; Among them, X 1 X 2 Y 1 Y 2 Y 3 R 2A R 5 R 6 R 3 and R 9 As defined in the present invention (I).

22. The compound according to claim 21, characterized in that, R 2A Selected from H, D, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic, C(O)R B C(O)NR C R D C(O)OR A S(O)R B S(O)NR C R D S(O)2R B S(O)2NR C R D SiR G R H R I ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic group, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

23. The compound according to claim 22, characterized in that, R 2A Selected from H, D, CN, C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocyclic; wherein each is optionally substituted by 1, 2, 3, 4, or 5 independent substituents selected from: D, halogen, CN, oxo, C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic, OR a SR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a SiR g R h R i B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d S(O)(=NR) c )R b or NR c S(O)(=NR c )R b ; wherein the C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, 5-6 heteroaryl, and 4-6 heterocyclic groups are optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, NHC1-C4 alkyl, N(C1-C4 alkyl)2.

24. The compound according to claim 22, characterized in that, R 2A For H, D, CN, CH3, CH2CH3, CH(CH3)2, 25. The compound according to claims 1-23, characterized in that, The compound represented by formula (I) is: Or its pharmaceutically acceptable salt.

26. A pharmaceutical composition comprising: The compound of claims 1-24, comprising a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug or deuterated compound, and at least one pharmaceutically acceptable carrier or excipient.

27. The use of the compound of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound thereof, in the preparation of a therapeutic medicament.

28. An in vitro method for recruiting co-inhibitory ligands or blocking the binding of co-activating ligands to PPARγ protein, comprising: Contact the PPARγ protein with the compound of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound, or the pharmaceutical composition of claim 25.

29. A method for regulating PPARγ in cells, the method being associated with the activation function of PPARγ (gain-of-function mutation, amplification, or overexpression) or a gain-of-function mutation of RXRα (e.g., S427F / Y), comprising: The cells are contacted with the compounds of claims 1-24, or pharmaceutically acceptable salts, stereoisomers, solvates, N-oxides, tautomers, isotope derivatives, prodrugs, or deuterated compounds, or the pharmaceutical composition of claim 25.

30. A method of treating a disease, comprising: The subject is given a therapeutically effective amount of the compound of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotope derivative, prodrug, or deuterated compound, or the pharmaceutical composition of claim 25.

31. The method according to claim 29, characterized in that, The subjects had a disease or condition that required treatment and presented with symptoms of PPARγ amplification, overexpression, gain-of-function mutation, or RXRα gain-of-function mutation.

32. The method according to claim 30, characterized in that, The disease or symptom mentioned is cancer.

33. The method according to claim 31, characterized in that, The cancer in question is one with PPARγ activation function (gain-of-function mutation, amplification, or overexpression) or RXRα gain-of-function mutation (such as S427F / Y).

34. The method according to claim 31 or 32, characterized in that, The cancer in question is bladder cancer.

35. The method according to claim 30, characterized in that, The subjects were humans.

Images