Indene compounds, pharmaceutical compositions thereof, and therapeutic applications thereof

Abstract

This invention provides an indene compound, such as the compound of formula (I), and a pharmaceutical composition thereof. This invention also provides a method for treating, preventing, or alleviating one or more symptoms of fibrosis using the indene compound and the pharmaceutical composition thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 038,737, filed June 12, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0003] References to sequence lists

[0004] This specification is submitted together with a computer-readable format (CRF) sequence list, the name of which is

[0005] 294A002WO01_SEQ_LIST_ST25.txt, with a size of 1,427 bytes, was created on May 23, 2021; its contents are incorporated herein by reference in their entirety. Technical Field

[0006] This invention provides an indene compound and a pharmaceutical composition thereof. This invention also provides a method for treating, preventing, or alleviating one or more symptoms of fibrosis using the indene compound and the pharmaceutical composition thereof. Background Technology

[0007] Fibrosis is the accumulation of extracellular matrix components in organs or tissues, altering their structure and leading to the disruption of normal function, and in many cases ultimately resulting in organ failure and death. (Hernandez-Gea et al., *Annu. Rev. Pathol.* 2011, 6, 425-56; Makarev et al., *Cell Cycle* 2016, 15, 1667-73). Fibrosis can occur in almost any organ or tissue and is associated with a variety of diseases, causing up to 45% of deaths in developed countries. (Mehal et al., *Nat. Med.* 2011, 17, 552-3; Makarev et al., *Cell Cycle* 2016, 15, 1667-73).

[0008] Nonalcoholic steatohepatitis (NASH) is a progressive disease caused by excessive fat accumulation in the liver, unrelated to alcohol consumption. It induces chronic inflammation and damage to hepatocytes (ballooning degeneration), which can lead to fibrosis, resulting in cirrhosis, liver failure, and death. (Roenn, *Clinical Liver Dis.* (Hoboken), 2018, 12, 35-6; Sheka et al., *JAMA*, 2020, 323, 1175-83). The stage of liver fibrosis is a strong predictor of clinical outcomes in NASH patients. (Angulo et al., *Hepatology*, 1999, 30, 1356-62; Dulai et al., *Hepatology*, 2017, 65, 1557-65). With the increasing prevalence of diabetes and the continued prevalence of obesity, the incidence of NASH is expected to increase significantly in the coming years, and the disease is projected to become a leading cause of liver transplantation in the United States. Roenn, Clinical Hepatology (Hoboken) 2018, 12, 35-6; Sheka et al., JAMA 2020, 323, 1175-83. There are currently no FDA-approved treatments for NASH. (Ibid.) Therefore, an effective treatment is needed for fibrotic diseases, especially NASH. Summary of the Invention

[0009] This invention provides a compound of formula (I):

[0010]

[0011] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0012] R 1 It is (a) hydrogen, deuterium, cyano, halo, or nitro; or (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[0013] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or heteroaryl; wherein R 2a R2b and R 2c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[0014] R 3 R 4 R 5 and R 6 Each is independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR 1b R 1c –OC(NR) 1a )NR 1b R 1c –OS(O)R 1a –OS(O)2R 1a –OS(O)NR 1b R 1c –OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R 1c –NR 1a S(O)R1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c –NR 1a S(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ;

[0015] R A C 6-14 arylene or heteroarylene;

[0016] R B And X can be (i), (ii), or (iii):

[0017] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0018] R B C 6-14 aryl or heteroaryl;

[0019] (ii)X is –N(R) X )–;

[0020] R B C 6-14 aryl or heteroaryl; and

[0021] R X For hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups; or

[0022] (iii) X is –N(R) X )-;and

[0023] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0024] L is C 1-6 Alkylene, C 2-6 imidene group, C 3-10Cycloalkyl or heterocyclic groups; and

[0025] R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms it is attached to, it forms a heterocyclic group; or R 1b and R 1c Together with the N atom it is attached to, it forms a heterocyclic group;

[0026] The alkyl, alkylene, alkenyl, alkenylene, ynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclic, and heterocyclic groups are each optionally substituted by one or more, in one embodiment by one, two, three, or four substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Substitution; and (c)–C(O)R a –C(O)OR a –C(O)NR b R c –C(O)SR a –C(NR) a )NR b R c –C(S)R a –C(S)OR a –C(S)NR b R c –OR a –OC(O)R a –OC(O)OR a –OC(O)NR b R c –OC(O)SR a –OC(NR) a)NR b R c –OC(S)R a –OC(S)OR a –OC(S)NR b R c –OS(O)R a –OS(O)2R a –OS(O)NR b R c –OS(O)2NR b R c –NR b R c –NR a C(O)R d –NR a C(O)OR d –NR a C(O)NR b R c –NR a C(O)SR d –NR a C(NR d )NR b R c –NR a C(S)R d –NR a C(S)OR d –NR a C(S)NR b R c –NR a S(O)R d –NR a S(O)2R d –NR a S(O)NR b R c –NR a S(O)2NR b R c –SR a –S(O)R a –S(O)2R a –S(O)NR b R c and –S(O)2NR b R c , where R a R b R c and R d Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Replace; or (iii)R b and R c Together with the N atom it is attached to, it forms an optional group Q via one or more, in one embodiment via one, two, three or four substituents. a Substituted heterocyclic groups;

[0027] Q a Each is independently selected from: (a) deuterium, cyano, halogen, nitro, and oxonide; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl, and heterocyclic groups; and (c)–C(O)R e –C(O)OR e –C(O)NR f R g –C(O)SR e –C(NR) e )NR f R g –C(S)R e –C(S)OR e –C(S)NR f R g –OR e –OC(O)R e –OC(O)OR e –OC(O)NR f R g –OC(O)SR e –OC(NR) e )NR f R g –OC(S)R e –OC(S)OR e –OC(S)NR f R g –OS(O)R e –OS(O)2R e –OS(O)NR f R g –OS(O)2NRf R g –NR f R g –NR e C(O)R h –NR e C(O)OR f –NR e C(O)NR f R g –NR e C(O)SR f –NR e C(NR h )NR f R g –NR e C(S)R h –NR e C(S)OR f –NR e C(S)NR f R g –NR e S(O)R h –NR e S(O)2R h –NR e S(O)NR f R g –NR e S(O)2NR f R g –SR e –S(O)R e –S(O)2R e –S(O)NR f R g and –S(O)2NR f R g ;where R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii)R f and R g Together with the N atom it is attached to, it forms a heterocyclic group.

[0028] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0029] In addition, the present invention provides a method for treating, preventing or alleviating one or more symptoms of fibrotic disease in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0030] Furthermore, the present invention provides a method for treating, preventing, or alleviating one or more symptoms of a proliferative disease in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0031] The present invention provides a method for inhibiting cell growth, comprising contacting cells with an effective amount of a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0032] This invention provides a method for treating, preventing, or alleviating one or more symptoms of fibrotic disease in a subject, comprising administering a therapeutically effective amount of a compound of formula (IA) to the subject in need:

[0033]

[0034] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0035] R 1 It is (a) hydrogen, deuterium, cyano, halo, or nitro; or (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[0036] R 2 For –CN, –C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c –OR 2a –NR 2b R 2c Or heteroaryl; wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[0037] R 3 R 4 R 5 and R 6 Each is independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR 1b R 1c –OC(NR) 1a )NR 1b R 1c –OS(O)R 1a –OS(O)2R 1a –OS(O)NR 1b R 1c–OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R 1c –NR 1a S(O)R 1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c –NR 1a S(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ;

[0038] R 7 Each is independently (a) deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR 1b R 1c –OC(NR) 1a )NR 1b R1c –OS(O)R 1a –OS(O)2R 1a –OS(O)NR 1b R 1c –OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R 1c –NR 1a S(O)R 1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c –NR 1a S(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ; or two adjacent R 7 Together with the phenyl group it is attached to, it forms a naphthyl or a bicyclic heteroaryl group;

[0039] R C It is (a) hydrogen, deuterium, cyano, halo, or nitro; or (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–OR 1a –NR 1b R 1c Or –NR 1a C(O)R 1d ;

[0040] L is C 1-6 Alkylene or C2-6 alkenyl;

[0041] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0042] R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms it is attached to, it forms a heterocyclic group; or R 1b and R 1c Together with the N atom it is attached to, it forms a heterocyclic group;

[0043] The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are optionally substituted by one or more, in one embodiment by one, two, three, or four substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, nitro, and oxoalkyl; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Substitution; and (c)–C(O)R a –C(O)OR a –C(O)NR b R c –C(O)SR a –C(NR) a )NR b R c –C(S)R a –C(S)OR a –C(S)NR b R c –OR a –OC(O)R a –OC(O)OR a –OC(O)NR b R c –OC(O)SR a–OC(NR) a )NR b R c –OC(S)R a –OC(S)OR a –OC(S)NR b R c –OS(O)R a –OS(O)2R a –OS(O)NR b R c –OS(O)2NR b R c –NR b R c –NR a C(O)R d –NR a C(O)OR d –NR a C(O)NR b R c –NR a C(O)SR d –NR a C(NR d )NR b R c –NR a C(S)R d –NR a C(S)OR d –NR a C(S)NR b R c –NR a S(O)R d –NR a S(O)2R d –NR a S(O)NR b R c –NR a S(O)2NR b R c –SR a –S(O)R a –S(O)2R a –S(O)NR b R c and –S(O)2NR b R c , where R a R b R c and R d Each is independently (i) hydrogen or deuterium; (ii) C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Replace; or (iii)R b and R c Together with the N atom it is attached to, it forms an optional group Q via one or more, in one embodiment via one, two, three or four substituents. a Substituted heterocyclic groups;

[0044] Q a Each is independently selected from: (a) deuterium, cyano, halogen, nitro, and oxonide; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl, and heterocyclic groups; and (c)–C(O)R e –C(O)OR e –C(O)NR f R g –C(O)SR e –C(NR) e )NR f R g –C(S)R e –C(S)OR e –C(S)NR f R g –OR e –OC(O)R e –OC(O)OR e –OC(O)NR f R g –OC(O)SR e –OC(NR) e )NR f R g –OC(S)R e –OC(S)OR e –OC(S)NR f R g –OS(O)R e –OS(O)2R e –OS(O)NR f R g–OS(O)2NR f R g –NR f R g –NR e C(O)R h –NR e C(O)OR f –NR e C(O)NR f R g –NR e C(O)SR f –NR e C(NR h )NR f R g –NR e C(S)R h –NR e C(S)OR f –NR e C(S)NR f R g –NR e S(O)R h –NR e S(O)2R h –NR e S(O)NR f R g –NR e S(O)2NR f R g –SR e –S(O)R e –S(O)2R e –S(O)NR f R g and –S(O)2NR f R g ;where R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii)R f and R g Together with the N atom it is attached to, it forms a heterocyclic group. Attached Figure Description

[0045] Figure 1 The effects of malotilate (Mal) and compounds A11 and B9 on body weight in C57 / BL6 mice were shown.

[0046] Figure 2 The effects of Mal, along with compounds A11 and B9, on α-SMA mRNA levels in C57 / BL6 mice were shown.

[0047] Figure 3 The effects of Mal, as well as compounds A11 and B9, on the mRNA levels of Col1a1 in C57 / BL6 mice were shown.

[0048] Figure 4 Sirius red case-stained images of liver samples from C57 / BL6 mice treated with Mal or compounds A11 or B9 are shown, indicating that each compound reversed CCl4-induced fibrosis.

[0049] Figure 5 The effects of Mal and compound A23 on the mRNA levels of α-SMA in C57 / BL6 mice were shown.

[0050] Figure 6 The effects of Mal and compound A23 on the mRNA levels of Col1a1 in C57 / BL6 mice were shown. Detailed Implementation

[0051] To facilitate understanding of the public information presented in this article, the following are definitions of some terms.

[0052] The nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are generally those well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0053] The term "subject" refers to an animal, including (but not limited to) primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, when referring to a mammalian subject, such as a human subject. In one implementation, the subject is a human.

[0054] The term "treatment" refers to the relief or elimination of a symptom, disease, or condition, or one or more symptoms associated with that symptom, disease, or condition; or the relief or eradication of the cause of that symptom, disease, or condition itself.

[0055] The term "preventing" refers to methods that include delaying and / or preventing the onset of a condition, disease, or illness and / or its accompanying symptoms; preventing a subject from developing a condition, disease, or illness; or reducing the risk of a subject developing a condition, disease, or illness.

[0056] The term "alleviate / alleviating" refers to the relief or reduction of one or more symptoms (e.g., pain) of a symptom, disease, or condition. The term may also refer to a reduction in side effects associated with the active ingredient. Sometimes, the beneficial effects experienced by a subject from a preventative or therapeutic agent do not lead to a cure for the symptom, disease, or condition.

[0057] The term "contacting" refers to the binding of a therapeutic agent with a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue to produce physiological and / or chemical effects as a result of such contact. Contact can occur in vitro, ex vivo, or in vivo. In one embodiment, the therapeutic agent is contacted in vitro with a biomolecule to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, the therapeutic agent is contacted (in vitro) with cells in a cell culture to determine the effect of the therapeutic agent on the cells. In yet another embodiment, contacting the therapeutic agent with a biomolecule, cell, or tissue includes administering the therapeutic agent to a subject having the biomolecule, cell, or tissue to be contacted.

[0058] The term "therapeutic effective amount" or "effective amount" refers to an amount of compound, including, when administered, sufficient to prevent the development of one or more symptoms of a disease, illness, or condition being treated, or to alleviate, to some extent, one or more symptoms of that disease, illness, or condition. The term "therapeutic effective amount" or "effective amount" also refers to an amount of compound sufficient to elicit a biological or medical response in a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by researchers, veterinarians, physicians, or clinicians.

[0059] The terms “pharmaceutically acceptable carrier,” “pharmaceutical acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to pharmaceutically acceptable materials, compositions, or mediators, such as liquid or solid fillers, diluents, solvents, or encapsulating materials. In one embodiment, each component is “pharmaceutically acceptable” in the sense of compatibility with other components of a pharmaceutical preparation and is suitable for contact with the tissues or organs of a subject (e.g., a human) without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. See, for example, *Remington: The Science and Practice of Pharmacy*, 23rd edition; edited by Adejare; Academic Press, 2020; *Handbook of Pharmaceutical Excipients*, 9th edition; edited by Sheskey et al.; Pharmaceutical Press, 2020; *Handbook of Pharmaceutical Additives*, 3rd edition; edited by Ash and Ash; *Synapse Information Resources*, 2007; *Pharmaceutical Preformulation and Formulation*, 1st edition; edited by Gibson; CRC Press, 2015.

[0060] The terms "about" or "approximately" refer to an acceptable error for a particular value as determined by those skilled in the art, depending in part on how the value was measured or determined. In some embodiments, the terms "about" or "approximately" mean within 1, 2, or 3 standard deviations. In some embodiments, the terms "about" or "approximately" mean within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0061] The term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the alkyl group is optionally substituted by one or more substituents Q as described herein. For example, C 1-6 Alkyl groups refer to straight-chain saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In some embodiments, alkyl groups are those having 1 to 20 carbon atoms (C1 to C2). 1-20 ), 1 to 15 carbon atoms (C 1-15), 1 to 10 carbon atoms (C 1-10 ) or 1 to 6 carbon atoms (C 1-6 Straight-chain saturated monovalent hydrocarbon groups or having 3 to 20 carbon atoms (C 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ) or 3 to 6 carbon atoms (C 3-6 Branched saturated monovalent hydrocarbon groups. As used herein, straight-chain C 1-6 and branch C 3-6 Alkyl groups are also called "low-carbon alkyl groups". Examples of alkyl groups include (but are not limited to) methyl, ethyl, propyl (including all isomers, such as n-propyl and isopropyl), butyl (including all isomers, such as n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including all isomers, such as n-pentyl, isopentyl, sec-pentyl, octylpentyl and tert-pentyl) and hexyl (including all isomers, such as n-hexyl, isohexyl and sec-hexyl).

[0062] The terms "alkylene" and "alkyldiyl" are used interchangeably herein when referring to a straight-chain or branched saturated divalent hydrocarbon group, wherein the alkylene group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkylene refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, alkylene is a hydrocarbon group having 1 to 30 carbon atoms (C1 to C2). 1-30 ), 1 to 20 carbon atoms (C 1-20 ), 1 to 15 carbon atoms (C 1-15 ), 1 to 10 carbon atoms (C 1-10 ) or 1 to 6 carbon atoms (C 1-6 Straight-chain saturated divalent hydrocarbon groups or those with 3 to 30 carbon atoms (C 3-30 ), 3 to 20 carbon atoms (C 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ) or 3 to 6 carbon atoms (C 3-6 Branched saturated divalent hydrocarbon groups. As used herein, straight-chain C 1-6 and branch C 3-6Alkylenes are also called "low-carbon-number alkylenes". Examples of alkylenes include (but are not limited to) methylene, ethylene (including all isomers such as ethane-1,1-diyl and ethane-1,2-diyl), propylene (including all isomers such as propane-1,1-diyl, propane-1,2-diyl and propane-1,3-diyl), butylene (including all isomers such as butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl and butane-1,4-diyl), pentylene (including all isomers such as pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl and pentane-1,5-diyl), and hexylene (including all isomers such as hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl and hexane-1,6-diyl).

[0063] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing one or more carbon-carbon double bonds. In one embodiment, it contains one, two, three, or four carbon-carbon double bonds, and in another embodiment, it contains one carbon-carbon double bond. The alkenyl group is optionally substituted with one or more substituents Q as described herein. As those skilled in the art will appreciate, the term "alkenyl" encompasses groups having a "cis" or "trans" configuration or a mixture thereof, or having a "Z" or "E" configuration or a mixture thereof. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, the alkenyl group has 2 to 20 carbon atoms (C... 2-20 ), 2 to 15 carbon atoms (C 2-15 ), 2 to 10 carbon atoms (C 2-10 ) or 2 to 6 carbon atoms (C 2-6 Straight-chain monovalent hydrocarbon groups or those with 3 to 20 carbon atoms (C 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ) or 3 to 6 carbon atoms (C 3-6 Alkenyl is a branched monovalent hydrocarbon group with 1 carbon atom. Examples of alkenyl include (but are not limited to) vinyl, propenyl (including all isomers such as propen-1-yl, propen-2-yl and allyl) and butenyl (including all isomers such as buten-1-yl, buten-2-yl, buten-3-yl and 2-buten-1-yl).

[0064] The terms "alkenyl" and "alkenyl" are used interchangeably herein to refer to a straight-chain or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds, which in one embodiment contains one, two, three, or four carbon-carbon double bonds, and in another embodiment contains one carbon-carbon double bond. The alkenyl group is optionally substituted with one or more substituents Q as described herein. As those skilled in the art will appreciate, the term "alkenyl" encompasses a group having a "cis" or "trans" configuration or a mixture thereof, or having a "Z" or "E" configuration or a mixture thereof. For example, C 2-6 An alkenyl group refers to a straight-chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, the alkenyl group has 2 to 30 carbon atoms (C... 2-30 ), 2 to 20 carbon atoms (C 2-20 ), 2 to 15 carbon atoms (C 2-15 ), 2 to 10 carbon atoms (C 2-10 ) or 2 to 6 carbon atoms (C 2-6 Straight-chain divalent hydrocarbon groups or those with 3 to 30 carbon atoms (C 3-30 ), 3 to 20 carbon atoms (C 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ) or 3 to 6 carbon atoms (C 3-6 Branched divalent hydrocarbon groups. Examples of alkenyl groups include (but are not limited to) vinylene (including all isomers, such as ethylene-1,1-diyl or ethylene-1,2-diyl), propenyl (including all isomers, such as 1-propen-1,1-diyl, 1-propen-1,2-diyl and 1-propen-1,3-diyl), butenyl (including all isomers, such as 1-buten-1,1-diyl, 1-buten-1,2-diyl and 1-buten-1,4-diyl), pentenyl (including all isomers, such as 1-penten-1,1-diyl, 1-penten-1,2-diyl and 1-penten-1,5-diyl) and hexenyl (including all isomers, such as 1-hexen-1,1-diyl, 1-hexen-1,2-diyl and 1-hexen-1,6-diyl).

[0065] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing one or more carbon-carbon triple bonds. In one embodiment, it contains one, two, three, or four carbon-carbon triple bonds, and in another embodiment, it contains one carbon-carbon triple bond. The alkynyl group may optionally be substituted with one or more substituents Q as described herein. For example, C 2-6The alkynyl group refers to a straight-chain unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 4 to 6 carbon atoms. In some embodiments, the alkynyl group has 2 to 20 carbon atoms (C... 2-20 ), 2 to 15 carbon atoms (C 2-15 ), 2 to 10 carbon atoms (C 2-10 ) or 2 to 6 carbon atoms (C 2-6 Straight-chain monovalent hydrocarbon groups or those with 4 to 20 carbon atoms (C 4-20 ), 4 to 15 carbon atoms (C 4-15 ), 4 to 10 carbon atoms (C 4-10 ) or 4 to 6 carbon atoms (C 4-6 The branched monovalent hydrocarbon group of ). Examples of alkynyl groups include (but are not limited to) ethynyl (–C≡CH), propynyl (including all isomers, such as 1-propynyl (–C≡CCH3) and propynyl (–CH2C≡CH)), butynyl (including all isomers, such as 1-butyn-1-yl and 2-butyn-1-yl), penynyl (including all isomers, such as 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomers, such as 1-hexyn-1-yl and 2-hexyn-1-yl).

[0066] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group, optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl group is a saturated or unsaturated but non-aromatic, and / or bridged or unbridged, and / or fused bicyclic group. In some embodiments, the cycloalkyl group has 3 to 20 carbon atoms (C20 to C20). 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ) or 3 to 7 carbon atoms (C 3-7 In one embodiment, the cycloalkyl group is monocyclic. In another embodiment, the cycloalkyl group is bicyclic. In yet another embodiment, the cycloalkyl group is tricyclic. In yet another embodiment, the cycloalkyl group is polycyclic. Examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decahydronaphthyl, and adamantyl.

[0067] The terms "cycloalkylene" and "cycloalkyldiyl" are used interchangeably herein when referring to a cyclic divalent hydrocarbon group, which may optionally be substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl group may be a saturated or unsaturated but non-aromatic, and / or bridged or unbridged, and / or fused bicyclic group. In some embodiments, the cycloalkylene group has 3 to 30 carbon atoms (C60-C60). 3-30 ), 3 to 20 carbon atoms (C 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ) or 3 to 7 carbon atoms (C 3-10 Examples of cycloalkylene compounds include (but are not limited to) cyclopropylene (including all isomers, such as cyclopropyl-1,1-diyl and cyclopropyl-1,2-diyl), cyclobutylene (including all isomers, such as cyclobut-1,1-diyl, cyclobut-1,2-diyl and cyclobut-1,3-diyl), cyclopentylene (including all isomers, such as cyclopentyl-1,1-diyl, cyclopentyl-1,2-diyl and cyclopentyl-1,3-diyl), and cyclohexylene (including all isomers, such as cyclohexyl-1,1-diyl and cyclohexyl-1,2-diyl). Cyclohexyl-1,3-diyl and cyclohexyl-1,4-diyl), cycloheptanyl (including all isomers, such as cycloheptan-1,1-diyl, cycloheptan-1,2-diyl, cycloheptan-1,3-diyl and cycloheptan-1,4-diyl), decahydronaphthyl (including all isomers, such as decahydronaphthyl-1,1-diyl, decahydronaphthyl-1,2-diyl and decahydronaphthyl-1,8-diyl), and adamantylyl (including all isomers, such as adamantane-1,2-diyl, adamantane-1,3-diyl and adamantane-1,8-diyl).

[0068] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and / or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic carbon ring. In some embodiments, the aryl group has 6 to 20 ring carbon atoms (C64-C64). 6-20 ), 6 to 15 ring carbon atoms (C 6-15 ) or 6 to 10 ring carbon atoms (C 6-10 Examples of aryl groups include (but are not limited to) phenyl, naphthyl, fluorenyl, azulel, anthracel, phenanthryl, pyrene, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocyclic ring, where one ring is aromatic and the other rings may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indenyl, or tetrahydronaphthyl (naphthyl). In one embodiment, the aryl group is monocyclic. In another embodiment, the aryl group is bicyclic. In yet another embodiment, the aryl group is tricyclic. In still another embodiment, the aryl group is polycyclic. In some embodiments, the aryl group is optionally substituted with one or more substituents Q as described herein.

[0069] The terms "arylene" and "arylene dimethyl" are used interchangeably herein when referring to a divalent monocyclic aromatic hydrocarbon group or a divalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon ring. In some embodiments, the arylene has 6 to 20 ring atoms (C... 6-20 ), 6 to 15 ring atoms (C 6-15 ) or 6 to 10 ring atoms (C 6-10 Examples of arylene groups include (but are not limited to) phenylene (including all isomers, such as phenyl-1,2-diyl, phenyl-1,3-diyl, and phenyl-1,4-diyl), naphthylene (including all isomers, such as naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorene (including all isomers, such as fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), azulene (including all isomers, such as azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), and anthracene (including all isomers, such as anthracene-1,2-diyl). Anthracene-1,3-diyl and anthracene-1,8-diyl), phenanthrene-1,2-diyl, phenanthrene-1,3-diyl and phenanthrene-1,8-diyl, pyrene-1,2-diyl, pyrene-1,3-diyl and pyrene-1,8-diyl, biphenyl-1,3-diyl, biphenyl-3,4'-diyl and biphenyl-4,4'-diyl, and terphenyl-1,3-diyl (including all isomers of biphenyl-2,3-diyl, biphenyl-3,4'-diyl and biphenyl-4,4'-diyl) and terphenyl-1,3-diyl (including all isomers of terphenyl-2,3-diyl, terphenyl-3,4'-diyl and terphenyl-4,4'-diyl). Arylidene also refers to a bicyclic or tricyclic carbocyclic ring, where one ring is aromatic and the other rings can be saturated, partially unsaturated, or aromatic, such as dihydronaphthylene (including all isomers, e.g., dihydronaphth-1,2-diyl or dihydronaphth-1,8-diyl), indenylene (including all isomers, e.g., indane-1,2-diyl, indane-1,5-diyl or indane-1,7-diyl), indenmanylene (including all isomers, e.g., indane-1,2-diyl, indane-1,5-diyl or indane-1,7-diyl), or tetrahydronaphthylene (including all isomers, e.g., tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl or tetrahydronaphth-1,8-diyl). In some embodiments, the arylidene may optionally be substituted with one or more substituents Q as described herein.

[0070] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In some embodiments, the aralkyl group has 7 to 30 carbon atoms (C60-C60). 7-30 ), 7 to 20 carbon atoms (C 7-20 ) or 7 to 16 carbon atoms (C 7-16Examples of aralkyl groups include (but are not limited to) benzyl, phenylethyl (including all isomers, such as 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomers, such as 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In some embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

[0071] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring contains one or more heteroatoms, each heteroatom independently selected from O, S, and N. The heteroaryl group is bonded to the remainder of the molecule through the aromatic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, and / or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In some embodiments, the heteroaryl group has 5 to 20 ring atoms, 5 to 15 ring atoms, or 5 to 10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include (but are not limited to) furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroleyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic. Examples of bicyclic heteroaryl groups include (but are not limited to) benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopiperanyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furanopyridyl, imidazopyridyl, imidazothiazolyl, indoleazinyl, indoleyl, indazoleyl, isobenzofuranyl, isobenzothiaphenyl, isoindoleyl, isoquinolinyl, isothiazolyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienzopyridyl. In yet another embodiment, the heteroaryl group is tricyclic. Examples of tricyclic heteroaryl groups include (but are not limited to) acridinel, benzoindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrololinyl, phenanthidyl, phenarsazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, and xanthanel. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0072] The terms "heteroaryl" and "heteroaryl dimethyl" are used interchangeably herein when referring to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring contains one or more heteroatoms, each heteroatom being independently selected from O, S, and N. The heteroaryl group has at least one bond to the remainder of the molecule through its aromatic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In some embodiments, the heteroaryl group has 5 to 20 ring atoms, 5 to 15 ring atoms, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include (but are not limited to) furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyrroleyl, thiadiazolyl, thiazolyl, thiaphenyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include (but are not limited to) benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzopiperanyl, benzothiadiazolyl, benzothiazolyl, benzothiophene, benzotriazolyl, benzoxazolyl, benzofuranopyridyl, imidazopyridyl, imidazothiazolyl, indoleazinyl, indoleyl, indazoleyl, isobenzofuranyl, isobenzothiaphene, isoindoleyl, isoquinolinyl, isothiazolyl, naphthinyl, oxazolopyridyl, phthalazinyl, phthalidinyl, purineyl, pyridinylpyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinoxalinyl, quinoxalazolinyl, thiazopyrimidinyl, and thiaphenepyridyl. Examples of tricyclic heteroaryl groups include (but are not limited to) acridineyl, benzoindolyl, carbazolyl, dibenzofuranyl, perimidinylene, phenanthrolinel, phenanthidyl, phenarsazinylene, phenazinyl, phenanthiazinyl, phenoxazinyl, and oxazaneyl. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0073] The term "heterocyclic group" or "heterocycle" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each heteroatom being independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In some embodiments, the heterocyclic group or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclic group is bonded to the remainder of the molecule through the non-aromatic ring. In some embodiments, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may be fused or bridged, and wherein the nitrogen or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclic group may be attached to the host structure at any heteroatom or carbon atom, resulting in the formation of a stable compound. Examples of heterocyclic groups and heterocyclic groups include (but are not limited to) nitrogen-containing heterocyclic groups. Benzadioxane, benzodioxane-hexyl, benzodioxane-pentenyl, benzofuranone, benzopyranone, benzopiperanyl, benzotetrahydrofuranyl, benzotetrahydrothiophene, benzothiaranyl, benzooxazinyl, β-carbolinyl, benzodihydropyranyl, cronone, cenolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisothiazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropiperanyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrroleyl, dioxolane, 1,4-dithiaalkyl, furanone, imidazoalkyl, imidazolide The heterocyclic group comprises phyrinyl, indololinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothiophenyl, isobenzodihydropyranyl, isocoumarinyl, isoindololinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinoneyl, oxazolyl, ethylene oxide, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolyl, pyrrolyl, pyrrololinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropiperolinyl, tetrahydrothiophenyl, thiamorpholinyl, thiazolyl, tetrahydroquinolinyl, and 1,3,5-trithiaalkyl. In some embodiments, the heterocyclic group is optionally substituted with one or more substituents Q as described herein.

[0074] The term "hypoheterocyclic group" refers to a divalent monocyclic nonaromatic ring system or a divalent polycyclic system containing at least one nonaromatic ring, wherein one or more of the nonaromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. The hypoheterocyclic group is bonded to the remainder of the molecule via the nonaromatic ring. In some embodiments, the hypoheterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some embodiments, the hypoheterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may be fused or bridged, and wherein the nitrogen or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, and some rings may be partially or fully saturated or aromatic. The hypoheterocyclic group may be attached to the host structure at any heteroatom or carbon atom, resulting in the formation of a stable compound. Examples of said hypoheterocyclic groups include (but are not limited to) nitrous oxides. alkyl, benzodioxane-hexyl, benzodioxane-pentenyl, benzofuranone-yl, benzopyranone-yl, benzopiperanyl, benzotetrahydrofuranyl, benzotetrahydrothiophene-yl, benzothiaranyl, benzooxazinyl, β-carbamoyl, benzodihydropyranyl, benzoxone-yl, benzopyrinyl, coumarinyl, decahydroisoquinoline-yl, dihydrobenzisothiazinyl, dihydrobenzisothiazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropiperanyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrroleyl, dioxopentyl, 1,4-dithiaalkyl, benzofuranone-yl, imidazole Alkyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothiophenyl, isobenzodihydropyranyl, isocoumarinyl, isoindolinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinone, oxazolyl, ethylene oxide, piperazine, piperidinyl, 4-piperidinone, pyrazolyl, pyrazoleyl, pyrrolidinyl, pyrrolinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropiperanyl, tetrahydrothiophenyl, thiamethoxolinyl, thiazolinyl, tetrahydroquinolinyl, and 1,3,5-trithiaalkyl. In some embodiments, the heterocyclic group is optionally substituted with one or more substituents Q as described herein.

[0075] The terms “halogen,” “halogen ion,” or “halogen group” refer to fluorine, chlorine, bromine, and / or iodine groups.

[0076] The term "optionally substituted" refers to a group or substituent, such as alkyl, alkylene, alkenyl, alkenylene, ynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclic, or heterocyclic, which may be substituted by one or more, in one embodiment by one, two, three, or four substituents Q, each of which is independently selected, for example, (a) deuterium (–D), cyano (–CN), halo, nitro (–NO2), and oxo (=O); (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Substitution; and (c)–C(O)R a –C(O)OR a –C(O)NR b R c –C(O)SR a –C(NR) a )NR b R c –C(S)R a –C(S)OR a –C(S)NR b R c –OR a –OC(O)R a –OC(O)OR a –OC(O)NR b R c –OC(O)SR a –OC(NR) a )NR b R c –OC(S)R a –OC(S)OR a –OC(S)NR b R c –OS(O)R a –OS(O)2R a –OS(O)NR b R c –OS(O)2NR b R c –NR b R c –NR a C(O)R d –NRa C(O)OR d –NR a C(O)NR b R c –NR a C(O)SR d –NR a C(NR d )NR b R c –NR a C(S)R d –NR a C(S)OR d –NR a C(S)NR b R c –NR a S(O)R d –NR a S(O)2R d –NR a S(O)NR b R c –NR a S(O)2NR b R c –SR a –S(O)R a –S(O)2R a –S(O)NR b R c and –S(O)2NR b R c , where R a R b R c and R d Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Replace; or (iii)R b and R c Together with the N atom to which it is attached, it forms a Q group optionally substituted with one or more, or in one embodiment with one, two, three, or four substituents. a Substituted heterocyclic groups. As used herein, all substitutable groups are “optionally substituted”.

[0077] In one implementation, Q a Each is independently selected from: (a) deuterium, cyano, halogen, nitro, and oxonide; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl, and heterocyclic groups; and (c)–C(O)R e –C(O)OR e –C(O)NR f R g –C(O)SR e –C(NR) e )NR f R g –C(S)R e –C(S)OR e –C(S)NR f R g –OR e –OC(O)R e –OC(O)OR e –OC(O)NR f R g –OC(O)SR e –OC(NR) e )NR f R g –OC(S)R e –OC(S)OR e –OC(S)NR f R g –OS(O)R e –OS(O)2R e –OS(O)NR f R g –OS(O)2NR f R g –NR f R g –NR e C(O)R h –NR e C(O)OR f –NR e C(O)NR f R g –NR e C(O)SR f –NR e C(NR h )NR f Rg –NR e C(S)R h –NR e C(S)OR f –NR e C(S)NR f R g –NR e S(O)R h –NR e S(O)2R h –NR e S(O)NR f R g –NR e S(O)2NR f R g –SR e –S(O)R e –S(O)2R e –S(O)NR f R g and –S(O)2NR f R g ;where R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii)R f and R g Together with the N atom it is attached to, it forms a heterocyclic group.

[0078] In some embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomer excess of not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In some embodiments, based on the total weight of the enantiomer mixture under discussion, the optically active compound comprises about 95% or more of one enantiomer and about 5% or less of another enantiomer. In some embodiments, based on the total weight of the enantiomer mixture under discussion, the optically active compound comprises about 98% or more of one enantiomer and about 2% or less of another enantiomer. In some embodiments, based on the total weight of the enantiomer mixture under discussion, the optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer.

[0079] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the compound about its chiral center. (+) and (-) are used to indicate the optical activity of the compound, i.e., the direction in which the optically active compound rotates the plane of polarization. The prefix (-) indicates that the compound is levorotatory, meaning it rotates the plane of polarization to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, meaning it rotates the plane of polarization to the right or clockwise. However, the optical activity indices (+) and (-) are independent of the compound's absolute configuration (R and S).

[0080] The term "isotope-enriched" refers to a compound that contains an unnatural proportion of isotopes on one or more atoms constituting the compound. In some embodiments, the isotope-enriched compound contains one or more isotopes in unnatural proportions, including (but not limited to) hydrogen (…). 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), Carbon-12 ( 12 C), Carbon-13 ( 13 C), Carbon-14 ( 14 C) Nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Oxygen-16 ( 16 O), Oxygen-17 ( 17 O), Oxygen-18 ( 18O), Fluorine-17 ( 17 F), Fluorine-18 ( 18 F), Phosphorus-31 ( 31 P), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), Chlorine-35 ( 35 Cl), Chlorine-36 ( 36 Cl), Chlorine-37 ( 37 Cl), Bromine-79 ( 79 Br), bromine-81 ( 81 Br), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and Iodine-131 131 I). In some embodiments, the isotope-enriched compound is in a stable form, i.e., non-radioactive. In some embodiments, the isotope-enriched compound contains one or more isotopes in non-natural proportions, including (but not limited to) hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), Carbon-13 ( 13 C) Nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), Oxygen-16 ( 16 O), Oxygen-17 ( 17 O), Oxygen-18 ( 18 O), Fluorine-17 ( 17 F), Phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), Chlorine-35 ( 35 Cl), Chlorine-37 ( 37 Cl), Bromine-79 ( 79 Br), bromine-81 ( 81 Br) and iodine-127 127I). In some embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In some embodiments, the isotopically enriched compound contains one or more isotopes in non-natural proportions, including (but not limited to) tritium. 3 H), carbon-11 ( 11 C), Carbon-14 ( 14 C) Nitrogen-13 ( 13 N), Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Fluorine-18 ( 18 F), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), sulfur-35 ( 35 S), Chlorine-36 ( 36 Cl), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-129( 129 I) and Iodine-131 131 I). It should be understood that in compounds as provided herein, any hydrogen can be, for example... 2 H, or any carbon, can be, for example... 13 C, or any nitrogen can be, for example 15 N or any oxygen can be, for example 18 O, is feasible according to the judgment of a person skilled in the art.

[0081] The term "isotope enrichment" refers to the incorporation of a less common isotope of an element (e.g., D for deuterium or hydrogen-2) at a given position in a molecule in place of a more common isotope of that element (e.g., ...). 1 H is a percentage of protium or hydrogen (-1). As used herein, when an atom at a particular position in a molecule is designated as a particular, less common isotope, it should be understood that the abundance of that isotope at that position is much greater than its natural abundance.

[0082] The term "isotope enrichment factor" refers to the ratio of the isotope abundance in an isotope-enriched compound to the natural abundance of a particular isotope.

[0083] The term "hydrogen" or the symbol "H" refers to the composition of hydrogen isotopes that exist naturally in their natural abundance, including protium (H). 1 H), deuterium ( 2 H or D) and tritium ( 3 Protium is the most common hydrogen isotope, with a natural abundance greater than 99.98%. Deuterium is a less common hydrogen isotope, with a natural abundance of approximately 0.0156%.

[0084] The term "deuterium enrichment" refers to the percentage of deuterium that has been incorporated into a molecule at a given position, replacing hydrogen. For example, a 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that specified location. Because the naturally occurring deuterium distribution averages about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials will average about 0.0156%. As used herein, when a specific position in an isotopically enriched compound is specified to contain deuterium, it should be understood that the deuterium abundance at that position in the compound is much greater than its natural abundance (0.0156%).

[0085] The term "carbon" or the symbol "C" refers to the composition of carbon isotopes that exist naturally in their natural abundance, including carbon-12 (…). 12 C) and carbon-13 ( 13 C). Carbon-12 is the most common carbon isotope, with a natural abundance greater than 98.89%. Carbon-13 is a less common carbon isotope, with a natural abundance of approximately 1.11%.

[0086] The term "carbon-13 enrichment" or " 13 "C enrichment" refers to the percentage of carbon-13 incorporated at a given position in a molecule, replacing carbon. For example, 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at the specified location. Because the average distribution of naturally occurring carbon-13 is about 1.11%, the average carbon-13 enrichment at any location in a compound synthesized using non-enriched starting materials is about 1.11%. As used herein, when a specific position in an isotopically enriched compound is specified to contain carbon-13, it should be understood that the abundance of carbon-13 at that position in the compound is much greater than its natural abundance (1.11%).

[0087] The terms "substantially pure" and "substantially homogeneous" mean sufficiently homogeneous to indicate the absence of readily detectable impurities as determined by standard analytical methods (including, but not limited to, thin-layer chromatography (TLC), gel electrophoresis, high-performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS)) used by those skilled in the art; or sufficiently pure such that further purification does not detectably alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic and biological activities. In some embodiments, "substantially pure" and "substantially homogeneous" refer to a collection of molecules wherein, as determined by standard analytical methods, at least about 95% by weight, at least about 96% by weight, at least about 97% by weight, at least about 98% by weight, at least about 99% by weight, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers. As used herein, when an atom at a specific position in an isotopically enriched molecule is designated as a particular, less common isotope, a molecule containing an isotope other than the designated isotope at that position is an impurity relative to the isotopically enriched compound. Therefore, for a deuterated compound having an atom designated as deuterium at a specific position, a compound containing protium at the same position is an impurity.

[0088] The term "solvate" refers to a complex or aggregate formed of one or more solute molecules (such as the compounds provided herein) and one or more solvent molecules, wherein the solute and solvent molecules are present in stoichiometric or non-stoichiometric amounts. Suitable solvents include (but are not limited to) water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include (but are not limited to) hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0089] For the divalent groups described herein, the orientation of the divalent group does not imply orientation. For example, unless a specific orientation is specified, the formula –C(O)NH– represents –C(O)NH– and –NHC(O)–.

[0090] The phrase “enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants of the compound mentioned herein; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof” has the same meaning as the phrase “(i) enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants of the compound mentioned herein; (ii) pharmaceutically acceptable salts, solvates, hydrates, or prodrugs of the compound mentioned herein; or (iii) pharmaceutically acceptable salts, solvates, hydrates, or prodrugs of enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants of the compound mentioned herein”.

[0091] compound

[0092] In one embodiment, a compound of formula (I) is provided herein:

[0093]

[0094] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0095] R 1 It is (a) hydrogen, deuterium, cyano, halo, or nitro; or (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[0096] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or heteroaryl; wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[0097] R 3 R 4 R 5 and R 6 Each is independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR 1b R 1c –OC(NR) 1a )NR 1b R 1c –OS(O)R 1a –OS(O)2R 1a –OS(O)NR 1b R 1c –OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R 1c –NR 1a S(O)R 1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c –NR 1aS(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ;

[0098] R A C 6-14 arylene or heteroarylene;

[0099] R B C 6-14 aryl or heteroaryl;

[0100] R B And X can be (i), (ii), or (iii):

[0101] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0102] R B C 6-14 aryl or heteroaryl;

[0103] (ii)X is –N(R) X )–;

[0104] R B C 6-14 aryl or heteroaryl; and

[0105] R X For hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups; or

[0106] (iii) X is –N(R) X )-;and

[0107] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0108] L is C 1-6 Alkylene, C 2-6 imidene group, C 3-10 Cycloalkyl or heterocyclic groups; and

[0109] R 1a R1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms it is attached to, it forms a heterocyclic group; or R 1b and R 1c Together with the N atom it is attached to, it forms a heterocyclic group;

[0110] The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroaryl, heterocyclic, and heterocyclic groups are each optionally substituted by one or more, in one embodiment by one, two, three, or four substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, nitro, and oxoalkyl; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Substitution; and (c)–C(O)R a –C(O)OR a –C(O)NR b R c –C(O)SR a –C(NR) a )NR b R c –C(S)R a –C(S)OR a –C(S)NR b R c –OR a –OC(O)R a –OC(O)OR a –OC(O)NR b R c –OC(O)SR a –OC(NR) a )NR b R c –OC(S)R a–OC(S)OR a –OC(S)NR b R c –OS(O)R a –OS(O)2R a –OS(O)NR b R c –OS(O)2NR b R c –NR b R c –NR a C(O)R d –NR a C(O)OR d –NR a C(O)NR b R c –NR a C(O)SR d –NR a C(NR d )NR b R c –NR a C(S)R d –NR a C(S)OR d –NR a C(S)NR b R c –NR a S(O)R d –NR a S(O)2R d –NR a S(O)NR b R c –NR a S(O)2NR b R c –SR a –S(O)R a –S(O)2R a –S(O)NR b R c and –S(O)2NR b R c , where R a R b R c and R d Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Replace; or (iii)R b and R c Together with the N atom it is attached to, it forms an optional group Q via one or more, in one embodiment via one, two, three or four substituents. a Substituted heterocyclic groups;

[0111] Q a Each is independently selected from: (a) deuterium, cyano, halogen, nitro, and oxonide; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl, and heterocyclic groups; and (c)–C(O)R e –C(O)OR e –C(O)NR f R g –C(O)SR e –C(NR) e )NR f R g –C(S)R e –C(S)OR e –C(S)NR f R g –OR e –OC(O)R e –OC(O)OR e –OC(O)NR f R g –OC(O)SR e –OC(NR) e )NR f R g –OC(S)R e –OC(S)OR e –OC(S)NR f R g –OS(O)R e –OS(O)2R e –OS(O)NR f R g –OS(O)2NR f R g –NR f R g –NRe C(O)R h –NR e C(O)OR f –NR e C(O)NR f R g –NR e C(O)SR f –NR e C(NR h )NR f R g –NR e C(S)R h –NR e C(S)OR f –NR e C(S)NR f R g –NR e S(O)R h –NR e S(O)2R h –NR e S(O)NR f R g –NR e S(O)2NR f R g –SR e –S(O)R e –S(O)2R e –S(O)NR f R g and –S(O)2NR f R g ;where R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii)R f and R g Together with the N atom it is attached to, it forms a heterocyclic group.

[0112] In another embodiment, a compound of formula (II) is provided herein:

[0113]

[0114] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3 R 4 R 5 R 6 R A R B L and X are each defined as described in this article.

[0115] In one implementation, in formula (I) or (II),

[0116] R 1 Halogenated or C 1-6 alkyl;

[0117] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or heteroaryl, wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0118] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0119] R A C 6-14 arylene or heteroarylene;

[0120] R B And X can be (i), (ii), or (iii):

[0121] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0122] R B C 6-14 aryl or heteroaryl;

[0123] (ii)X is –NR X –;

[0124] R B C6-14 aryl or heteroaryl; and

[0125] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0126] (iii) X is –NR X -;and

[0127] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group; and

[0128] L is C 1-6 Alkylene, C 2-6 imide or C 3-10 Cycloalkylene;

[0129] The alkyl, alkylene, alkenyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[0130] In another implementation, in formula (I) or (II),

[0131] R 1 Halogenated or C 1-6 alkyl;

[0132] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or a monocyclic heteroaryl group, wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0133] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0134] R A C 6-14 arylene or monocyclic heteroarylene;

[0135] R B And X can be (i), (ii), or (iii):

[0136] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0137] R B C 6-14 aryl or heteroaryl;

[0138] (ii)X is –NR X –;

[0139] R B C 6-14 aryl or heteroaryl; and

[0140] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0141] (iii) X is –NR X -;and

[0142] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group; and

[0143] L is C 1-6 Alkylene or C 2-6 alkenyl;

[0144] The alkyl, alkylene, alkenyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0145] In yet another implementation, in formula (I) or (II),

[0146] R 1 C 1-6 alkyl;

[0147] R 2 –C(O)OH, –C(O)NR 2b R 2c –C(O)N(R)2b OR 2c Or a 5-membered heteroaryl group, in which R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0148] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0149] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0150] R A C 6-14 arylene or 6-membered heteroarylene;

[0151] R B And X can be (i), (ii), or (iii):

[0152] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0153] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl;

[0154] (ii)X is –NR X –;

[0155] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl; and

[0156] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0157] (iii) X is –NR X -;and

[0158] R B and R X Together with the N atom it is attached to, it forms a monocyclic or bicyclic heteroaryl group, or a monocyclic or bicyclic heterocyclic group; and

[0159] L is C 1-6 Alkylene or C 2-6 alkenyl;

[0160] The alkyl, alkylene, alkenyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0161] In yet another implementation, in formula (I) or (II),

[0162] R 1 It is methyl;

[0163] R 2 It can be –C(O)OH, –C(O)NH2, –C(O)NHCH3, –C(O)NHCH2CH2OH, –C(O)NHOH, –C(O)NH (tetrazolyl), tetrazolyl, or 1,2,4-oxadiazolyl;

[0164] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0165] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0166] R A It is phenylene, chloro-phenylene, methoxy-phenylene, pyridylene, or methyl-pyridylene;

[0167] R B And X can be (i), (ii), or (iii):

[0168] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0169] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl or quinolinyl;

[0170] (ii)X is –NR X –;

[0171] R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0172] R XIt can be hydrogen, methyl, ethyl, hydroxyethyl, propyl, phenyl, fluorophenyl, formylphenyl, or benzyl; or

[0173] (iii) X is –NR X -;and

[0174] R B and R X Together with the nitrogen atom it is attached to, it forms a pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, amino-imidazolyl, or indoleyl group; and

[0175] L represents methylene, ethylene, or vinylene.

[0176] In yet another implementation, in formula (I) or (II),

[0177] R 1 It is methyl;

[0178] R 2 It is –C(O)OH, –C(O)NH2, –C(O)NHCH3, –C(O)NHCH2CH2OH, –C(O)NHOH, –C(O)NH (tetrazole-5-yl), tetrazolazole-5-yl or 1,2,4-oxadiazol-5-yl;

[0179] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0180] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0181] R A It is phenyl-1,3-diyl, phenyl-1,4-diyl, 2-chloro-phenyl-1,4-diyl, 2-methoxy-phenyl-1,4-diyl, pyridine-2,5-diyl, or 3-methyl-pyridine-2,5-diyl;

[0182] R B And X can be (i), (ii), or (iii):

[0183] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0184] R BIt is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0185] (ii)X is –NR X –;

[0186] R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0187] R X It is hydrogen, methyl, ethyl, 2-hydroxyethyl, n-propyl, phenyl, 4-fluorophenyl, 4-formylphenyl, or benzyl; or

[0188] (iii) X is –NR X -;and

[0189] R B and R X Together with the N atom it is attached to, it forms pyrrolidin-1-yl, 2-amino-imidazol-1-yl, indol-1-yl, pyrrolidine-1-yl, piperidin-1-yl, or 4-morpholino-4-yl; and L is methylene, ethane-1,2-diyl, or ethylene-1,2-diyl.

[0190] In yet another embodiment, a compound of formula (III) is provided herein:

[0191]

[0192] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0193] U 1 V 1 W 1 and X1 Each is independently (i) C or N; or (ii) –CR 7a =、–N=、–NR 7b –、–O– or –S–;

[0194] Y 1 For (i) C or N; or (ii) key, –CR 7a =、–N=、–NR 7b –、–O– or –S–;

[0195] Z 1 It can be C or N;

[0196] R 7a Each is independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR 1b R 1c –OC(NR) 1a )NR 1b R 1c –OS(O)R 1a –OS(O)2R 1a –OS(O)NR 1b R 1c –OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R1c –NR 1a S(O)R 1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c –NR 1a S(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ;

[0197] R 7b Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups; and

[0198] R 1 R 2 R 3 R 4 R 5 R 6 R B R 1a R 1b R 1c R 1d L and X are each defined as in this paper;

[0199] The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more substituents, and in one embodiment by one, two, three, or four substituents Q.

[0200] In yet another embodiment, a compound of formula (IV) is provided herein:

[0201]

[0202] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R2 R 3 R 4 R 5 R 6 R B L, X, U 1 V 1 W 1 X 1 Y 1 and Z 1 Each as defined in this article.

[0203] In yet another embodiment, a compound of formula (V) is provided herein:

[0204]

[0205] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0206] U 1 V 1 and X 1 Each independently as –CR 7a =、–N=、–NR 7b –、–O– or –S–;

[0207] W 1 It can be C or N;

[0208] Y 1 For key, –CR 7a =、–N=、–NR 7b –, –O– or –S–; and

[0209] R 1 R 2 R 3 R 4 R 5 R 6 R B R 7a R 7b L, X and Z 1 Each as defined in this article.

[0210] In yet another embodiment, a compound of formula (VI) is provided herein:

[0211]

[0212] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0213] U 1 V 1 and X 1 Each independently as –CR 7a =、–N=、–NR 7b –、–O– or –S–;

[0214] W 1 It can be C or N;

[0215] Y 1 For key, –CR 7a =、–N=、–NR 7b –, –O– or –S–; and

[0216] R 1 R 2 R 3 R 4 R 5 R 6 R B R 7a R 7b L, X and Z 1 Each as defined in this article.

[0217] In yet another embodiment, a compound of formula (VII) is provided herein:

[0218]

[0219] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0220] U 1 W 1 and X 1 Each independently as –CR 7a =、–N=、–NR 7b –、–O– or –S–;

[0221] V 1 It can be C or N;

[0222] Y 1 For key, –CR 7a =、–N=、–NR7b –, –O– or –S–; and

[0223] R 1 R 2 R 3 R 4 R 5 R 6 R B R 7a R 7b L, X and Z 1 Each as defined in this article.

[0224] In yet another embodiment, a compound of formula (VIII) is provided herein:

[0225]

[0226] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0227] U 1 W 1 and X 1 Each independently as –CR 7a =、–N=、–NR 7b –、–O– or –S–;

[0228] V 1 It can be C or N;

[0229] Y 1 For key, –CR 7a =、–N=、–NR 7b –, –O– or –S–; and

[0230] R 1 R 2 R 3 R 4 R 5 R 6 R B R 7a R 7b L, X and Z 1 Each as defined in this article.

[0231] In yet another embodiment, a compound of formula (IX) is provided herein:

[0232]

[0233] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0234] R 7 Each is independently (a) deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR 1b R 1c –OC(NR) 1a )NR 1b R 1c –OS(O)R 1a –OS(O)2R 1a –OS(O)NR 1b R 1c –OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R 1c –NR 1a S(O)R 1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c–NR 1a S(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ;

[0235] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0236] R 1 R 2 R 3 R 4 R 5 R 6 R B R 1a R 1b R 1c R 1d L and X are each defined as in this paper;

[0237] The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more substituents, and in one embodiment by one, two, three, or four substituents Q.

[0238] In yet another embodiment, a compound of formula (X) is provided herein:

[0239]

[0240] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 R B L, X and n are each defined as in this paper.

[0241] In yet another embodiment, a compound of formula (XI) is provided herein:

[0242]

[0243] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 R B L, X and n are each defined as in this paper.

[0244] In yet another embodiment, a compound of formula (XII) is provided herein:

[0245]

[0246] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7a R B L and X are each defined as described in this article.

[0247] In yet another embodiment, a compound of formula (XIII) is provided herein:

[0248]

[0249] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 R B L, X and n are each defined as in this paper.

[0250] In one implementation, in any of equations (IX) to (XI) and (XIII),

[0251] R 1 Halogenated or C 1-6 alkyl;

[0252] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or heteroaryl, wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0253] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0254] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0255] R B And X can be (i), (ii), or (iii):

[0256] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0257] R B C 6-14 aryl or heteroaryl;

[0258] (ii)X is –NR X –;

[0259] R B C 6-14 aryl or heteroaryl; and

[0260] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0261] (iii) X is –NR X -;and

[0262] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0263] L is C 1-6Alkylene, C 2-6 imide or C 3-10 cycloalkylene; and

[0264] n is an integer, which can be 0, 1, 2, 3 or 4;

[0265] The alkyl, alkylene, alkenyl, cycloalkylene, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[0266] In another implementation, in any of equations (IX) to (XI) and (XIII),

[0267] R 1 Halogenated or C 1-6 alkyl;

[0268] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or a monocyclic heteroaryl group, wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0269] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0270] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0271] R B And X can be (i), (ii), or (iii):

[0272] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0273] R B C 6-14 aryl or heteroaryl;

[0274] (ii)X is –NR X –;

[0275] R B C 6-14 aryl or heteroaryl; and

[0276] RX For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0277] (iii) X is –NR X -;and

[0278] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0279] L is C 1-6 Alkylene or C 2-6 alkenyl; and

[0280] n is an integer, which can be 0, 1, 2, 3 or 4;

[0281] The alkyl, alkylene, alkenyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0282] In yet another implementation, in any of equations (IX) to (XI) and (XIII),

[0283] R 1 C 1-6 alkyl;

[0284] R 2 –C(O)OH, –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or a 5-membered heteroaryl group, in which R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0285] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0286] R5 and R 6 Each is independently either hydrogen or deuterium;

[0287] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0288] R B And X can be (i), (ii), or (iii):

[0289] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0290] R B C is a single-ring or double-ring 6-14 Aryl, or monocyclic or bicyclic heteroaryl;

[0291] (ii)X is –NR X –;

[0292] R B C is a single-ring or double-ring 6-14 Aryl, or monocyclic or bicyclic heteroaryl; and

[0293] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0294] (iii) X is –NR X -;and

[0295] R B and R X Together with the N atom it is attached to, it forms a monocyclic or bicyclic heteroaryl group, or a monocyclic or bicyclic heterocyclic group;

[0296] L is C 1-6 Alkylene or C 2-6 alkenyl; and

[0297] n is an integer, 0, 1, or 2;

[0298] The alkyl, alkylene, alkenyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0299] In yet another implementation, in any of equations (IX) to (XI) and (XIII),

[0300] R 1 It is methyl;

[0301] R 2 It can be –C(O)OH, –C(O)NH2, –C(O)NHCH3, –C(O)NHCH2CH2OH, –C(O)NHOH, –C(O)NH (tetrazolyl), tetrazolyl, or 1,2,4-oxadiazolyl;

[0302] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0303] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0304] R 7 It is chloro or methoxy;

[0305] R B And X can be (i), (ii), or (iii):

[0306] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0307] R B The following compounds are used: phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, and fluoromethyl.

[0308] Pyridyl or quinolinyl;

[0309] (ii)X is –NR X –;

[0310] R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0311] R X It can be hydrogen, methyl, ethyl, hydroxyethyl, propyl, phenyl, fluorophenyl, formylphenyl, or benzyl; or

[0312] (iii) X is –NR X -;and

[0313] R B and R X Together with the nitrogen atom it is attached to, it forms pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, and amino-imidazolium.

[0314] Indole or indole group;

[0315] L is methylene, ethylene, or vinylene; and

[0316] n is an integer, either 0 or 1.

[0317] In yet another implementation, in any of equations (IX) to (XI) and (XIII),

[0318] R 1 It is methyl;

[0319] R 2 It is –C(O)OH, –C(O)NH2, –C(O)NHCH3, –C(O)NHCH2CH2OH, –C(O)NHOH, –C(O)NH (tetrazole-5-yl), tetrazolazole-5-yl or 1,2,4-oxadiazol-5-yl;

[0320] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0321] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0322] R 7 It is chloro or methoxy;

[0323] R B And X can be (i), (ii), or (iii):

[0324] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0325] R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0326] (ii)X is –NR X –;

[0327] R BIt is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0328] R X It is hydrogen, methyl, ethyl, 2-hydroxyethyl, n-propyl, phenyl, 4-fluorophenyl, 4-formylphenyl, or benzyl; or

[0329] (iii) X is –NR X -;and

[0330] R B and R X Together with the nitrogen atom it is attached to, they form pyrrole-1-yl, 2-amino-imidazol-1-yl, indole-1-yl, and pyrrole.

[0331] Alkyl-1-yl, piperidin-1-yl, or 4-morpholin-4-yl;

[0332] L is methylene, ethane-1,2-diyl, or ethylene-1,2-diyl; and

[0333] n is an integer, either 0 or 1.

[0334] In one implementation, in formula (XII),

[0335] R 1 Halogenated or C 1-6 alkyl;

[0336] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or heteroaryl, wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0337] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0338] R7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0339] R B And X can be (i), (ii), or (iii):

[0340] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0341] R B C 6-14 aryl or heteroaryl;

[0342] (ii)X is –NR X –;

[0343] R B C 6-14 aryl or heteroaryl; and

[0344] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0345] (iii) X is –NR X -;and

[0346] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group; and

[0347] L is C 1-6 Alkylene, C 2-6 imide or C 3-10 Cycloalkylene;

[0348] The alkyl, alkylene, alkenyl, cycloalkylene, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[0349] In another implementation, in formula (XII),

[0350] R 1 Halogenated or C 1-6 alkyl;

[0351] R 2 -C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or a monocyclic heteroaryl group, wherein R 2a R 2b and R2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0352] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0353] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0354] R B And X can be (i), (ii), or (iii):

[0355] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0356] R B C 6-14 aryl or heteroaryl;

[0357] (ii)X is –NR X –;

[0358] R B C 6-14 aryl or heteroaryl; and

[0359] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0360] (iii) X is –NR X -;and

[0361] R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group; and

[0362] L is C 1-6 Alkylene or C 2-6 alkenyl;

[0363] The alkyl, alkylene, alkenyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NRb R c , where R a R b and R c Each as defined in this article.

[0364] In yet another implementation, in formula (XII),

[0365] R 1 C 1-6 alkyl;

[0366] R 2 –C(O)OH, –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c Or a 5-membered heteroaryl group, in which R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0367] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0368] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0369] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0370] R B And X can be (i), (ii), or (iii):

[0371] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0372] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl;

[0373] (ii)X is –NR X –;

[0374] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl; and

[0375] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0376] (iii) X is –NR X -;and

[0377] R B and R X Together with the N atom it is attached to, it forms a monocyclic or bicyclic heteroaryl group or a monocyclic or bicyclic heterocyclic group; and

[0378] L is C 1-6 Alkylene or C 2-6 alkenyl;

[0379] The alkyl, alkylene, alkenyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0380] In yet another implementation, in formula (XII),

[0381] R 1 It is methyl;

[0382] R 2 It can be –C(O)OH, –C(O)NH2, –C(O)NHCH3, –C(O)NHCH2CH2OH, –C(O)NHOH, –C(O)NH (tetrazolyl), tetrazolyl, or 1,2,4-oxadiazolyl;

[0383] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0384] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0385] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0386] R B And X can be (i), (ii), or (iii):

[0387] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0388] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl or quinolinyl;

[0389] (ii)X is –NRX –;

[0390] R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0391] R X It can be hydrogen, methyl, ethyl, hydroxyethyl, propyl, phenyl, fluorophenyl, formylphenyl, or benzyl; or

[0392] (iii) X is –NR X -;and

[0393] R B and R X Together with the nitrogen atom it is attached to, it forms a pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, amino-imidazolyl, or indoleyl group; and

[0394] L represents methylene, ethylene, or vinylene.

[0395] In yet another implementation, in formula (XII),

[0396] R 1 It is methyl;

[0397] R 2 It is –C(O)OH, –C(O)NH2, –C(O)NHCH3, –C(O)NHCH2CH2OH, –C(O)NHOH, –C(O)NH (tetrazole-5-yl), tetrazolazole-5-yl or 1,2,4-oxadiazol-5-yl;

[0398] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0399] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0400] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0401] R B And X can be (i), (ii), or (iii):

[0402] (i) X is –O–, –S–, –S(O)– or –S(O)2–; and

[0403] R BIt is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0404] (ii)X is –NR X –;

[0405] R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0406] R X It is hydrogen, methyl, ethyl, 2-hydroxyethyl, n-propyl, phenyl, 4-fluorophenyl, 4-formylphenyl, or benzyl; or

[0407] (iii) X is –NR X -;and

[0408] R B and R X Together with the nitrogen atom it is attached to, it forms pyrrolidinyl, 2-aminoimidazolyl-1-yl, indolyl-1-yl, pyrrolidine-1-yl, piperidinyl-1-yl, or 4-morpholino-4-yl; and

[0409] L represents methylene, ethane-1,2-diyl, or ethylene-1,2-diyl.

[0410] In yet another embodiment, a compound of formula (XIV) is provided herein:

[0411]

[0412] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0413] R 2A For –OR2a –NR 2b R 2c or –N(R) 2b OR 2c ;

[0414] p is an integer 1, 2, or 3; and

[0415] R 1 R 3 R 4 R 5 R 6 R 7 R B R 2a R 2b R 2c and n are as defined in this article.

[0416] In yet another embodiment, a compound of formula (XV) is provided herein:

[0417]

[0418] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R 2A n and p are each defined as in this paper.

[0419] In yet another embodiment, a compound of formula (XVI) is provided herein:

[0420]

[0421] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R 2A n and p are each defined as in this paper.

[0422] In yet another embodiment, a compound of formula (XVII) is provided herein:

[0423]

[0424] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7a R B R 2A p and p are as defined in this paper.

[0425] In yet another embodiment, a compound of formula (XVIII) is provided herein:

[0426]

[0427] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R 2A n and p are each defined as in this paper.

[0428] In one implementation, in any of formulas (XIV) to (XVI) and (XVIII),

[0429] R 1 Halogenated or C 1-6 alkyl;

[0430] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R 2a R 2b and R 2c Each independently is hydrogen, C1-6 Alkyl or heteroaryl;

[0431] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0432] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0433] R B C 6-14 aryl or heteroaryl;

[0434] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0435] p is an integer 1, 2, or 3;

[0436] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q.

[0437] In another embodiment, in any of formulas (XIV) to (XVI) and (XVIII),

[0438] R 1 Halogenated or C 1-6 alkyl;

[0439] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0440] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0441] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0442] R B C 6-14 aryl or heteroaryl;

[0443] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0444] p is an integer, either 1 or 2;

[0445] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0446] In yet another embodiment, in any of formulas (XIV) to (XVI) and (XVIII),

[0447] R 1 C 1-6 alkyl;

[0448] R 2A For –OH, –NR 2b R 2c or –N(R) 2b OR 2c , where R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0449] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0450] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0451] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0452] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl;

[0453] n is an integer 0, 1, or 2; and

[0454] p is an integer, either 1 or 2;

[0455] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0456] In yet another embodiment, in any of formulas (XIV) to (XVI) and (XVIII),

[0457] R 1 It is methyl;

[0458] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole);

[0459] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0460] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0461] R 7 It is chloro or methoxy;

[0462] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl or quinolinyl;

[0463] n is an integer, either 0 or 1; and

[0464] p is an integer, either 1 or 2.

[0465] In yet another embodiment, in any of formulas (XIV) to (XVI) and (XVIII),

[0466] R 1 It is methyl;

[0467] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole);

[0468] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0469] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0470] R 7 It is chloro or methoxy;

[0471] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl;

[0472] n is an integer, either 0 or 1; and

[0473] p is an integer, either 1 or 2.

[0474] In yet another embodiment, in any of formulas (XIV) to (XVI) and (XVIII),

[0475] R 1 It is methyl;

[0476] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole-5-yl);

[0477] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0478] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0479] R 7 It is chloro or methoxy;

[0480] R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0481] n is an integer, either 0 or 1; and

[0482] p is an integer, either 1 or 2.

[0483] In yet another embodiment, in any of formulas (XIV) to (XVI) and (XVIII),

[0484] R 1 It is methyl;

[0485] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole-5-yl);

[0486] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0487] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0488] R 7 It is chloro or methoxy;

[0489] R B It is phenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0490] n is an integer, either 0 or 1; and

[0491] p is an integer, either 1 or 2.

[0492] In one implementation, in formula (XVII),

[0493] R 1 Halogenated or C 1-6 alkyl;

[0494] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0495] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0496] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0497] R B C 6-14 aryl or heteroaryl; and

[0498] p is an integer 1, 2, or 3;

[0499] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q.

[0500] In another implementation, in formula (XVII),

[0501] R 1 Halogenated or C 1-6 alkyl;

[0502] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0503] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0504] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0505] R B C 6-14 aryl or heteroaryl; and

[0506] p is an integer, either 1 or 2;

[0507] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0508] In yet another implementation, in formula (XVII),

[0509] R 1 C 1-6 alkyl;

[0510] R 2A For –OH, –NR 2b R 2c or –N(R) 2b OR 2c , where R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0511] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0512] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0513] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0514] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl; and

[0515] p is an integer, either 1 or 2;

[0516] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0517] In yet another implementation, in formula (XVII),

[0518] R 1 It is methyl;

[0519] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole);

[0520] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0521] R 5 and R6 Each is independently either hydrogen or deuterium;

[0522] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0523] R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0524] p is an integer, either 1 or 2.

[0525] In yet another implementation, in formula (XVII),

[0526] R 1 It is methyl;

[0527] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole);

[0528] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0529] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0530] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0531] R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0532] p is an integer, either 1 or 2.

[0533] In yet another implementation, in formula (XVII),

[0534] R 1 It is methyl;

[0535] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole-5-yl);

[0536] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0537] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0538] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0539] R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0540] p is an integer, either 1 or 2.

[0541] In yet another implementation, in formula (XVII),

[0542] R 1 It is methyl;

[0543] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole-5-yl);

[0544] R 3 R 5 and R 6 Each is independently either hydrogen or deuterium;

[0545] R 4 It can be hydrogen, deuterium, or fluorine-based;

[0546] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0547] R B It is phenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0548] p is an integer, either 1 or 2.

[0549] In yet another embodiment, this document provides a compound of formula (XIX):

[0550]

[0551] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X R 2A n and p are each defined as in this paper.

[0552] In yet another embodiment, this document provides a compound of formula (XX):

[0553]

[0554] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X R 2A n and p are each defined as in this paper.

[0555] In yet another embodiment, a compound of formula (XXI) is provided herein:

[0556]

[0557] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X R2A n and p are each defined as in this paper.

[0558] In yet another embodiment, this document provides a compound of formula (XXII):

[0559]

[0560] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7a R B R X R 2A p and p are as defined in this paper.

[0561] In yet another embodiment, a compound of formula (XXIII) is provided herein:

[0562]

[0563] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X R 2A n and p are each defined as in this paper.

[0564] In one implementation, in any of formulas (XIX) to (XXI) and (XXIII),

[0565] R 1 Halogenated or C 1-6 alkyl;

[0566] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0567] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0568] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0569] R B and R X For (i) or (ii):

[0570] (i)R B C 6-14 aryl or heteroaryl; and

[0571] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0572] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0573] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0574] p is an integer 1, 2, or 3;

[0575] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[0576] In another implementation, in any of equations (XIX) to (XXI) and (XXIII),

[0577] R 1 Halogenated or C 1-6 alkyl;

[0578] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R 2a R 2b and R 2cEach independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0579] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0580] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0581] R B and R X For (i) or (ii):

[0582] (i)R B C 6-14 aryl or heteroaryl; and

[0583] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0584] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0585] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0586] p is an integer, either 1 or 2;

[0587] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0588] In yet another implementation, in any of formulas (XIX) to (XXI) and (XXIII),

[0589] R 1 C 1-6 alkyl;

[0590] R 2A For –OH, –NR 2b R 2c or –N(R) 2b OR 2c , where R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0591] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0592] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0593] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0594] R B and R X For (i) or (ii):

[0595] (i)R B C is a single-ring or double-ring 6-14 Aryl, or monocyclic or bicyclic heteroaryl; and

[0596] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0597] (ii)R B and R X Together with the N atom it is attached to, it forms a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heterocyclic group;

[0598] n is an integer 0, 1, or 2; and

[0599] p is an integer, either 1 or 2;

[0600] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0601] In yet another implementation, in any of formulas (XIX) to (XXI) and (XXIII),

[0602] R 1 It is methyl;

[0603] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole);

[0604] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0605] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0606] R 7 It is chloro or methoxy;

[0607] R B and R X For (i) or (ii):

[0608] (i)R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0609] R X It can be hydrogen, methyl, ethyl, hydroxyethyl, propyl, phenyl, fluorophenyl, formylphenyl, or benzyl; or

[0610] (ii)R B and R X Together with the N atom it is attached to, it forms pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, amino-imidazolyl, or indoleyl.

[0611] n is an integer, either 0 or 1; and

[0612] p is an integer, either 1 or 2.

[0613] In yet another implementation, in any of formulas (XIX) to (XXI) and (XXIII),

[0614] R 1 It is methyl;

[0615] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole-5-yl);

[0616] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0617] R5 and R 6 Each is independently either hydrogen or deuterium;

[0618] R 7 It is chloro or methoxy;

[0619] R B and R X For (i) or (ii):

[0620] (i)R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0621] R X It can be hydrogen, methyl, ethyl, 2-hydroxyethyl, n-propyl, phenyl, 4-fluorophenyl, 4-formylphenyl, or benzyl;

[0622] or

[0623] (ii)R B and R X Together with the nitrogen atom it is attached to, they form pyrrole-1-yl, 2-amino-imidazol-1-yl, indole-1-yl, and pyrrole-1-yl groups.

[0624] 1-pyrrolidine-1-yl, piperidin-1-yl, or 4-morpholin-4-yl;

[0625] n is an integer, either 0 or 1; and

[0626] p is an integer, either 1 or 2.

[0627] In one implementation, in formula (XXII),

[0628] R 1 Halogenated or C 1-6 alkyl;

[0629] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0630] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0631] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0632] R B and R X For (i) or (ii):

[0633] (i)R B C 6-14 aryl or heteroaryl; and

[0634] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0635] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group; and

[0636] p is an integer 1, 2, or 3;

[0637] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[0638] In another implementation, in formula (XXII),

[0639] R 1 Halogenated or C 1-6 alkyl;

[0640] R 2A For –OR 2a –NR 2b R 2c or –N(R) 2b OR 2c , where R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0641] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0642] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0643] R B and R X For (i) or (ii):

[0644] (i)R B C 6-14 aryl or heteroaryl; and

[0645] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0646] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group; and

[0647] p is an integer, either 1 or 2;

[0648] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0649] In yet another implementation, in formula (XXII),

[0650] R 1 C 1-6 alkyl;

[0651] R 2A For –OH, –NR 2b R 2c or –N(R) 2b OR 2c , where R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl or heteroaryl;

[0652] R 3 and R4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0653] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0654] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0655] R B and R X For (i) or (ii):

[0656] (i)R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl; and

[0657] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0658] (ii)R B and R X Together with the N atom it is attached to, it forms a monocyclic or bicyclic heteroaryl group or a monocyclic or bicyclic heterocyclic group; and

[0659] p is an integer, either 1 or 2;

[0660] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0661] In yet another implementation, in formula (XXII),

[0662] R 1 It is methyl;

[0663] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole);

[0664] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0665] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0666] R 7aIt can be hydrogen, deuterium, chloro, or methoxy;

[0667] R B and R X For (i) or (ii):

[0668] (i)R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0669] R X It can be hydrogen, methyl, ethyl, hydroxyethyl, propyl, phenyl, fluorophenyl, formylphenyl, or benzyl; or

[0670] (ii)R B and R X Together with the nitrogen atom it is attached to, it forms a pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, amino-imidazolyl, or indoleyl group; and

[0671] p is an integer, either 1 or 2.

[0672] In yet another implementation, in formula (XXII),

[0673] R 1 It is methyl;

[0674] R 2A It can be –OH, –NH2, –NHCH3, –NHCH2CH2OH, –NHOH or –NH (tetrazole-5-yl);

[0675] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0676] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0677] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0678] R B and R X For (i) or (ii):

[0679] (i)R BIt is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0680] R X It is hydrogen, methyl, ethyl, 2-hydroxyethyl, n-propyl, phenyl, 4-fluorophenyl, 4-formylphenyl, or benzyl; or

[0681] (ii)R B and R X Together with the nitrogen atom it is attached to, it forms pyrrolidinyl, 2-aminoimidazolyl-1-yl, indolyl-1-yl, pyrrolidine-1-yl, piperidinyl-1-yl, or 4-morpholino-4-yl; and

[0682] p is an integer, either 1 or 2.

[0683] In yet another embodiment, a compound of formula (XXIV) is provided herein:

[0684]

[0685] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[0686] U 2 For –N= or –O–;

[0687] V 2 For –N= or –C(OH)=; and

[0688] R 1 R 3 R 4 R 5 R 6 R 7 R B n and p are each defined as in this paper.

[0689] In yet another embodiment, this document provides a compound of formula (XXV):

[0690]

[0691] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B U 2 V 2 n and p are each defined as in this paper.

[0692] In yet another embodiment, a compound of formula (XXVI) is provided herein:

[0693]

[0694] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B U 2 V 2 n and p are each defined as in this paper.

[0695] In yet another embodiment, this document provides a compound of formula (XXVII):

[0696]

[0697] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7a R B U 2 V 2 p and p are as defined in this paper.

[0698] In yet another embodiment, a compound of formula (XXVIII) is provided herein:

[0699]

[0700] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B U 2 V 2 n and p are each defined as in this paper.

[0701] In one implementation, in any of formulas (XXIV) to (XXVI) and (XXVIII),

[0702] R 1 Halogenated or C 1-6 alkyl;

[0703] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0704] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0705] R B C 6-14 aryl or heteroaryl;

[0706] U 2 For –N= or –O–;

[0707] V 2 For –N= or –C(OH)=;

[0708] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0709] p is an integer 1, 2, or 3;

[0710] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q.

[0711] In another implementation, in any of formulas (XXIV) to (XXVI) and (XXVIII),

[0712] R 1 Halogenated or C 1-6 alkyl;

[0713] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0714] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0715] R B C 6-14 aryl or heteroaryl;

[0716] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0717] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0718] p is an integer, either 1 or 2;

[0719] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0720] In yet another embodiment, in any of formulas (XXIV) to (XXVI) and (XXVIII),

[0721] R 1 C 1-6 alkyl;

[0722] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0723] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0724] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0725] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl;

[0726] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0727] n is an integer 0, 1, or 2; and

[0728] p is an integer, either 1 or 2;

[0729] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0730] In yet another embodiment, in any of formulas (XXIV) to (XXVI) and (XXVIII),

[0731] R 1 It is methyl;

[0732] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0733] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0734] R 7 It is chloro or methoxy;

[0735] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl or quinolinyl;

[0736] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2–C(OH)=;

[0737] n is an integer, either 0 or 1; and

[0738] p is an integer, either 1 or 2.

[0739] In yet another embodiment, in any of formulas (XXIV) to (XXVI) and (XXVIII),

[0740] R 1 It is methyl;

[0741] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0742] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0743] R 7 It is chloro or methoxy;

[0744] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl;

[0745] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0746] n is an integer, either 0 or 1; and

[0747] p is an integer, either 1 or 2.

[0748] In yet another embodiment, in any of formulas (XXIV) to (XXVI) and (XXVIII),

[0749] R 1 It is methyl;

[0750] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0751] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0752] R 7 It is chloro or methoxy;

[0753] R BIt is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0754] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0755] n is an integer, either 0 or 1; and

[0756] p is an integer, either 1 or 2.

[0757] In yet another embodiment, in any of formulas (XXIV) to (XXVI) and (XXVIII),

[0758] R 1 It is methyl;

[0759] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0760] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0761] R 7 It is chloro or methoxy;

[0762] R B It is phenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0763] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0764] n is an integer, either 0 or 1; and

[0765] p is an integer, either 1 or 2.

[0766] In one implementation, in formula (XXVII),

[0767] R 1 Halogenated or C 1-6 alkyl;

[0768] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0769] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0770] R B C 6-14 aryl or heteroaryl;

[0771] U 2 For –N= or –O–;

[0772] V 2 For –N= or –C(OH)=; and

[0773] p is an integer 1, 2, or 3;

[0774] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q.

[0775] In another implementation, in formula (XXVII),

[0776] R 1 Halogenated or C 1-6 alkyl;

[0777] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0778] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0779] R B C 6-14 aryl or heteroaryl;

[0780] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0781] p is an integer, either 1 or 2;

[0782] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0783] In yet another implementation, in formula (XXVII),

[0784] R 1 C 1-6 alkyl;

[0785] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0786] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0787] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0788] R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl;

[0789] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0790] p is an integer, either 1 or 2;

[0791] The alkyl, aryl, and heteroaryl groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0792] In yet another implementation, in formula (XXVII),

[0793] R 1 It is methyl;

[0794] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0795] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0796] R 7a It is chloro or methoxy;

[0797] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl or quinolinyl;

[0798] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0799] p is an integer, either 1 or 2.

[0800] In yet another implementation, in formula (XXVII),

[0801] R 1 It is methyl;

[0802] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0803] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0804] R 7a It is chloro or methoxy;

[0805] R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl;

[0806] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0807] p is an integer, either 1 or 2.

[0808] In yet another implementation, in formula (XXVII),

[0809] R 1 It is methyl;

[0810] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0811] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0812] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0813] R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0814] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0815] p is an integer, either 1 or 2.

[0816] In yet another implementation, in formula (XXVII),

[0817] R 1 It is methyl;

[0818] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0819] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0820] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0821] R BIt is phenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl;

[0822] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0823] p is an integer, either 1 or 2.

[0824] In yet another embodiment, this document provides a compound of formula (XXIX):

[0825]

[0826] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X U 2 V 2 n and p are each defined as in this paper.

[0827] In yet another embodiment, this document provides a compound of formula (XXX):

[0828]

[0829] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X U2 V 2 n and p are each defined as in this paper.

[0830] In yet another embodiment, a compound of formula (XXXI) is provided herein:

[0831]

[0832] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X U 2 V 2 n and p are each defined as in this paper.

[0833] In yet another embodiment, a compound of formula (XXXII) is provided herein:

[0834]

[0835] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7a R B R X U 2 V 2 p and p are as defined in this paper.

[0836] In yet another embodiment, a compound of formula (XXXIII) is provided herein:

[0837]

[0838] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 3 R 4 R 5 R 6 R 7 R B R X U 2 V 2 n and p are each defined as in this paper.

[0839] In one implementation, in any of formulas (XXIX) to (XXXI) and (XXXIII),

[0840] R 1 Halogenated or C 1-6 alkyl;

[0841] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0842] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0843] R B and R X For (i) or (ii):

[0844] (i)R B C 6-14 aryl or heteroaryl; and

[0845] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0846] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0847] U 2 For –N= or –O–;

[0848] V 2 For –N= or –C(OH)=;

[0849] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0850] p is an integer 1, 2, or 3;

[0851] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[0852] In another implementation, in any of formulas (XXIX) to (XXXI) and (XXXIII),

[0853] R 1 Halogenated or C 1-6 alkyl;

[0854] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0855] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0856] R B and R X For (i) or (ii):

[0857] (i)R B C 6-14 aryl or heteroaryl; and

[0858] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0859] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0860] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0861] n is an integer, which can be 0, 1, 2, 3, or 4; and

[0862] p is an integer, either 1 or 2;

[0863] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0864] In yet another implementation, in any of formulas (XXIX) to (XXXI) and (XXXIII),

[0865] R 1 C 1-6 alkyl;

[0866] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0867] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0868] R 7 For deuterium, halogen, or –O–C 1-6 alkyl;

[0869] R B and R X For (i) or (ii):

[0870] (i)R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl; and

[0871] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0872] (ii)R B and R X Together with the N atom it is attached to, it forms a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heterocyclic group;

[0873] U 2 and V 2 Each is –N=; or U 2 For –O– and V2 –C(OH)=;

[0874] n is an integer 0, 1, or 2; and

[0875] p is an integer, either 1 or 2;

[0876] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0877] In yet another implementation, in any of formulas (XXIX) to (XXXI) and (XXXIII),

[0878] R 1 It is methyl;

[0879] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0880] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0881] R 7 It is chloro or methoxy;

[0882] R B and R X For (i) or (ii):

[0883] (i)R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0884] R X It can be hydrogen, methyl, ethyl, hydroxyethyl, propyl, phenyl, fluorophenyl, formylphenyl, or benzyl; or

[0885] (ii)R B and R X Together with the N atom it is attached to, it forms pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, amino-imidazolyl, or indoleyl.

[0886] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0887] n is an integer, either 0 or 1; and

[0888] p is an integer, either 1 or 2.

[0889] In yet another implementation, in any of formulas (XXIX) to (XXXI) and (XXXIII),

[0890] R 1 It is methyl;

[0891] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0892] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0893] R 7 It is chloro or methoxy;

[0894] R B and R X For (i) or (ii):

[0895] (i)R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0896] R X It can be hydrogen, methyl, ethyl, 2-hydroxyethyl, n-propyl, phenyl, 4-fluorophenyl, 4-formylphenyl, or benzyl;

[0897] or

[0898] (ii)R B and R X Together with the N atom it is attached to, it forms pyrrolidin-1-yl, 2-amino-imidazol-1-yl, indol-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4-morpholin-4-yl;

[0899] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 –C(OH)=;

[0900] n is an integer, either 0 or 1; and

[0901] p is an integer, either 1 or 2.

[0902] In one implementation, in formula (XXX),

[0903] R 1 Halogenated or C 1-6 alkyl;

[0904] R 3 R 4 R 5 and R 6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0905] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0906] R B and R X For (i) or (ii):

[0907] (i)R B C 6-14 aryl or heteroaryl; and

[0908] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0909] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0910] U 2 For –N= or –O–;

[0911] V 2 For –N= or –C(OH)=; and

[0912] p is an integer 1, 2, or 3;

[0913] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[0914] In another implementation, in formula (XXX),

[0915] R 1 Halogenated or C 1-6 alkyl;

[0916] R 3 R 4 R 5 and R6 Each can be independently hydrogen, deuterium, halo group or C 1-6 alkyl;

[0917] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0918] R B and R X For (i) or (ii):

[0919] (i)R B C 6-14 aryl or heteroaryl; and

[0920] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0921] (ii)R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group;

[0922] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0923] p is an integer, either 1 or 2;

[0924] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted by one or more substituents Q. a Replacement C 1-6 Alkyl groups; and (iii)–C(O)R a –OR a and –NR b R c , where R a R b and R c Each as defined in this article.

[0925] In another implementation, in formula (XXX),

[0926] R 1 C 1-6 alkyl;

[0927] R 3 and R 4 Each can be independently hydrogen, deuterium, halo group or C1-6 alkyl;

[0928] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0929] R 7a It can be hydrogen, deuterium, halogen, or –O–C. 1-6 alkyl;

[0930] R B and R X For (i) or (ii):

[0931] (i)R B C is a single-ring or double-ring 6-14 Aryl or monocyclic or bicyclic heteroaryl; and

[0932] R X For hydrogen, C 1-6 Alkyl, C 6-14 Aryl or C 7-15 Aryl alkyl; or

[0933] (ii)R B and R X Together with the N atom it is attached to, it forms a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heterocyclic group;

[0934] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0935] p is an integer, either 1 or 2;

[0936] The alkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q, each substituent Q being independently selected from bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, formyl, hydroxy, methoxy, and amino groups.

[0937] In another implementation, in formula (XXX),

[0938] R 1 It is methyl;

[0939] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0940] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0941] R 7aIt can be hydrogen, deuterium, chloro, or methoxy;

[0942] R B and R X For (i) or (ii):

[0943] (i)R B It is phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl; and

[0944] R X It can be hydrogen, methyl, ethyl, hydroxyethyl, propyl, phenyl, fluorophenyl, formylphenyl, or benzyl; or

[0945] (ii)R B and R X Together with the N atom it is attached to, it forms pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, amino-imidazolyl, or indoleyl.

[0946] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0947] p is an integer, either 1 or 2.

[0948] In another implementation, in formula (XXX),

[0949] R 1 It is methyl;

[0950] R 3 and R 4 Each can be independently hydrogen, deuterium, fluorine, or methyl;

[0951] R 5 and R 6 Each is independently either hydrogen or deuterium;

[0952] R 7a It can be hydrogen, deuterium, chloro, or methoxy;

[0953] R B and R X For (i) or (ii):

[0954] (i)R BIt is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl; and

[0955] R X It can be hydrogen, methyl, ethyl, 2-hydroxyethyl, n-propyl, phenyl, 4-fluorophenyl, 4-formylphenyl, or benzyl;

[0956] or

[0957] (ii)R B and R X Together with the N atom it is attached to, it forms pyrrolidin-1-yl, 2-amino-imidazol-1-yl, indol-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4-morpholin-4-yl;

[0958] U 2 and V 2 Each is –N=; or U 2 For –O– and V 2 For –C(OH)=; and

[0959] p is an integer, either 1 or 2.

[0960] The formulas described herein include the group R in formulas (I) to (XXXIII). 1 R 2 R 3 R 4 R 5 R 6 R 7 R 2A R 7a R A R B R X L, X, U 1 V 1 W 1 X 1 Y 1 Z 1 U 2 V 2 , n, and p are further defined in the embodiments described herein. All combinations of the groups provided herein are within the scope of this invention.

[0961] In some implementations, R 1It is hydrogen. In some embodiments, R 1 For deuterium. In some implementations, R 1 It is cyano. In some embodiments, R 1 It is a halogen group. In some embodiments, R 1 It is fluorinated or chlorinated. In some embodiments, R 1 It is nitro. In some embodiments, R 1 C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 1 It is methyl, optionally substituted with one or more substituents Q. In some embodiments, R 1 It is methyl. In some embodiments, R 1 C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R 1 C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R 1 C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R 1 C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R 1 C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R 1 It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 1 It is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0962] In some implementations, R 2 -C(O)OR 2a , where R 2a As defined herein. In some implementations, R 2 It is –C(O)OH. In some embodiments, R 2 –C(O)O–C 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more substituents Q. In some embodiments, R 2 For –C(O)NR 2b R 2c , where R 2b and R 2c Each as defined herein. In some implementations, R 2 For –C(O)NR 2b R 2c , where R2b and R 2c Each is independently (i) hydrogen; or (ii) each optionally substituted with one or more substituents Q. 1-6 Alkyl or heteroaryl. In some embodiments, R 2 For –C(O)NR 2b R 2c , where R 2b and R 2c Each is independently (i) hydrogen; or (ii) a methyl, ethyl, or tetrazolium group, each optionally substituted with one or more substituents Q. In some embodiments, R 2 –C(O)NHR 2c , where R 2c As defined herein. In some implementations, R 2 for

[0963] –C(O)NHR 2c , where R 2c (i) hydrogen; or (ii) C, each optionally substituted with one or more substituents Q. 1-6 Alkyl or heteroaryl. In some embodiments, R 2 –C(O)NHR 2c , where R 2c It is (i) hydrogen; or (ii) a methyl, ethyl, or tetrazolium group, each optionally substituted with one or more substituents Q. In some embodiments, R 2 For –C(O)NH2, –C(O)NHCH3,

[0964] –C(O)NHCH2CH2OH or –C(O)NH (tetrazolyl). In some embodiments, R 2 –C(O)N(R) 2b OR 2c , where R 2b and R 2c Each as defined herein. In some implementations, R 2 –C(O)N(R) 2b OR 2c , where R 2b and R 2c Each of the C atoms is independently hydrogen or optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 2 for

[0965] –C(O)NHOR 2c , where R 2c As defined herein. In some implementations, R 2 –C(O)NHOR 2c, where R 2c C is hydrogen or optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 2 –C(O)NHO–C 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more substituents Q. In some embodiments, R 2 It is –C(O)NHOH. In some embodiments, R 2 It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 2 It is a monocyclic heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 2 It is a 6-membered heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 2 It is a 5-membered heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 2 Each is optionally substituted with one or more substituents Q, and is either a tetrazolium or a 1,2,4-oxadiazolium. In some embodiments, R 2 It is tetrazol-5-yl or 5-hydroxy-1,2,4-oxadiazol-5-yl.

[0966] In some implementations, R 3 It is hydrogen. In some embodiments, R 3 For deuterium. In some implementations, R 3 It is cyano. In some embodiments, R 3 It is a halogen group. In some embodiments, R 3 It is fluorine-based. In some embodiments, R 3 It is a chlorine-based group. In some embodiments, R... 3 It is nitro. In some embodiments, R 3 C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 3 It is methyl. In some embodiments, R 3 C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R 3 C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R 3 C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R 3C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R 3 It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 3 It is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0967] In some implementations, R 3 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 3 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 3 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –OR 1a , where R 1a As defined herein. In some implementations, R 3 It is methoxylated. In some embodiments, R 3 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 3 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 3 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 3 For –OS(O)2R 1a , where R 1a As defined herein. In some implementations, R 3 For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1a C(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R 1c and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a S(O)R 1d , where R 1a and R 1dEach as defined herein. In some implementations, R 3 For –NR 1a S(O)2R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1a S(O)2NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –SR 1a , where R 1a As defined herein. In some implementations, R 3 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 3 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 3 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0968] In some implementations, R 4 It is hydrogen. In some embodiments, R 4 For deuterium. In some implementations, R 4 It is cyano. In some embodiments, R 4 It is a halogen group. In some embodiments, R 4 It is fluorine-based. In some embodiments, R 4 It is a chlorine-based group. In some embodiments, R... 4 It is nitro. In some embodiments, R4 C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 4 It is methyl. In some embodiments, R 4 C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R 4 C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R 4 C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R 4 C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R 4 C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R 4 It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 4 It is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0969] In some implementations, R 4 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 4 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 4 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 4 For –OR 1a , where R 1a As defined herein. In some implementations, R 4 It is methoxylated. In some embodiments, R 4 For –OC(O)R 1a , where R 1aAs defined herein. In some implementations, R 4 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 4 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 4 For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 4 For –OS(O)2R 1a , where R 1a As defined herein. In some implementations, R 4 For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 For –NR 1a C(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 4 For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 4 For –NR 1a C(O)NR1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 4 For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R 1c and R 1d Each as defined herein. In some implementations, R 4 For –NR 1a S(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 4 For –NR 1a S(O)2R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 4 For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 4 For –NR 1a S(O)2NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 4 For –SR 1a , where R 1a As defined herein. In some implementations, R 4 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 4 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 4 For –S(O)NR 1b R 1c , where R 1b and R 1cEach as defined herein. In some implementations, R 4 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0970] In some implementations, R 5 It is hydrogen. In some embodiments, R 5 For deuterium. In some implementations, R 5 It is cyano. In some embodiments, R 5 It is a halogen group. In some embodiments, R 5 It is fluorine-based. In some embodiments, R 5 It is a chlorine-based group. In some embodiments, R... 5 It is nitro. In some embodiments, R 5 C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 5 It is methyl. In some embodiments, R 5 C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R 5 C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R 5 C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R 5 C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R 5 C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R 5 It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 5 It is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0971] In some implementations, R 5 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 5 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 5 For –C(O)NR 1b R1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 5 For –OR 1a , where R 1a As defined herein. In some implementations, R 5 It is methoxylated. In some embodiments, R 5 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 5 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 5 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 5 For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 5 For –OS(O)2R 1a , where R 1a As defined herein. In some implementations, R 5 For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R5 For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 For –NR 1a C(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 5 For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 5 For –NR 1a C(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 5 For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R 1c and R 1d Each as defined herein. In some implementations, R 5 For –NR 1a S(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 5 For –NR 1a S(O)2R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 5 For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 5 For –NR 1a S(O)2NR 1b R 1c , where R 1a R1b and R 1c Each as defined herein. In some implementations, R 5 For –SR 1a , where R 1a As defined herein. In some implementations, R 5 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 5 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 5 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0972] In some implementations, R 6 It is hydrogen. In some embodiments, R 6 For deuterium. In some implementations, R 6 It is cyano. In some embodiments, R 6 It is a halogen group. In some embodiments, R 6 It is fluorine-based. In some embodiments, R 6 It is a chlorine-based group. In some embodiments, R... 6 It is nitro. In some embodiments, R 6 C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 6 It is methyl. In some embodiments, R 6 C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R 6 C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R 6 C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R 6 C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R 6C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R 6 It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 6 It is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0973] In some implementations, R 6 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 6 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 6 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 6 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 6 For –OR 1a , where R 1a As defined herein. In some implementations, R 6 It is methoxylated. In some embodiments, R 6 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 6 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 6 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 6 For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 6For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 6 For –OS(O)2R 1a , where R 1a As defined herein. In some implementations, R 6 For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 6 For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 6 For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 6 For –NR 1a C(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 6 For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 6 For –NR 1a C(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 6 For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R 1c and R 1d Each as defined herein. In some implementations, R 6 For –NR 1a S(O)R 1d , where R 1a and R 1dEach as defined herein. In some implementations, R 6 For –NR 1a S(O)2R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 6 For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 6 For –NR 1a S(O)2NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 6 For –SR 1a , where R 1a As defined herein. In some implementations, R 6 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 6 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 6 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 6 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0974] In some implementations, R 7 For deuterium. In some implementations, R 7 It is cyano. In some embodiments, R 7 It is a halogen group. In some embodiments, R 7 It is fluorine-based. In some embodiments, R 7 It is a chlorine-based group. In some embodiments, R... 7 It is nitro. In some embodiments, R 7C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 7 It is methyl. In some embodiments, R 7 C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R 7 C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R 7 C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R 7 C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R 7 C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R 7 It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 7 It is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0975] In some implementations, R 7 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 7 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 7 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7 For –OR 1a , where R 1a As defined herein. In some implementations, R 7 It is methoxylated. In some embodiments, R 7 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R7 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 7 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7 For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7 For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 7 For –OS(O)2R 1a , where R 1a As defined herein. In some implementations, R 7 For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7 For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7 For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7 For –NR 1a C(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 7 For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 7 For –NR 1a C(O)NR 1b R 1c, where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7 For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R 1c and R 1d Each as defined herein. In some implementations, R 7 For –NR 1a S(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 7 For –NR 1a S(O)2R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 7 For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7 For –NR 1a S(O)2NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7 For –SR 1a , where R 1a As defined herein. In some implementations, R 7 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 7 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 7 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0976] In some implementations, R 2A For –OR 2a , where R 2a As defined herein. In some implementations, R 2A For –OH. In some embodiments, R 2A For –O–C 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more substituents Q. In some embodiments, R 2A For –NR 2b R 2c , where R 2b and R 2c Each as defined herein. In some implementations, R 2A For –NR 2b R 2c , where R 2b and R 2c Each is independently (i) hydrogen; or (ii) each optionally substituted with one or more substituents Q. 1-6 Alkyl or heteroaryl. In some embodiments, R 2A For –NR 2b R 2c , where R 2b and R 2c Each is independently (i) hydrogen; or (ii) a methyl, ethyl, or tetrazolium group, each optionally substituted with one or more substituents Q. In some embodiments, R 2A For –NHR 2c , where R 2c As defined herein. In some implementations, R 2A For –NHR 2c , where R 2c (i) hydrogen; or (ii) C, each optionally substituted with one or more substituents Q. 1-6 Alkyl or heteroaryl. In some embodiments, R 2A For –NHR 2c , where R 2c It is (i) hydrogen; or (ii) a methyl, ethyl, or tetrazolium group, each optionally substituted with one or more substituents Q. In some embodiments, R 2A It is –NH2, –NHCH3, –NHCH2CH2OH, or –NH (tetrazole). In some embodiments, R 2A For –N(R) 2b OR2c , where R 2b and R 2c Each as defined herein. In some implementations, R 2A For –N(R) 2b OR 2c , where R 2b and R 2c Each of the C atoms is independently hydrogen or optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 2A For –NHOR 2c , where R 2c As defined herein. In some implementations, R 2A For –NHO–C 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more substituents Q. In some embodiments, R 2A It is –NHOH.

[0977] In some implementations, R 7a It is hydrogen. In some embodiments, R 7a For deuterium. In some implementations, R 7a It is cyano. In some embodiments, R 7a It is a halogen group. In some embodiments, R 7a It is fluorine-based. In some embodiments, R 7a It is a chlorine-based group. In some embodiments, R... 7a It is nitro. In some embodiments, R 7a C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, R 7a It is methyl. In some embodiments, R 7a C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R 7a C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R 7a C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R 7a C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R 7a C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R 7a It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R 7aIt is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0978] In some implementations, R 7a For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 7a -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 7a For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7a For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7a For –OR 1a , where R 1a As defined herein. In some implementations, R 7a It is methoxylated. In some embodiments, R 7a For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 7a –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 7a For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7a For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7a For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 7a For –OS(O)2R 1a , where R1a As defined herein. In some implementations, R 7a For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7a For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7a For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7a For –NR 1a C(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 7a For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 7a For –NR 1a C(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7a For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R 1c and R 1d Each as defined herein. In some implementations, R 7a For –NR 1a S(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 7a For –NR 1a S(O)2R 1d , where R 1a and R 1dEach as defined herein. In some implementations, R 7a For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7a For –NR 1a S(O)2NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 7a For –SR 1a , where R 1a As defined herein. In some implementations, R 7a For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 7a is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 7a For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 7a For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0979] In some implementations, R A C is optionally substituted with one or more substituents Q. 6-14 Aromatic. In some embodiments, R A It is a phenylene group optionally substituted with one or more substituents Q. In some embodiments, R A It is a phenyl-1,2-diyl group optionally substituted with one or more substituents Q. In some embodiments, R A It is a phenyl-1,3-diyl group optionally substituted with one or more substituents Q. In some embodiments, R A It is a phenyl-1,4-diyl group optionally substituted with one or more substituents Q. In some embodiments, R AThese are either phenyl-1,3-diyl or phenyl-1,4-diyl, each optionally substituted with one or more substituents Q. In some embodiments, R A For each of the optional halogenated or –O–C 1-6 Alkyl-substituted benzene-1,3-diyl or benzene-1,4-diyl. In some embodiments, R A Each is optionally substituted with a fluorinated, chloro, or methoxy group, and is a phenyl-1,3-diyl or phenyl-1,4-diyl group. In some embodiments, R A It is phenyl-1,3-diyl, phenyl-1,4-diyl, 2-chloro-phenyl-1,4-diyl, or 2-methoxy-phenyl-1,4-diyl. In some embodiments, R A It is a naphthylene group optionally substituted with one or more substituents Q. In some embodiments, R A It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R A It is a monocyclic heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R A It is a 5-membered heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R A It is a 6-membered heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R A It is a pyridyl group optionally substituted with one or more substituents Q. In some embodiments, R A It is a pyridine-2,5-diyl group optionally substituted with one or more substituents Q. In some embodiments, R A It is pyridyl or methyl-pyridyl. In some embodiments, R A It is pyridine-2,5-diyl or 3-methyl-pyridine-2,5-diyl. In some embodiments, R A It is a bicyclic heteroaryl group optionally substituted with one or more substituents Q.

[0980] In some implementations, R B C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R B A monocyclic C24 optionally substituted with one or more substituents Q 6-14 Aryl. In some embodiments, R B It is a phenyl group optionally substituted with one or more substituents Q. In some embodiments, R B The phenyl group is optionally substituted with one, two, or three substituents Q, each of which is independently selected from (i) bromo, chloro, fluoro, and cyano groups; (ii) optionally substituted with one or more substituents Q. a Replacement C1-6 Alkyl; and (iii)–OR a and –C(O)R a , where R a Each as defined herein. In some implementations, R B The phenyl group is optionally substituted with one, two, or three substituents Q, each of which is independently selected from bromo, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, methoxy, and formyl. In some embodiments, R B The phenyl group is optionally substituted with one, two, or three substituents Q, each of which is independently selected from bromo, fluoro, cyano, methyl, trifluoromethyl, ethyl, propyl, and methoxy. In some embodiments, R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, or trifluorophenyl. In some embodiments, R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, bromo-fluorophenyl, difluorophenyl, or trifluorophenyl. In some embodiments, R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, or 2,4,5-trifluorophenyl. In some embodiments, R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl or 2,4,5-trifluorophenyl.

[0981] In some implementations, R B A bicyclic C that is optionally substituted with one or more substituents Q 6-14 Aryl. In some embodiments, R B The naphthyl group is optionally substituted with one or more substituents Q. In some embodiments, R B It is a naphthyl-1-yl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a naphth-2-yl group optionally substituted with one or more substituents Q.

[0982] In some implementations, R BIt is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a monocyclic heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a 5-membered heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a 6-membered heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a pyridinyl group optionally substituted with one or more substituents Q. In some embodiments, R B It is fluoropyridinyl or fluoromethylpyridinyl. In some embodiments, R B It is 2-fluoropyridin-5-yl or 2-fluoro-3-methylpyridin-5-yl.

[0983] In some implementations, R B It is a bicyclic heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a 5,6-fused heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a 6,6-fused heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a quinolinyl group optionally substituted with one or more substituents Q. In some embodiments, R B It is a quinoline-5-yl group optionally substituted with one or more substituents Q.

[0984] In some implementations, R B It can be phenyl, bromophenyl, fluorophenyl, cyanophenyl, methylphenyl, trifluoromethylphenyl, ethylphenyl, propylphenyl, methoxyphenyl, formylphenyl, bromo-fluorophenyl, difluorophenyl, trifluorophenyl, naphthyl, fluoropyridyl, fluoromethylpyridyl, or quinolinyl. In some embodiments, R B It is phenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-formylphenyl, 2-bromo-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl, naphth-2-yl, 2-fluoropyridin-5-yl, 2-fluoro-3-methylpyridin-5-yl, or quinoline-5-yl.

[0985] In some implementations, R X It is hydrogen. In some embodiments, R X C is optionally substituted with one or more substituents Q. 1-6 Alkyl group. In some embodiments, RX Each of the following is optionally substituted with one or more substituents Q: methyl, ethyl, or propyl. X It is methyl, ethyl, 2-hydroxyethyl, or n-propyl. In some embodiments, R X C is optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, R X C is optionally substituted with one or more substituents Q. 2-6 Alkyne group. In some embodiments, R X C is optionally substituted with one or more substituents Q. 3-10 Cycloalkyl. In some embodiments, R X C is optionally substituted with one or more substituents Q. 6-14 Aryl. In some embodiments, R X It is a phenyl group optionally substituted with one or more substituents Q. In some embodiments, R X It is phenyl, fluorophenyl, or formylphenyl. In some embodiments, R X It is phenyl, 4-fluorophenyl, or 4-formylphenyl. In some embodiments, R X C is optionally substituted with one or more substituents Q. 7-15 Aryl alkyl group. In some embodiments, R X It is a benzyl group optionally substituted with one or more substituents Q. In some embodiments, R X It is a heteroaryl group optionally substituted with one or more substituents Q. In some embodiments, R X It is a heterocyclic group that is optionally substituted by one or more substituents Q.

[0986] In some implementations, when X is –N(R) X When ) – R B and R X Together with the N atom it is attached to, it forms a heteroaryl or heterocyclic group, each optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, a heteroaryl group is formed, which may optionally be substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a monocyclic heteroaryl group, which is optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R XTogether with the N atom it is attached to, it forms a 5-membered heteroaryl group, which is optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a pyrrole group or an imidazole group, each optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a pyrrole-1-yl or 2-amino-imidazol-1-yl group. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a 6-membered heteroaryl group, which is optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a bicyclic heteroaryl group, which is optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms an indole group, which is optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a 5- or 6-membered heterocyclic group, each optionally substituted by one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a pyrrolidinyl, piperidinyl, or morpholinyl group, each optionally substituted with one or more substituents Q. In some embodiments, when X is –N(R X When ) – R B and R XTogether with the N atom it is attached to, it forms a pyrrolidine-1-yl, piperidin-1-yl, or 4-morpholino-4-yl group. In some embodiments, when X is –N(R X When ) – R B and R X Together with the N atom it is attached to, it forms a bicyclic heterocyclic group, which may optionally be substituted by one or more substituents Q.

[0987] In some embodiments, L is C optionally substituted with one or more substituents Q. 1-6 Alkylene. In some embodiments, L is a methylene, ethylene, or propylene group, each optionally substituted with one or more substituents Q. In some embodiments, L is –(CH2). p – where p is an integer 1, 2, 3, or 4. In some implementations, L is –(CH2). p – where p is an integer 1, 2, or 3. In some implementations, L is –(CH2). p – where p is an integer 1 or 2. In some embodiments, L is –CH2CH2–. In some embodiments, L is –CH2–. In some embodiments, L is C optionally substituted with one or more substituents Q. 2-6 Alkenyl. In some embodiments, L is an alkenylene optionally substituted with one or more substituents Q. In some embodiments, L is an ethylene-1,2-diyl optionally substituted with one or more substituents Q. In some embodiments, L is (E)-ethylene-1,2-diyl. In some embodiments, L is (Z)-ethylene-1,2-diyl. In some embodiments, L is a C-alkenyl optionally substituted with one or more substituents Q. 3-10 Cycloalkylene. In some embodiments, L is a heterocyclic group optionally substituted with one or more substituents Q.

[0988] In some implementations, X is –O–. In some implementations, X is –NR. X –, where R X As defined herein. In some embodiments, X is –NH–. In some embodiments, X is –S–. In some embodiments, X is –S(O)–. In some embodiments, X is –S(O)2–.

[0989] In some implementations, U 1 For C. In some implementations, U 1 For N. In some implementations, U 1 For –CR 7a =, where R 7a As defined herein. In some implementations, U 1For –N=. In some implementations, U 1 For –NR 7b –, where R 7b As defined herein. In some implementations, U 1 For –O–. In some implementations, U 1 For –S–.

[0990] In some implementations, V 1 For C. In some implementations, V 1 For N. In some implementations, V 1 For –CR 7a =, where R 7a As defined herein. In some implementations, V 1 For –N=. In some implementations, V 1 For –NR 7b –, where R 7b As defined herein. In some implementations, V 1 For –O–. In some implementations, V 1 For –S–.

[0991] In some implementations, W 1 For C. In some implementations, W 1 For N. In some implementations, W 1 For –CR 7a =, where R 7a As defined herein. In some implementations, W 1 For –N=. In some implementations, W 1 For –NR 7b –, where R 7b As defined herein. In some implementations, W 1 For –O–. In some implementations, W 1 For –S–.

[0992] In some implementations, X 1 For C. In some implementations, X 1 Let N be the number of elements. In some implementations, X is the number of elements. 1 For –CR 7a =, where R 7a As defined herein. In some implementations, X 1 For –N=. In some implementations, X 1 For –NR 7b –, where R 7b As defined herein. In some implementations, X 1 For –O–. In some implementations, X1 For –S–.

[0993] In some implementations, Y 1 For C. In some implementations, Y 1 For N. In some implementations, Y 1 As a key. In some implementations, Y 1 For –CR 7a =, where R 7a As defined herein. In some implementations, Y 1 For –N=. In some implementations, Y 1 For –NR 7b –, where R 7b As defined herein. In some implementations, Y 1 For –O–. In some implementations, Y 1 For –S–.

[0994] In some implementations, Z 1 C. In some implementations, Z 1 Let N be the number of elements in the array.

[0995] In some implementations, U 2 For –N=. In some implementations, U 2 For –O–.

[0996] In some implementations, V 2 For –N=. In some implementations, V 2 For –O–. In some implementations, V 2 It is –C(OH)=.

[0997] In some implementations, U 2 and V 2 Each is –N=. In some implementations, U 2 For –O– and V 2 It is –C(OH)=.

[0998] In some implementations, n is an integer 0. In some implementations, n is an integer 1. In some implementations, n is an integer 2. In some implementations, n is an integer 3. In some implementations, n is an integer 4.

[0999] In some implementations, p is an integer 1. In some implementations, p is an integer 2. In some implementations, p is an integer 3. In some implementations, p is an integer 4.

[1000] In one embodiment, this document provides a compound as follows:

[1001] 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid A1;

[1002] 2-[(1Z)-5-fluoro-1-{[4-(4-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A2;

[1003] 2-[(1Z)-1-({2-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A3;

[1004] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(4-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A4;

[1005] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid A5;

[1006] 2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A6;

[1007] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A7;

[1008] 2-[(1Z)-1-{[4-(3-cyanophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A8;

[1009] (Z)-2-(5-fluoro-2-methyl-1-(4-(3-(trifluoromethyl)phenoxy)benzylidene)-1H-inden-3-yl)acetic acid A9;

[1010] 2-[(1Z)-1-{[4-(4-ethylphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A10;

[1011] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A11;

[1012] 2-[(1Z)-1-{[2-chloro-4-(4-methoxyphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A12;

[1013] 2-[(1Z)-5-fluoro-1-({2-methoxy-4-[4-(propane-2-yl)phenoxy]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A13;

[1014] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A14;

[1015] 2-[(1Z)-1-({2-chloro-4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A15;

[1016] 2-[(1Z)-1-{[4-(2,4-difluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A16;

[1017] 2-[(1Z)-1-{[4-(2-bromo-4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A17;

[1018] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(2,4,5-trifluorophenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A18;

[1019] 3-[(1Z)-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]propionic acid A19;

[1020] 2-[(1Z)-5-fluoro-1-({4-[(6-fluoropyridin-3-yl)oxy]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A20;

[1021] 2-[(1Z)-5-fluoro-1-({4-[(6-fluoro-5-methylpyridin-3-yl)oxy]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A21;

[1022] (Z)-2-(5-fluoro-2-methyl-1-(4-(quinolin-5-yloxy)benzylidene)-1H-inden-3-yl)acetic acid A22;

[1023] 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]-N-hydroxyacetamide A23;

[1024] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A24;

[1025] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetamide A25;

[1026] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-methylacetamide A26;

[1027] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-(2-hydroxyethyl)acetamide A27;

[1028] (Z)-2-(5-fluoro-2-methyl-1-(4-phenoxybenzyl)-1H-inden-3-yl)-N-(1H-tetrazol-5-yl)acetamide A28;

[1029] (2E)-3-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]prop-2-enoic acid A61;

[1030] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorobenzenesulfonyl)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A62;

[1031] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorobenzenesulfinyl)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A63;

[1032] 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)thio]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A64;

[1033] 2-[(1Z)-5-fluoro-1-{[6-(4-fluorophenoxy)pyridin-3-yl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A65;

[1034] 2-[(1Z)-5-fluoro-1-{[6-(4-fluorophenoxy)-5-methylpyridin-3-yl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A66;

[1035] (2E)-4-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]but-2-enoic acid A67;

[1036] 2-[(1Z)-4,5-difluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A68;

[1037] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2,4-dimethyl-1H-inden-3-yl]acetic acid A69;

[1038] (2E)-3-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyprop-2-enamide A76;

[1039] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorobenzenesulfonyl)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A77;

[1040] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorobenzenesulfinyl)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A78;

[1041] 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)thio]phenyl}methylene)-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A79;

[1042] 2-[(1Z)-5-fluoro-1-{[6-(4-fluorophenoxy)pyridin-3-yl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A80;

[1043] 2-[(1Z)-5-fluoro-1-{[6-(4-fluorophenoxy)-5-methylpyridin-3-yl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A81;

[1044] (2E)-4-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxybut-2-enamide A82;

[1045] 2-[(1Z)-4,5-difluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A83; or

[1046] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2,4-dimethyl-1H-inden-3-yl]-N-hydroxyacetamide A84;

[1047] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1048] In another embodiment, this document provides a compound as follows:

[1049] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[methyl(phenyl)amino]phenyl}methylene)-1H-inden-3-yl]acetic acid A29;

[1050] 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A30;

[1051] 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(methyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A31;

[1052] 2-[(1Z)-1-({4-[ethyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A32;

[1053] 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(propyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A33;

[1054] 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(2-hydroxyethyl)amino]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A34;

[1055] 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(4-formylphenyl)amino]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A35;

[1056] 2-[(1Z)-5-fluoro-1-({4-[(4-formylphenyl)(phenyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A36;

[1057] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[methyl(phenyl)amino]phenyl}methylene)-1H-inden-3-yl]-N-hydroxyacetamide A37;

[1058] 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A38;

[1059] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(morpholin-4-yl)phenyl]methylene}-1H-inden-3-yl]acetic acid A55;

[1060] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(piperidin-1-yl)phenyl]methylene}-1H-inden-3-yl]acetic acid A56;

[1061] 2-[(1Z)-5-fluoro-1-{[4-(1H-indol-1-yl)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A57;

[1062] 2-[(1Z)-1-{[4-(2-amino-1H-imidazol-1-yl)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A58;

[1063] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(pyrrolidone-1-yl)phenyl]methylene}-1H-inden-3-yl]acetic acid A59;

[1064] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(1H-pyrrolo-1-yl)phenyl]methylene}-1H-inden-3-yl]acetic acid A60;

[1065] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(morpholin-4-yl)phenyl]methylene}-1H-inden-3-yl]-N-hydroxyacetamide A70;

[1066] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(piperidin-1-yl)phenyl]methylene}-1H-inden-3-yl]-N-hydroxyacetamide A71;

[1067] 2-[(1Z)-5-fluoro-1-{[4-(1H-indol-1-yl)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A72;

[1068] 2-[(1Z)-1-{[4-(2-amino-1H-imidazol-1-yl)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A73;

[1069] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(pyrrolidone-1-yl)phenyl]methylene}-1H-inden-3-yl]-N-hydroxyacetamide A74;

[1070] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(1H-pyrrolo-1-yl)phenyl]methylene}-1H-inden-3-yl]-N-hydroxyacetamide A75; or

[1071] 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(2-hydroxyethyl)amino]phenyl}-methylene)-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A85;

[1072] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1073] In yet another embodiment, this document provides a compound as follows:

[1074] 5-{[(1Z)-2-methyl-1-[(3-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazole A39;

[1075] 5-{[(1Z)-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazolium A40;

[1076] 5-{2-[(1Z)-2-methyl-1-{[4-(4-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A41;

[1077] 5-{2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A42;

[1078] 5-{2-[(1Z)-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A43;

[1079] 5-{2-[(1Z)-1-{[4-(4-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A44;

[1080] 5-{2-[(1Z)-2-methyl-1-({4-[4-(trifluoromethyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A45;

[1081] 5-{2-[(1Z)-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A46;

[1082] 3-(4-{[(1Z)-2-methyl-3-[2-(1H-1,2,3,4-tetrazo-5-yl)ethyl]-1H-indene-1-yl]methyl}phenoxy)benzylnitrile A47;

[1083] 5-{2-[(1Z)-1-{[4-(3-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A48;

[1084] 5-{2-[(1Z)-1-{[4-(3-bromophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A49;

[1085] 5-{2-[(1Z)-2-methyl-1-({4-[3-(trifluoromethyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A50;

[1086] 5-{2-[(1Z)-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A51; or

[1087] (Z)-3-((2-methyl-1-(4-phenoxybenzylidene)-1H-inden-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one A52;

[1088] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1089] In another embodiment, this document provides a compound as follows: 5-{[(1E)-1-[(4-phenoxyphenyl)methylene]-1H-indene-3-yl]methyl}-1H-1,2,3,4-tetrazolium A53; or 5-{[(1E)-1-[(3-phenoxyphenyl)methylene]-1H-indene-3-yl]methyl}-1H-1,2,3,4-tetrazolium A54; or a tautomer thereof, a mixture of two or more tautomers thereof, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[1090] In yet another embodiment, this document provides a compound as follows:

[1091] 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]-N-hydroxy-N-methylacetamide C1;

[1092] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxy-N-methylacetamide C2; ​​or

[1093] (Z)-2-(5-fluoro-2-methyl-1-(3-phenoxybenzyl)-1H-inden-3-yl)-N-hydroxy-N-methylacetamide C3;

[1094] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1095] In yet another embodiment, this document provides a compound as follows:

[1096] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]-N-hydroxyacetamide D1;

[1097] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(tert-butyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D2;

[1098] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3-(tert-butyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D3;

[1099] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3-fluoro-4-methylphenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D4;

[1100] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3,4-difluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D5;

[1101] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3-nitrophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D6;

[1102] 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(trifluoromethyl)phenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D7;

[1103] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-(2-methylpropyl)-1H-inden-3-yl]acetic acid D8;

[1104] 2-[(1Z)-5-fluoro-2-benzyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D9;

[1105] 2-[(1Z)-5-methoxy-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D10;

[1106] 2-[(1Z)-5-methoxy-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid D11;

[1107] 2-[(1Z)-1-{[2-trifluoromethyl-4-(4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid D12;

[1108] 2-[(1Z)-1-{[3-methyl-4-(4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid D13;

[1109] 2-[(1Z)-1-{[2-methyl-4-(4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid D14;

[1110] 2-[(1Z)-5,7-difluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D15;

[1111] 2-[(1Z)-4,6-difluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D16;

[1112] 2-[(1Z)-5-tert-butyl-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D17;

[1113] (Z)-2-(5-fluoro-2-methyl-1-(3-phenoxybenzylidene)-1H-inden-3-yl)acetic acid D18;

[1114] 2-[(1Z)-5-fluoro-1-(2-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid D19;

[1115] 2-[(1Z)-5,7-difluoro-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D20;

[1116] 2-[(1Z)-4,6-difluoro-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D21;

[1117] 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-methoxyphenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D22;

[1118] 2-[(1Z)-5-fluoro-1-(4-fluoro-3-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid D23;

[1119] 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-cyanophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D24;

[1120] 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-chlorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D25;

[1121] 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-trifluoromethylphenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D26;

[1122] 2-[(1Z)-5-fluoro-2-methyl-1-({3-[3-trifluoromethylphenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D27;

[1123] 2-[(1Z)-4-methoxy-1-(4-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid D28;

[1124] 2-[(1Z)-6-methoxy-1-(4-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid D29;

[1125] 2-[(1Z)-6-trifluoromethyl-2-methyl-1-({4-[4-fluorophenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D30;

[1126] 2-[(1Z)-5-trifluoromethyl-2-methyl-1-({4-[4-fluorophenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D31;

[1127] 2-[(1Z)-1-{[4-(4-fluorophenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid D32;

[1128] 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid D33;

[1129] 2-[(1Z)-5-trifluoromethyl-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D34;

[1130] 2-[(1Z)-6-methoxy-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D35;

[1131] 2-[(1Z)-6-trifluoromethyl-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D36;

[1132] 2-[(1Z)-5-fluoro-2-methyl-1-({3-[methyl(phenyl)amino]phenyl}methylene)-1H-inden-3-yl]acetic acid D37; or

[1133] 2-[(1Z)-5-fluoro-1-[(3-methoxy-5-phenoxyphenyl)methylene]-2-methyl-1H-inden-3-yl]acetic acid D38;

[1134] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1135] In yet another embodiment, this document provides a compound as follows:

[1136] 2-[(1E)-5-fluoro-2-methyl-1-({4-[3,4-difluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E1;

[1137] 2-[(1E)-5-fluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E2;

[1138] 2-[(1E)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid E3;

[1139] 2-[(1E)-5,7-difluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E4;

[1140] 5-{2-[(1E)-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazolium E5; and

[1141] 2-[(1E)-5,7-difluoro-1-(3-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid E6;

[1142] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1143] In some embodiments, the compounds provided herein are enriched for deuterium. In some embodiments, the compounds provided herein are enriched for carbon-13. In some embodiments, the compounds provided herein are enriched for carbon-14. In some embodiments, the compounds provided herein contain one or more less common isotopes of other elements, including (but not limited to) nitrogen. 15 N; oxygen 17 O or 18 O and sulfur 34 S, 35 S or 36 S.

[1144] In some embodiments, the isotope enrichment factors of the compounds provided herein are not less than about 5, not less than about 10, not less than about 20, not less than about 50, not less than about 100, not less than about 200, not less than about 500, not less than about 1,000, not less than about 2,000, not less than about 5,000, or not less than about 10,000. However, in any case, the isotope enrichment factor of a specified isotope is not greater than the maximum isotope enrichment factor of that specified isotope, which is the isotope enrichment factor when the compound at a given position is 100% enriched in that specified isotope. Therefore, the maximum isotope enrichment factors are different for different isotopes. The maximum isotope enrichment factor for deuterium is 6,410, and the maximum isotope enrichment factor for carbon-13 is 90.

[1145] In some embodiments, the deuterium enrichment factors of the compounds provided herein are not less than about 64 (about 1% deuterium enrichment), not less than about 130 (about 2% deuterium enrichment), not less than about 320 (about 5% deuterium enrichment), not less than about 640 (about 10% deuterium enrichment), not less than about 1,300 (about 20% deuterium enrichment), not less than about 3,200 (about 50% deuterium enrichment), not less than about 4,800 (about 75% deuterium enrichment), and not less than about 5. The concentrations are: 130 (approximately 80% deuterium enrichment), not less than 5,450 (approximately 85% deuterium enrichment), not less than 5,770 (approximately 90% deuterium enrichment), not less than 6,090 (approximately 95% deuterium enrichment), not less than 6,220 (approximately 97% deuterium enrichment), not less than 6,280 (approximately 98% deuterium enrichment), not less than 6,350 (approximately 99% deuterium enrichment), or not less than 6,380 (approximately 99.5% deuterium enrichment). Deuterium enrichment can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In some embodiments, as specified with respect to deuterium enrichment, the deuterium enrichment of at least one atom of the compound provided herein is not less than about 1%, not less than about 2%, not less than about 5%, not less than about 10%, not less than about 20%, not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, or not less than about 98%.

[1146] In some embodiments, the compounds provided herein are isolated or purified. In some embodiments, the compounds provided herein have a purity of at least about 90% by weight, at least about 95% by weight, at least about 98% by weight, at least about 99% by weight, or at least about 99.5% by weight.

[1147] Unless a specific stereochemistry is specified, the compounds presented herein are intended to cover all possible stereoisomers. When the compounds presented herein contain an alkenyl group, the compound may exist as one or a mixture of geometric cis / trans (or Z / E) isomers. When the structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in compounds containing, for example, imino, ketone, or oxime groups; or so-called valence tautomerism in compounds containing aromatic moieties. Thus, a compound may exhibit more than one isomer.

[1148] The compounds described herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or may be a mixture of stereoisomers, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Therefore, those skilled in the art will recognize that, for compounds that have undergone in vivo epimerization, the application of the (R) form is equivalent to the application of the (S) form. Conventional techniques for preparing / separating single enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of mixtures of enantiomers, such as chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts, followed by separation.

[1149] When the compounds provided herein contain an acidic or basic moiety, they may also be provided as pharmaceutically acceptable salts. See Berge et al., *Journal of Pharmaceutical Science*, 1977, 66, 1-19; *Handbook of Pharmaceutical Salts: Properties, Selection and Use*, 2nd ed.; Stahl and Wermuth; John Wiley & Sons, 2011. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[1150] Suitable acids for preparing pharmaceutically acceptable salts of the compounds provided herein include (but are not limited to) acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, D-gluconic acid, D-glucuronic acid. L-Glutamic acid, α-ketoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, glycolic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate, p-toluenesulfonic acid, undecenoic acid, and valeric acid.

[1151] Suitable bases for preparing pharmaceutically acceptable salts of the compounds provided herein include (but are not limited to) inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including (but not limited to) L-arginine, benzylethylenediamine, benzylethylenediamine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino) Ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucosamine, hydrabamine, 1H-imidazolium, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucosamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[1152] The compounds described herein can also be provided as prodrugs, which are functional derivatives of the compounds and readily converted into the parent compound in vivo. Prodrugs are often useful because, in certain situations, they may be easier to administer than the parent compound. For example, they may be bioavailable via oral administration, while the parent compound may not. Prodrugs may also have greater solubility in pharmaceutical compositions compared to the parent compound. Prodrugs can be converted into the parent drug through various mechanisms, including enzymatic processes and metabolic hydrolysis.

[1153] Pharmaceutical Composition

[1154] In one embodiment, this document provides a pharmaceutical composition comprising a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[1155] The pharmaceutical compositions described herein can be formulated into various dosage forms, including (but not limited to) oral, parenteral, and topical formulations. The pharmaceutical compositions can also be formulated into modulated release dosage forms, including delayed release, extended release, sustained release, pulsatile release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retention formulations. These dosage forms can be prepared using conventional methods and techniques known to those skilled in the art. See, for example, Remington: Pharmaceutical Science and Practice, ibid.; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., eds.; Drugs and the Pharmaceutical Sciences, 184; CRC Press: Boca Raton, Florida (FL), 2008.

[1156] In one embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for subcutaneous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for topical administration.

[1157] The pharmaceutical compositions described herein may be provided in single-dosage forms or multiple-dosage forms. As used herein, a single-dosage form refers to a physically discrete unit suitable for administration to a subject and individually packaged as known in the art. Each unit dose contains a predetermined amount of active ingredient (e.g., the compound described herein) sufficient to produce the desired therapeutic effect, along with the desired pharmaceutical excipients. Examples of single-dosage forms include (but are not limited to) ampoules, syringes, and individually packaged tablets and capsules. Single-dosage forms can be administered in multiple doses or fractions. Multiple-dosage forms refer to multiple identical single-dosage forms packaged in a single container for administration in separate single-dosage forms. Examples of multiple-dosage forms include (but are not limited to) vials, tablet bottles, or capsule bottles, or pint bottles or gallon bottles.

[1158] The pharmaceutical compositions described herein may be administered once or multiple times at intervals. It should be understood that the precise dosage and duration of treatment may vary depending on the age, weight, and condition of the subject receiving treatment, and may be determined empirically using known trial protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It should also be understood that, for any given individual, the specific dosage regimen should be adjusted over time based on the subject's needs and the professional judgment of the person administering the pharmaceutical composition or supervising its administration.

[1159] A. Oral administration

[1160] The pharmaceutical compositions for oral administration described herein may be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, tongue, and sublingual administration. Suitable oral dosage forms include (but are not limited to) tablets, instant dissolvers, chewable tablets, capsules, pills, strips, lozenges, rhomboid tablets, pellets, capsules, granules, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, tablets, sprays, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including (but not limited to) binders, fillers, diluents, disintegrants, humectants, lubricants, flow aids, colorants, dye migration inhibitors, sweeteners, flavorings, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources.

[1161] Binders or granulators impart adhesiveness to the tablets to ensure they remain intact after compression. Suitable binders or granulators include (but are not limited to) starches, such as corn starch, potato starch, and pregelatinized starches (e.g., starch...). Gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as gum arabic, alginate, alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethyl cellulose, methyl cellulose, and polyvinylpyrrolidone (PVP). Larch arabogalactan, powdered astragalus gum and guar gum; cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); and microcrystalline cellulose, such as PH-101 PH-103 PH-105 and RC-581. Suitable fillers include (but are not limited to) talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose dextrorate, kaolin, mannitol, silica, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain from about 50% to about 99% by weight of binder or filler.

[1162] Suitable diluents include (but are not limited to) calcium hydrogen phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugars. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantities, can impart certain compressed tablets with the property of disintegrating in the mouth through chewing. These compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein can vary depending on the type of formulation and is readily discernible to those skilled in the art.

[1163] Suitable disintegrants include (but are not limited to) agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginate; gums, such as guar gum and... HV; citrus pomace; cross-linked cellulose, such as cross-linked carboxymethyl cellulose; cross-linked polymers, such as crosspovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starch, such as corn starch, potato starch, cassava starch, and pregelatinized starch; clay; and alginate. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant.

[1164] Suitable lubricants include (but are not limited to) calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurylate; agar; starch; pine nuts; and silica or silica gel, such as... 200 and CAB-O- The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of lubricant.

[1165] Suitable flow aids include (but are not limited to) colloidal silica, CAB-O- And asbestos-free talc. Suitable colorants include (but are not limited to) any of approved, certified water-soluble and water-insoluble FD&C dyes suspended on alumina hydrates, and lakes. A lake is a combination of dyes produced by adsorbing water-soluble dyes onto hydrated oxides of heavy metals, thereby creating an insoluble form. Suitable flavorings include (but are not limited to) natural flavorings extracted from plants (such as fruits), and synthetic blends of compounds that produce a pleasant taste (such as peppermint and methyl salicylate). Suitable sweeteners include (but are not limited to) sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include (but are not limited to) gelatin, gum arabic, astragalus gum, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (POM). 20), Polyoxyethylene sorbitan monooleate 80 ( 80) and triethanolamine oleate. Suitable suspending and dispersing agents include (but are not limited to) sodium carboxymethyl cellulose, pectin, astragalus gum, Gum arabic, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include (but are not limited to) glycerin, methylparaben and propylparaben, benzoic acid and sodium benzoate, and alcohols. Suitable wetting agents include (but are not limited to) propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include (but are not limited to) glycerin, sorbitol, ethanol, and syrups. Suitable non-aqueous liquids used in emulsions include (but are not limited to) mineral oil and cottonseed oil. Suitable organic acids include (but are not limited to) citric acid and tartaric acid. Suitable sources of carbon dioxide include (but are not limited to) sodium bicarbonate and sodium carbonate.

[1166] It should be understood that many carriers and excipients can perform several functions, even in the same formulation.

[1167] The oral pharmaceutical compositions described herein are provided in the form of compressed tablets, formulated tablets, chewable diamond-shaped tablets, rapidly dissolving tablets, multi-compressed tablets, enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include (but are not limited to) fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help mask unpleasant tastes or odors and protect the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include (but are not limited to) hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multi-compression tablets are tablets produced through one or more compression cycles, including multi-layer tablets and compressed coated or dry-coated tablets.

[1168] Tablet dosage forms can be prepared alone from the active ingredient in powder, crystalline, or granular form, or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweeteners are particularly suitable for forming chewable tablets and diamond-shaped tablets.

[1169] The oral pharmaceutical compositions provided herein may be provided in the form of soft capsules or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two parts, one overlying the other, thereby completely encapsulating the active ingredient. Soft elastic capsules (SEC) are spherical shells, such as gelatin shells, plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions may be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. Capsules may also be coated, as is known to those skilled in the art, to adjust or maintain the dissolution of the active ingredient.

[1170] The oral pharmaceutical compositions described herein are available in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is dispersed in another liquid in the form of spheres; it may be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions may include pharmaceutically acceptable acetals, such as di(low-carbon alkyl) acetals of low-carbon alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of sugars (e.g., sucrose) and may also contain preservatives. For liquid dosage forms, such as solutions in polyethylene glycol, dilution with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) may be used for convenient measurement and administration.

[1171] Other applicable liquid and semi-solid dosage forms include (but are not limited to) dosage forms containing an active ingredient and a dialkylated monoalkylene glycol or polyalkylene glycol, said monoalkylene glycol or polyalkylene glycol including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These dosage forms may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[1172] The oral pharmaceutical compositions provided herein can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[1173] The pharmaceutical compositions for oral administration described herein may be provided in the form of non-foaming or foaming granules and powders for reconfiguration into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-foaming granules and powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in foaming granules or powders may include organic acids and carbon dioxide sources.

[1174] Colorants and flavorings may be used in all dosage forms described herein.

[1175] The oral pharmaceutical compositions provided herein can be formulated into dosage forms for immediate or modulated release, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[1176] B. External administration of medication

[1177] The pharmaceutical compositions described herein can be administered parenterally via injection, infusion, or implantation for local or systemic drug delivery. As used herein, parenterally administration includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intrabladder, and subcutaneous delivery.

[1178] The pharmaceutical compositions for parenteral administration described herein can be formulated into any dosage form suitable for parenteral administration, including (but not limited to) solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for forming a solution or suspension in a liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, for example, Remington's Pharmaceutical Science and Practice, ibid.

[1179] The pharmaceutical compositions for parenteral administration provided herein may include one or more pharmaceutically acceptable carriers and excipients, including (but not limited to) aqueous mediators, water-miscible mediators, non-aqueous mediators, antimicrobial agents or preservatives that inhibit microbial growth, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, clamping or chelating agents, cryoprotectants, lyophilization protectants, thickeners, pH adjusters, and inert gases.

[1180] Suitable aqueous mediators include (but are not limited to) water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextran injection, sterile water injection, dextran and lactated Ringer's injection. Suitable non-aqueous mediators include (but are not limited to) non-volatile oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil. Suitable water-miscible mediators include (but are not limited to) ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[1181] Suitable antimicrobial agents or preservatives include (but are not limited to) phenols, cresols, mercury, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride (e.g., benzyl chloride), methylparaben and propylparaben, and sorbic acid. Suitable isotonic agents include (but are not limited to) sodium chloride, glycerol, and dextran. Suitable buffers include (but are not limited to) phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfites and sodium metabisulfite. Suitable local anesthetics include (but are not limited to) procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable chelating or binding agents include (but are not limited to) EDTA. Suitable pH adjusters include (but are not limited to) sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include (but are not limited to) cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin.

[1182] When the pharmaceutical compositions provided herein are formulated for multiple-dose administration, the multiple-dose parenteral formulation must contain an antimicrobial agent at a concentration that inhibits bacteria or fungi. As is known and practiced in the art, all parenteral formulations must be sterile.

[1183] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry-soluble product, comprising lyophilized powder and subcutaneous tablets, to be reconstituted with a mediator prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile, dry, insoluble product, to be reconstituted with a mediator prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[1184] The pharmaceutical compositions for parenteral administration provided herein can be formulated into dosage forms that provide immediate or modulated release, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[1185] The pharmaceutical compositions provided herein for parenteral administration can be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration in the form of implantable receptacles. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix surrounded by an external polymeric membrane that is insoluble in body fluids but allows the active ingredients in the pharmaceutical composition to diffuse through.

[1186] Suitable internal matrices include (but are not limited to) polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers (such as hydrogels of acrylates and methacrylates), collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

[1187] Suitable external polymeric membranes include (but are not limited to) polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer.

[1188] C. Topical application of medication

[1189] The pharmaceutical compositions described herein can be applied topically to the skin, orifices, or mucous membranes. As used herein, topical application includes intradermal, conjunctival, intracorneal, intraocular, ocular, ocular, ear, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[1190] The pharmaceutical compositions described herein can be formulated into any dosage form suitable for topical application to achieve local or systemic effects, including (but not limited to) emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigates, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions described herein may also include liposomes, micelles, microspheres, and nanosystems.

[1191] Pharmaceutically acceptable carriers and excipients suitable for use in topical formulations include (but are not limited to) aqueous media, water-miscible media, non-aqueous media, antimicrobial agents or preservatives that inhibit microbial growth, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, clamping or chelating agents, penetration enhancers, cryoprotectants, lyophilization protectants, thickeners, and inert gases.

[1192] Drug compositions can also be administered topically via electroporation, iontophoresis, ultrasound penetration, ultrasound-enhanced penetration, or microneedle or needle-free injection, such as POWDERJECT. TM and BIOJECT TM .

[1193] The pharmaceutical compositions described herein are available in ointment, cream, and gel form. Suitable ointment mortises include oily or hydrocarbon mortises, including lard, benzoic acid lard, olive oil, cottonseed oil and other oils, and white petrolatum; emulsifiable or absorbable mortises, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable mortises, such as hydrophilic ointments; water-soluble ointment mortises, including polyethylene glycol of varying molecular weights; and emulsion mortises, water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, for example, Remington's Pharmaceutical Science and Practice, ibid. These mortises are emollients but often require the addition of antioxidants and preservatives.

[1194] A suitable cream base can be oil-in-water or water-in-oil. A suitable cream mordant can be water-washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, typically consists of petrolatum and fatty alcohols (such as cetyl alcohol or stearyl alcohol). The aqueous phase usually, but not necessarily, exceeds the volume of the oil phase and usually contains a humectant. Emulsifiers in cream formulations can be nonionic, anionic, cationic, or amphoteric surfactants.

[1195] Gels are semi-solid, suspension-type systems. Single-phase gels contain organic macromolecules that are substantially uniformly distributed throughout the liquid carrier. Suitable gelling agents include (but are not limited to) crosslinked acrylic polymers, such as carbomer, carboxylated polyalkylene compounds, and... Hydrophilic polymers, such as polyethylene oxide, polyethylene oxide-polypropylene copolymers, and polyvinyl alcohol; cellulose polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as astragalus gum and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, dispersants, such as alcohols or glycerols, may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[1196] The pharmaceutical compositions described herein can be administered rectally, urethra, vaginally, or perivatically in the form of suppositories, vaginal plugs, probes, mud dressings or boluses, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, lotions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes, such as those described in Remington's Pharmaceutical Science and Practice (ibid.).

[1197] Rectal suppositories, urethral suppositories, and vaginal suppositories are solids intended for insertion into bodily orifices. They are solid at room temperature but melt or soften at body temperature to release the active ingredient within the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include matrices or mediators (such as hardeners) that produce a melting point close to body temperature when formulated with the active ingredient; and antioxidants as described herein, including bisulfites and sodium metabisulfite. Suitable mediators include (but are not limited to) cocoa butter, glycerin-gelatin, carbowax (polyoxyethylene glycol), cetyl wax, paraffin wax, beeswax, and yellow wax, as well as suitable mixtures of monoglycerides, diglycerides, and triglycerides of fatty acids, and hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various mediators may also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[1198] The pharmaceutical compositions provided herein can be applied ocularly in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for use with solutions, gels, ophthalmic inserts, and implants.

[1199] The pharmaceutical compositions described herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions may be provided in aerosol or solution form for delivery alone or in combination with a suitable propellant (such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) using a pressurized container, pump, spray, atomizer (such as one that uses electrohydrodynamics to generate a fine mist), or nebulizer. The pharmaceutical compositions may also be provided in dry powder form for inhalation alone or in combination with an inert carrier (such as lactose or phospholipids) and nasal drops. For intranasal use, the powder may contain a bio-binder, including chitosan or cyclodextrin.

[1200] Solutions or suspensions used in pressurized containers, pumps, sprayers, atomizers or sprayers may be formulated as containing ethanol, aqueous ethanol solutions or suitable alternatives for dispersing, solubilizing or prolonging the release of active ingredients; propellants as solvents; and / or surfactants such as sorbitan trioleate, oleic acid or oligolactic acid.

[1201] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such size can be prepared using pulverization methods known to those skilled in the art, such as helical jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high-pressure homogenization, or spray drying.

[1202] Capsules, blister packs, and tubes for inhalers or blowpipes may be formulated as powder mixtures containing the pharmaceutical compositions provided herein; a suitable powder matrix, such as lactose or starch; and a performance modifier, such as L-leucine, mannitol, or magnesium stearate. Lactose may be in anhydrous or monohydrate form. Other suitable excipients or carriers include (but are not limited to) dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhalation / intranasal administration may also contain suitable flavorings, such as menthol and levonorgestrel; and / or sweeteners, such as saccharin and sodium saccharin.

[1203] The pharmaceutical compositions for local application provided herein can be formulated to release immediately or modulated release, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[1204] D. Regulation and release

[1205] The pharmaceutical compositions provided herein can be formulated into modulated-release dosage forms. As used herein, the term "modulated-release" refers to dosage forms in which the release rate or release site of the active ingredient differs from that of immediate-release dosage forms administered via the same route. Modulated-release dosage forms include (but are not limited to) delayed-release, extended-release, prolonged-release, sustained-release, pulsatile-release, controlled-release, accelerated-release, and rapid-release, targeted-release, programmed-release, and gastric-retention dosage forms. Pharmaceutical compositions of modulated-release dosage forms can be prepared using a variety of modulated-release devices and methods known to those skilled in the art, including (but not limited to) matrix-controlled-release devices, osmotic-controlled-release devices, multi-particle controlled-release devices, ion-exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modulated by changing the particle size and polymorphism of the active ingredient.

[1206] 1. Matrix controlled release device

[1207] The pharmaceutical compositions provided herein in the form of modulated-release formulations can be manufactured using matrix-controlled-release devices known to those skilled in the art. See, for example, Takada et al., Encyclopedia of Controlled Drug Delivery, Mathiowitz, ed.; Wiley, 1999; Vol. 2.

[1208] In some embodiments, the pharmaceutical compositions provided herein in a modulated release formulation are formulated using an erosive matrix device, which is a water-swellable, erosive, or soluble polymer, including (but not limited to) synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[1209] Materials that can be used to form an erosive matrix include (but are not limited to) chitin, chitosan, dextran, and pullulan; agarose, gum arabic, gum arabic, gum arabic, gum arabic, astragalus gum, carrageenan, solanum, guar gum, xanthan gum, and stearin; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginate; propylene glycol alginate; gelatin; collagen; and cellulose, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), and CME. C. Hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylic acid or methacrylic acid. Poly(2-hydroxyethyl methacrylate); polylactide; copolymers of L-glutamic acid and L-glutamic acid ethyl ester; biodegradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl) methacrylate chloride.

[1210] In some embodiments, an inert matrix device is used to formulate the pharmaceutical compositions provided herein. The active ingredient is dissolved or dispersed in an inert matrix and released primarily through diffusion across the inert matrix after administration. Materials suitable for use as non-erosion matrix devices include (but are not limited to) insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride-vinyl acetate copolymer, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane and silicone carbonate copolymers; hydrophilic polymers such as ethyl cellulose, cellulose acetate, cross-linked partially hydrolyzed polyvinyl acetate, etc.; and aliphatic compounds such as carnauba wax, microcrystalline wax and triglycerides.

[1211] In matrix-controlled release systems, the desired release kinetics can be controlled, for example, by the type of polymer used, polymer viscosity, particle size of the polymer and / or active ingredient, the ratio of the active ingredient to the polymer, and other excipients or carriers in the composition.

[1212] The pharmaceutical compositions provided herein in the form of controlled-release formulations can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[1213] 2. Osmotic controlled-release device

[1214] The pharmaceutical compositions provided herein, in a controlled-release formulation, can be manufactured using an osmotic controlled-release device, including (but not limited to) single-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extrusion core systems (ECS). Generally, such a device has at least two components: (a) a core containing the active ingredient; and (b) a semi-permeable membrane having at least one delivery port that encapsulates the core. The semi-permeable membrane controls the flow of water from the aqueous environment of use into the core, thereby causing drug release through extrusion via the delivery port.

[1215] In addition to the active ingredient, the core of the osmosis device optionally includes a permeabilizing agent that generates the driving force to transport water from the environment to the core of the device. One type of permeabilizing agent is a water-swellable hydrophilic polymer, also known as a "permeabilizing polymer" or "hydrogel". Suitable water-swellable hydrophilic polymers as penetrants include (but are not limited to) hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(hydroxyethyl 2-methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers (such as methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethyl cellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium glycolate starch.

[1216] Another type of permeabilizer is the osmogen, which can adsorb water to affect the osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens include (but are not limited to) inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edemaic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[1217] Penetrants with different dissolution rates can be used to influence the initial rate of delivery of the active ingredient from the dosage form. For example, an amorphous sugar such as MANNOGEMTMEZ can be used to provide faster delivery in the first few hours, thereby rapidly producing the desired therapeutic effect, and gradually and continuously releasing the remainder to maintain the desired level of therapeutic or preventative effect over a prolonged period. In this case, the active ingredient is released at this rate to replace the amount of active ingredient that is metabolized and excreted.

[1218] The core may also include a variety of other excipients and carriers as described herein to enhance the performance of the dosage form or promote stability or processing.

[1219] Materials suitable for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives, which are either water-permeable or water-insoluble at physiologically relevant pH levels, or readily become water-insoluble through chemical alterations such as crosslinking. Examples of polymers suitable for coating formation include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), ethyl carbamate, CAP, methyl carbamate, succinate, cellulose trimellitate (CAT), cellulose dimethylglycine, ethyl carbonate, chloroacetate, ethyl oxalate, methyl sulfonate, butyl sulfonate, p-toluenesulfonate, acetic agar, triacetic acid amyl starch, β-glucan acetate, etc. β-triacetic acid dextran, dimethyl acetaldehyde acetate, triacetic acid ester of locust bean gum, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMC, HPMCP, HPMCS, HPMC, poly(acrylic acid) and esters and poly(methacrylic acid) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrene, polyhalogenated polyethylene esters and ethers, natural waxes and synthetic waxes.

[1220] Semipermeable membranes can also be hydrophobic microporous membranes, wherein the pores are substantially filled with gas and are not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor-permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyhalogenated polyethylene, polyvinylidene fluoride, polyethylene esters and ethers, natural waxes and synthetic waxes.

[1221] Delivery ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can also be formed in situ by etching with a stopper of a water-soluble material or by causing a thinner portion of the membrane to rupture in a recess in the core. Furthermore, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[1222] The total amount and release rate of the active ingredients released can be largely adjusted by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[1223] Pharmaceutical compositions in the form of osmotic controlled-release formulations may further include additional conventional excipients or carriers as described herein to enhance the performance or processing of the formulation.

[1224] Osmotic controlled-release formulations can be prepared using conventional methods and techniques known to those skilled in the art. See, for example, Remington: Pharmaceutical Science and Practice, ibid.; Santus and Baker, Journal of Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma et al., Journal of Controlled Release, 2002, 79, 7-27.

[1225] In some embodiments, the pharmaceutical compositions provided herein are formulated into AMT controlled-release dosage forms comprising an asymmetric permeation membrane coating a core containing the active ingredient and other pharmaceutically acceptable excipients or carriers. See, for example, U.S. Patent Nos. 5,612,059 and WO 2002 / 17918. AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip-coating.

[1226] In some embodiments, the pharmaceutical compositions provided herein are formulated into ESC controlled-release dosage forms comprising a permeable membrane coated with a core containing an active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

[1227] 3. Multi-particle controlled-release device

[1228] The pharmaceutical compositions provided herein, in a controlled-release formulation, can be formulated into multi-particle controlled-release devices comprising a variety of particles, microparticles, or pellets with diameters ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. Such multiparticles can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, rolling, melt coagulation, and by spraying a seed core. See, for example, *Multiparticulate Oral Drug Delivery*; ed. Ghebre-Sellassie; *Drugs and the Pharmaceutical Sciences 65*; CRC Press: 1994; and *Pharmaceutical Pelletization Technology*; ed. Ghebre-Sellassie; *Drugs and the Pharmaceutical Sciences 37*; CRC Press: 1989.

[1229] Other excipients or carriers as described herein may be incorporated into the pharmaceutical composition to aid in processing and forming multiparticles. The resulting particles may themselves constitute a multiparticle device or may be coated with various film-forming materials, such as enteric polymers, water-swellable polymers, and water-soluble polymers. The multiparticles may be further processed into capsules or tablets.

[1230] 4. Targeted delivery

[1231] The pharmaceutical compositions described herein can also be formulated to target specific tissues, receptors, or other regions of the body of a subject to be treated, including delivery systems based on liposomes, resealed red blood cells, and antibodies. Examples include, but are not limited to, those disclosed in U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[1232] How to use

[1233] In one embodiment, this document provides a method for treating, alleviating, or preventing one or more symptoms of fibrotic disease in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[1234] In another embodiment, this document provides a method for treating, alleviating, or preventing one or more symptoms of fibrotic disease in a subject, comprising administering a therapeutically effective amount of a compound of formula (IA) to the subject in need:

[1235]

[1236] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein:

[1237] R 1It is (a) hydrogen, deuterium, cyano, halo, or nitro; or (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[1238] R 2 For –CN, –C(O)OR 2a –C(O)NR 2b R 2c –C(O)N(R) 2b OR 2c –OR 2a –NR 2b R 2c Or heteroaryl; wherein R 2a R 2b and R 2c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups;

[1239] R 3 R 4 R 5 and R 6 Each is independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR 1b R 1c –OC(NR) 1a )NR 1b R 1c –OS(O)R1a –OS(O)2R 1a –OS(O)NR 1b R 1c –OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R 1c –NR 1a S(O)R 1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c –NR 1a S(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ;

[1240] R 7 Each is independently (a) deuterium, cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–C(O)R 1a –C(O)OR 1a –C(O)NR 1b R 1c –C(NR) 1a )NR 1b R 1c –OR 1a –OC(O)R 1a –OC(O)OR 1a –OC(O)NR1b R 1c –OC(NR) 1a )NR 1b R 1c –OS(O)R 1a –OS(O)2R 1a –OS(O)NR 1b R 1c –OS(O)2NR 1b R 1c –NR 1b R 1c –NR 1a C(O)R 1d –NR 1a C(O)OR 1d –NR 1a C(O)NR 1b R 1c –NR 1a C(NR 1d )NR 1b R 1c –NR 1a S(O)R 1d –NR 1a S(O)2R 1d –NR 1a S(O)NR 1b R 1c –NR 1a S(O)2NR 1b R 1c –SR 1a –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ; or two adjacent R 7 Together with the phenyl group it is attached to, it forms a naphthyl or a bicyclic heteroaryl group;

[1241] R C It is (a) hydrogen, deuterium, cyano, halo, or nitro; or (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (c)–OR 1a –NR 1b R 1c Or –NR 1a C(O)R1d ;

[1242] L is C 1-6 Alkylene or C 2-6 alkenyl;

[1243] n is an integer, which can be 0, 1, 2, 3, or 4; and

[1244] R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms it is attached to, it forms a heterocyclic group; or R 1b and R 1c Together with the N atom it is attached to, it forms a heterocyclic group;

[1245] The alkyl, alkylene, alkenyl, alkenylene, ynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more, in one embodiment by one, two, three, or four substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, nitro, and oxoalkyl; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Substitution; and (c)–C(O)R a –C(O)OR a –C(O)NR b R c –C(O)SR a –C(NR) a )NR b R c –C(S)R a –C(S)OR a –C(S)NR b R c –OR a –OC(O)R a –OC(O)ORa 、 –OC(O)NR b R c 、 –OC(O)SR a 、 –OC(NR a )NR b R c 、 –OC(S)R a 、 –OC(S)OR a 、 –OC(S)NR b R c 、 –OS(O)R a 、 –OS(O)2R a 、 –OS(O)NR b R c 、 –OS(O)2NR b R c 、 –NR b R c 、 –NR a C(O)R d [[ID=4I]]、 –NR a C(O)OR d 、 –NR a C(O)NR b R c 、 –NR a C(O)SR d 、 –NR a C(NR[[ID=I8]] d )NR b R c 、 –NR a C(S)R[[ID=TI]] d 、 –NR a C(S)OR d 、 –NR a C(S)NR b R c 、 –NR a S(O)R d 、 –NR a S(O)2R d 、 –NR a S(O)NR b R c 、 –NR a S(O)2NR b R c 、 –SR a 、 –S(O)R a 、 –S(O)2R a 、 –S(O)NR b R c and –S(O)2NR b R c , where Ra R b R c and R d Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more, in one embodiment with one, two, three, or four substituents Q. a Replace; or (iii)R b and R c Together with the N atom it is attached to, it forms an optional group Q via one or more, in one embodiment via one, two, three or four substituents. a Substituted heterocyclic groups;

[1246] Q a Each is independently selected from: (a) deuterium, cyano, halogen, nitro, and oxonide; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl, and heterocyclic groups; and (c)–C(O)R e –C(O)OR e –C(O)NR f R g –C(O)SR e –C(NR) e )NR f R g –C(S)R e –C(S)OR e –C(S)NR f R g –OR e –OC(O)R e –OC(O)OR e –OC(O)NR f R g –OC(O)SR e –OC(NR) e )NR f R g –OC(S)R e –OC(S)OR e –OC(S)NR f R g–OS(O)R e –OS(O)2R e –OS(O)NR f R g –OS(O)2NR f R g –NR f R g –NR e C(O)R h –NR e C(O)OR f –NR e C(O)NR f R g –NR e C(O)SR f –NR e C(NR h )NR f R g –NR e C(S)R h –NR e C(S)OR f –NR e C(S)NR f R g –NR e S(O)R h –NR e S(O)2R h –NR e S(O)NR f R g –NR e S(O)2NR f R g –SR e –S(O)R e –S(O)2R e –S(O)NR f R g and –S(O)2NR f R g ;where R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii)R fand R g Together with the N atom it is attached to, it forms a heterocyclic group.

[1247] In one embodiment, the compound of formula (IA) has the structure of formula (II-A):

[1248]

[1249] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 R C L and n are each defined as in this paper.

[1250] In another embodiment, the compound of formula (IA) has the structure of formula (III-A):

[1251]

[1252] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 R C L and n are each defined as in this paper.

[1253] In yet another embodiment, the compound of formula (IA) has the structure of formula (IV-A):

[1254]

[1255] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein R 1 R 2 R 3R 4 R 5 R 6 R 7 R C L and n are each defined as in this paper.

[1256] In one implementation, in any of formulas (IA) to (IV-A),

[1257] R 1 It is hydrogen or C 1-6 alkyl;

[1258] R 2 For –CN, –C(O)OR 2a –C(O)NR 2b R 2c –OR 2a –NR 2b R 2c Or heteroaryl, wherein R 2a R 2b and R 2c Each is independently hydrogen or C 1-6 alkyl;

[1259] R 3 R 4 R 5 and R 6 Each is independently hydrogen, deuterium, halogen, C 1-6 Alkyl or –O–C 1-6 alkyl;

[1260] R 7 And n is (i) or (ii):

[1261] (i) n is an integer 0, 1, 2, 3, or 4; and

[1262] R 7 Each is independently of deuterium, halogen, and C. 1-6 Alkyl or –O–C 1-6 Alkyl; or

[1263] (ii) n is an integer 2, 3, or 4; and

[1264] Two adjacent R 7 Together with the phenyl group it is attached to, it forms a naphthyl group;

[1265] R C It is hydrogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 Cycloalkyl, heteroaryl, heterocyclic, –O–C 1-6 Alkyl group, –NHC(O)–C 1-6Alkyl or –N(C) 1-6 Alkyl)2; and

[1266] L is C 1-6 Alkylene or C 2-6 alkenyl;

[1267] The alkyl, alkylene, alkenyl, alkenylene, cycloalkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[1268] In another embodiment, in any of formulas (IA) to (IV-A),

[1269] R 1 It is hydrogen or C 1-6 alkyl;

[1270] R 2 For –CN, –C(O)OR 2a –C(O)NR 2b R 2c –OR 2a –NR 2b R 2c Or a 5-membered heteroaryl group, in which R 2a R 2b and R 2c Each is independently hydrogen or C 1-6 alkyl;

[1271] R 3 and R 5 Each is independently either hydrogen or deuterium;

[1272] R 4 and R 6 Each is independently hydrogen, deuterium, halogen, C 1-6 Alkyl or –O–C 1-6 alkyl;

[1273] R 7 And n is (i) or (ii):

[1274] (i) n is an integer 0, 1, or 2; and

[1275] R 7 Each is independently of deuterium, halogen, and C. 1-6 Alkyl or –O–C 1-6 Alkyl; or

[1276] (ii) n is an integer 2; and

[1277] Two adjacent R 7 Together with the phenyl group attached thereto, they form naphth-1-yl or naphth-2-yl;

[1278] R CIt is hydrogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 Cycloalkyl, heteroaryl, heterocyclic, –O–C 1-6 Alkyl group, –NHC(O)–C 1-6 Alkyl or –N(C) 1-6 Alkyl)2; and

[1279] L is C 1-6 Alkylene or C 2-6 alkenyl;

[1280] The alkyl, alkylene, alkenyl, alkenylene, cycloalkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one, two, or three substituents Q.

[1281] In yet another embodiment, in any of formulas (IA) to (IV-A),

[1282] R 1 It can be hydrogen, methyl, ethyl, or butyl;

[1283] R 2 It can be –CN, –C(O)OH, –C(O)NH2, –C(O)NHCH3, –OH, –NH2 or tetrazolium;

[1284] R 3 and R 5 Each is independently either hydrogen or deuterium;

[1285] R 4 It can be hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, methoxy, or ethoxy;

[1286] R 6 It can be hydrogen, deuterium, or fluorine-based;

[1287] R 7 And n is (i) or (ii):

[1288] (i) n is an integer 0, 1, or 2; and

[1289] R 7 Each is independently a fluorinated, chlorolated, or methoxy group; or

[1290] (ii) n is an integer 2; and

[1291] Two adjacent R 7 Together with the phenyl group attached thereto, they form naphth-1-yl or naphth-2-yl;

[1292] R CIt can be hydrogen, cyano, methyl, trifluoromethyl, ethyl, propyl, fluoropropyl, difluoropropyl, hexafluoropropyl, butyl, propenyl, cyclopropyl, cyclopentyl, pyridyl, pyrrolylyl, hydroxy, methoxy, ethoxy, acetamido, or dimethylamino; and

[1293] L represents methylene, ethylene, or vinylene.

[1294] In yet another embodiment, in any of formulas (IA) to (IV-A),

[1295] R 1 It can be hydrogen, methyl, ethyl, or (2-methyl)propyl;

[1296] R 2 It can be –CN, –C(O)OH, –C(O)NH2, –C(O)NHCH3, –OH, –NH2 or tetrazol-5-yl;

[1297] R 3 and R 5 Each is independently either hydrogen or deuterium;

[1298] R 4 It can be hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, methoxy, or ethoxy;

[1299] R 6 It can be hydrogen, deuterium, or fluorine-based;

[1300] R 7 And n is (i) or (ii):

[1301] (i) n is an integer 0, 1, or 2; and

[1302] R 7 Each is a fluorine group; or

[1303] (ii) n is an integer 2; and

[1304] Two adjacent R 7 Together with the phenyl group attached thereto, they form naphth-1-yl or naphth-2-yl;

[1305] R C It can be hydrogen, cyano, methyl, trifluoromethyl, ethyl, 2-fluoropropane-2-yl, 1,3-difluoropropane-2-yl, di(trifluoromethyl)methyl, isopropyl, t-butyl, propen-1-yl, cyclopropyl, cyclopentyl, pyridin-2-yl, pyrrolidone-1-yl, hydroxy, methoxy, ethoxy, acetamipridyl, or dimethylamino; and

[1306] L represents methylene, ethane-1,2-diyl, or ethylene-1,2-diyl.

[1307] In one embodiment, the compound of formula (IA) is:

[1308] (Z)-2-(2-methyl-1-(4-isopropylbenzyl)-1H-inden-3-yl)acetic acid B1;

[1309] (Z)-2-(5-fluoro-2-methyl-1-(benzylidene)-1H-inden-3-yl)acetic acid B2;

[1310] (Z)-2-(5-fluoro-2-methyl-1-(3-cyanobenzylidene)-1H-inden-3-yl)acetic acid B3;

[1311] (Z)-2-(5-fluoro-2-methyl-1-(4-cyanobenzylidene)-1H-inden-3-yl)acetic acid B4;

[1312] (Z)-2-(5-fluoro-2-methyl-1-(4-methylbenzyl)-1H-inden-3-yl)acetic acid B5;

[1313] (Z)-2-(5-fluoro-2-methyl-1-(3-trifluoromethylbenzyl)-1H-inden-3-yl)acetic acid B6;

[1314] (Z)-2-(5-fluoro-2-methyl-1-(4-trifluoromethylbenzyl)-1H-inden-3-yl)acetic acid B7;

[1315] (Z)-2-(5-fluoro-2-methyl-1-(4-ethylbenzyl)-1H-inden-3-yl)acetic acid B8;

[1316] (Z)-2-(5-fluoro-2-methyl-1-(4-isopropylbenzyl)-1H-inden-3-yl)acetic acid B9;

[1317] (Z)-2-(5-fluoro-2-methyl-1-(4-tert-butylbenzyl)-1H-inden-3-yl)acetic acid B10;

[1318] (Z)-2-(5-fluoro-2-ethyl-1-(4-isopropylbenzylene)-1H-inden-3-yl)acetic acid B11;

[1319] (Z)-2-(5-fluoro-2-(2-methylpropyl)-1-(4-isopropylbenzylene)-1H-inden-3-yl)acetic acid B12;

[1320] (Z)-2-(5-fluoro-2-methyl-1-(3-methoxybenzyl)-1H-inden-3-yl)acetic acid B13;

[1321] (Z)-2-(5-fluoro-2-methyl-1-(4-methoxybenzyl)-1H-inden-3-yl)acetic acid B14;

[1322] (Z)-2-(5-fluoro-2-methyl-1-(4-ethoxybenzyl)-1H-inden-3-yl)acetic acid B15;

[1323] (Z)-2-(5-fluoro-2-methyl-1-(4-(pyrrolidin-1-yl)benzylidene)-1H-inden-3-yl)acetic acid B16;

[1324] (Z)-2-(5-fluoro-2-methyl-1-(4-(pyridin-2-yl)benzylidene)-1H-inden-3-yl)acetic acid B17;

[1325] (Z)-2-(5-chloro-2-methyl-1-(4-tert-butylbenzyl)-1H-inden-3-yl)acetic acid B18;

[1326] (Z)-2-(5-methyl-2-methyl-1-(4-isopropylbenzyl)-1H-inden-3-yl)acetic acid B19;

[1327] (Z)-2-(5-ethyl-2-methyl-1-(4-isopropylbenzyl)-1H-inden-3-yl)acetic acid B20;

[1328] (Z)-2-(5-isopropyl-2-methyl-1-(4-isopropylbenzylene)-1H-inden-3-yl)acetic acid B21;

[1329] (Z)-2-(5-methoxy-2-methyl-1-(4-isopropylbenzyl)-1H-inden-3-yl)acetic acid B22;

[1330] (Z)-2-(5-ethoxy-2-methyl-1-(4-isopropylbenzyl)-1H-inden-3-yl)acetic acid B23;

[1331] (Z)-2-(5-fluoro-1-(4-isopropylbenzylene)-2-methyl-1H-inden-3-yl)acetamide B24;

[1332] (Z)-2-(5-fluoro-1-(4-isopropylbenzyl)-2-methyl-1H-inden-3-yl)-N-methylacetamide B25;

[1333] (Z)-2-(5-fluoro-1-(4-isopropylbenzyl)-2-methyl-1H-inden-3-yl)-N,N-dimethylacetamide B26;

[1334] (Z)-2-(1-(4-acetamidobenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetic acid B27;

[1335] (Z)-3-(5-fluoro-1-(4-isopropylbenzyl)-2-methyl-1H-inden-3-yl)propionic acid B28;

[1336] (Z)-5-(2-(5-fluoro-1-(4-isopropylbenzylene)-2-methyl-1H-inden-3-yl)ethyl)-1H-tetrazole B29;

[1337] (Z)-5-(2-(1-(4-isopropylbenzylene)-2-methyl-1H-inden-3-yl)ethyl)-1H-tetrazole B30;

[1338] (Z)-2-(4-fluoro-2-methyl-1-(benzylidene)-1H-inden-3-yl)acetic acid B31;

[1339] (Z)-2-(5-fluoro-1-(4-dimethylaminobenzylidene)-2-methyl-1H-inden-3-yl)propionic acid B32;

[1340] 2-[(1Z)-5-fluoro-1-[(2-hydroxynaphth-1-yl)methylene]-2-methyl-1H-inden-3-yl]acetic acid B33;

[1341] 2-[(1Z)-5-fluoro-2-methyl-1-[(naphth-2-yl)methylene]-1H-inden-3-yl]acetic acid B34;

[1342] 2-[(1Z)-5-fluoro-2-methyl-1-[(4-methylnaphth-1-yl)methylene]-1H-inden-3-yl]acetic acid B35;

[1343] 2-[(1Z)-5-fluoro-1-[(2-methoxynaphth-1-yl)methylene]-2-methyl-1H-inden-3-yl]acetic acid B36;

[1344] 2-[(1Z)-1-[(4-cyclopropylphenyl)methylene]-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid B37;

[1345] 2-[(1Z)-1-[(4-cyclopentylphenyl)methylene]-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid B38;

[1346] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(prop-1-en-2-yl)phenyl]methylene}-1H-inden-3-yl]acetic acid B39;

[1347] 2-[(1Z)-5-fluoro-1-{[4-(2-fluoropropane-2-yl)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid B40;

[1348] 2-[(1Z)-1-{[4-(dimethylamino)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid B41;

[1349] 2-[(1Z)-5-fluoro-1-{[4-(1,1,1,3,3,3-hexafluoropropane-2-yl)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid B42;

[1350] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(propane-2-yl)phenyl]methylene}-1H-inden-3-yl]propionic acid B43;

[1351] 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(trifluoromethyl)phenyl]methylene}-1H-inden-3-yl]propionic acid B44;

[1352] 2-[(1Z)-7-fluoro-2-methyl-1-{[4-(propane-2-yl)phenyl]methylene}-1H-inden-3-yl]acetic acid B45;

[1353] 2-[(1Z)-7-fluoro-2-methyl-1-{[4-(trifluoromethyl)phenyl]methylene}-1H-inden-3-yl]acetic acid B46;

[1354] 2-[(1Z)-1-{[4-(1,3-difluoropropane-2-yl)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid B47; or

[1355] 2-[(1Z)-5-fluoro-1-{[3-fluoro-4-(propane-2-yl)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid B48;

[1356] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1357] In another embodiment, the compound of formula (IA) is:

[1358] (E)-2-(5-fluoro-2-methyl-1-(4-isopropylbenzyl)-1H-inden-3-yl)acetic acid B49;

[1359] (E)-2-(5-fluoro-1-(4-isopropylbenzylene)-2-methyl-1H-inden-3-yl)acetamide B50; or

[1360] (E)-2-(5-fluoro-1-(4-isopropylbenzyl)-2-methyl-1H-inden-3-yl)-N-methylacetamide B51;

[1361] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1362] In yet another embodiment, the compound of formula (IA) is:

[1363] (Z)-2-(5-fluoro-1-(4-isopropylbenzylene)-2-methyl-1H-inden-3-yl)ethanol-1-ol B52;

[1364] (Z)-2-(5-fluoro-1-(4-isopropylbenzylene)-2-methyl-1H-inden-3-yl)ethyl-1-aminoB53; or

[1365] (Z)-3-(5-fluoro-1-(4-isopropylbenzylene)-2-methyl-1H-inden-3-yl)propionitrile B54;

[1366] Or its tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[1367] In some embodiments, the compound of formula (IA) is one of the compounds described in U.S. Patent No. 9,611,235, the disclosure of which is incorporated herein by reference in its entirety.

[1368] In some embodiments, the fibrotic disease is liver fibrosis. In some embodiments, the fibrotic disease is a metabolic disease. In some embodiments, the fibrotic disease is liver fibrosis. In some embodiments, the fibrotic disease is non-alcoholic fatty liver disease (NAFLD). In some embodiments, the fibrotic disease is non-alcoholic steatohepatitis (NASH). In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease is primary biliary cholangitis (PBC). In some embodiments, the fibrotic disease is scleroderma.

[1369] In yet another embodiment, this document provides a method for treating, alleviating, or preventing one or more symptoms of a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (IA) or an enantiomer thereof, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[1370] In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is refractory. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is drug-resistant. In some embodiments, the cancer is multidrug-resistant.

[1371] In some implementations, the subject is a mammal. In some implementations, the subject is a human.

[1372] In some embodiments, the therapeutically effective amount of the compound described herein is in the range of about 0.1 to about 100 mg / kg per day, about 0.2 to about 50 mg / kg per day, about 0.5 to about 25 mg / kg per day, or about 1 to about 10 mg / kg per day. In one embodiment, the therapeutically effective amount is in the range of about 0.1 to about 100 mg / kg per day. In another embodiment, the therapeutically effective amount is in the range of about 0.2 to about 50 mg / kg per day. In yet another embodiment, the therapeutically effective amount is in the range of about 0.5 to about 25 mg / kg per day. In still another embodiment, the therapeutically effective amount is in the range of about 1 to about 10 mg / kg per day.

[1373] It should be understood that drug dosage can also be expressed in units other than mg / kg / day. For example, the dosage for parenteral administration can be expressed as mg / m³. 2 / day. For a given subject's height or weight, or both, those skilled in the art will readily recognize how to convert the dose from mg / kg / day to mg / m². 2 / day. For example, for a 65kg person, 1mg / m² 2 The daily dose is approximately equal to 58 mg / kg / day.

[1374] Depending on the disease to be treated and the patient's condition, the compounds described herein may be administered via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or local (e.g., transdermal or local) routes of administration. The compounds described herein may be formulated with pharmaceutically acceptable excipients, carriers, adjuvants, or mediators to suit appropriate dosage units for each route of administration.

[1375] In one embodiment, the compound provided herein is administered orally. In another embodiment, the compound provided herein is administered parenterally. In yet another embodiment, the compound provided herein is administered intravenously. In yet another embodiment, the compound provided herein is administered intramuscularly. In yet another embodiment, the compound provided herein is administered subcutaneously. In yet another embodiment, the compound provided herein is administered topically.

[1376] The compounds described herein may be delivered as a single dose, such as a single bolus, or as oral tablets or pills; or delivered over time, such as continuous infusion over time or fractional bolus administration over time. If necessary, the compounds described herein may be repeatedly administered, for example until the subject experiences stable disease or remission, or until the subject experiences disease progression or unacceptable toxicity. Disease stability or the absence of stable disease is determined by methods known in the art, such as assessing the subject's symptoms, physical examination, visualization of cancer imaging using X-ray, CAT, PET, or MRI scans, and other routinely accepted assessment methods.

[1377] The compounds described herein can be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). Furthermore, administration can be continuous (i.e., daily) or intermittent. As used herein, the terms "intermittent" or "intermittently" refer to stopping and starting at regular or irregular intervals. For example, intermittent administration of the compounds described herein may involve administering the compound one to six days per week, periodic administration (e.g., daily administration for two to eight weeks followed by a rest period of up to one week), or administration every other day.

[1378] In some embodiments, the compounds provided herein are cyclically administered to the subject. Cyclic therapy involves administering the active agent for a period of time, followed by a rest period, and repeating this sequential administration. Cyclic therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of one of the therapies, and / or improve the efficacy of the treatment.

[1379] The compounds provided herein may also be used in combination with other therapeutic agents suitable for the treatment and / or prevention of the conditions, symptoms or diseases described herein.

[1380] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more preventative and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which therapies (e.g., preventative and / or therapeutic agents) are administered to a subject with a disease or condition. A first therapy (e.g., a preventative or therapeutic agent, such as the compounds provided herein) may be administered to the subject before (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to, concurrently with, or after (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) the administration of a second therapy (e.g., a preventative or therapeutic agent). Triple therapy is also covered herein.

[1381] The route of administration of the compounds provided herein is independent of the route of administration of the second therapy. In one embodiment, the compounds provided herein are administered orally. In another embodiment, the compounds provided herein are administered intravenously. Thus, according to these embodiments, the compounds provided herein are administered orally or intravenously, while the second therapy may be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, via liposomes, by inhalation, vaginally, intraocularly, locally via catheter or stent, subcutaneously, intra-fat, intra-articularly, intrathecally, or in a sustained-release formulation. In one embodiment, the compounds provided herein and the second therapy are administered via the same route of administration (orally or intravenously). In another embodiment, the compounds provided herein are administered via one route of administration (e.g., intravenously), while the second therapy is administered via another route of administration (e.g., orally).

[1382] In one embodiment, this document provides a method for inhibiting cell growth, comprising contacting cells with an effective amount of a compound of formula (I) or (IA), or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the cells are cancer cells.

[1383] The compounds described herein may also be provided in the form of articles using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,525,907, 5,052,558, and 5,055,252. Examples of medical packaging materials include, but are not limited to, blister packs, bottles, tubing, inhalers, pumps, bags, vials, containers, syringes, and any packaging materials suitable for the selected formulation and the intended mode of administration and treatment.

[1384] In some embodiments, this document provides a kit that, when used by a licensed physician, simplifies the administration of an appropriate amount of the compound provided herein as an active ingredient to a subject. In some embodiments, the kit provided herein includes a container and a dosage form of the compound provided herein.

[1385] The kits provided herein may further include a device for administering the active ingredient. Examples of such devices include (but are not limited to) syringes, needle-free injector drop bags, patches, and inhalers. The kits provided herein may also include a sanitary pad for administering the active ingredient.

[1386] The kits provided herein may further include pharmaceutically acceptable mediators for the administration of one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reformulated for parenteral administration, the kit may contain a sealed container of a suitable mediator in which the active ingredient is dissolved to form a particle-free, sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable mediators include (but are not limited to) aqueous mediators, including (but not limited to) water for injection USP, sodium chloride injection, Ringer's solution, dextran injection, dextran and sodium chloride injection, and lactate Ringer's solution; water-miscible mediators, including (but not limited to) ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous mediators, including (but not limited to) corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[1387] The invention will be further understood through the following non-limiting embodiments.

[1388] Example

[1389] As used herein, the symbols and conventions used in these methods, procedures, and examples, whether or not specific abbreviations are specifically defined, are consistent with those used in contemporary scientific literature, such as the *Journal of the American Chemical Society*, the *Journal of Medicinal Chemistry*, or the *Journal of Biological Chemistry*. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); L (liter); mL (milliliters); μL (microliter); mol (molar); mM (millimolecular concentration); μM (micromolar concentration); mmol (millimole); eq. (equivalent); h (hour); min (minute); Et (ethyl); Me (methyl); ACN (acetonitrile); DMF (dimethylformamide); EtOH (ethanol); MeOH (methanol); EtOAc (ethyl acetate); MTBE (methyl tert-butyl ether); THF (tetrahydrofuran); AcOH (acetic acid); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DIPEA (N,N-diisopropylethylamine); Et3N (triethylamine); PyBOP (benzotriazol-1-yl-oxytripyrrolidine hexafluorophosphate); LCMS (liquid chromatography-mass spectrometry); and NMR (nuclear magnetic resonance).

[1390] For all the following examples, standard post-processing and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise specified, all reactions are carried out at room temperature. The synthetic methods described herein are intended to illustrate applicable chemistry through the ...

Claims

1. A compound, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid A1; 2-[(1Z)-5-fluoro-1-{[4-(4-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A2; 2-[(1Z)-1-({2-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A3; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(4-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A4; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid A5; 2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A6; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A7; (Z)-2-(5-fluoro-2-methyl-1-(4-(3-(trifluoromethyl)phenoxy)benzylidene)-1H-inden-3-yl)acetic acid A9; 2-[(1Z)-1-{[4-(4-ethylphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A10; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A11; 2-[(1Z)-1-{[2-chloro-4-(4-methoxyphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A12; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A14; 2-[(1Z)-1-({2-chloro-4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A15; 2-[(1Z)-1-{[4-(2,4-difluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A16; 2-[(1Z)-1-{[4-(2-bromo-4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A17; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(2,4,5-trifluorophenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A18; 3-[(1Z)-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]propionic acid A19; 2-[(1Z)-5-fluoro-1-({4-[(6-fluoro-5-methylpyridin-3-yl)oxy]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A21; (Z)-2-(5-fluoro-2-methyl-1-(4-(quinolin-5-yloxy)benzylidene)-1H-inden-3-yl)acetic acid A22; 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]-N-hydroxyacetamide A23; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A24; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetamide A25; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-methylacetamide A26; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-(2-hydroxyethyl)acetamide A27; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[methyl(phenyl)amino]phenyl}methylene)-1H-inden-3-yl]acetic acid A29; 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A30; 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(methyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A31; 2-[(1Z)-1-({4-[ethyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A32; 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(propyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A33; (Z)-2-(5-fluoro-1-(4-((4-fluorophenyl)(2-hydroxyethyl)amino)benzylidene)-2-methyl-1H-inden-3-yl)acetic acid A34; 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(4-formylphenyl)amino]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A35; 2-[(1Z)-5-fluoro-1-({4-[(4-formylphenyl)(phenyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A36; 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A38; 5-{[(1Z)-2-methyl-1-[(3-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazole A39; 5-{[(1Z)-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazolium A40; 5-{2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A42; 5-{2-[(1Z)-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A43; 5-{2-[(1Z)-2-methyl-1-({4-[4-(trifluoromethyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A45; 5-{2-[(1Z)-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A46; 3-(4-{[(1Z)-2-methyl-3-[2-(1H-1,2,3,4-tetrazo-5-yl)ethyl]-1H-indene-1-yl]methyl}phenoxy)benzylnitrile A47; 5-{2-[(1Z)-1-{[4-(3-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A48; 5-{2-[(1Z)-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A51; 5-{[(1E)-1-[(3-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazole A54; 2-[(1Z)-4,5-difluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A68; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2,4-dimethyl-1H-inden-3-yl]acetic acid A69; 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(2-hydroxyethyl)amino]phenyl}-methylene)-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A85; 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]-N-hydroxy-N-methylacetamide C1; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxy-N-methylacetamide C2; (Z)-2-(5-fluoro-2-methyl-1-(3-phenoxybenzyl)-1H-inden-3-yl)-N-hydroxy-N-methylacetamide C3; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]-N-hydroxyacetamide D1; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(tert-butyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D2; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3-(tert-butyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D3; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3,4-difluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D5; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(trifluoromethyl)phenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D7; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-(2-methyl-propyl)-1H-inden-3-yl]acetic acid D8; 2-[(1Z)-5-methoxy-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D10; 2-[(1Z)-5-methoxy-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid D11; 2-[(1Z)-1-{[2-methyl-4-(4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid D14; 2-[(1Z)-5,7-difluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D15; (Z)-2-(5-fluoro-2-methyl-1-(3-phenoxybenzylidene)-1H-inden-3-yl)acetic acid D18; 2-[(1Z)-5,7-difluoro-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D20; 2-[(1Z)-4,6-difluoro-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D21; 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-methoxyphenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D22; 2-[(1Z)-5-fluoro-1-(4-fluoro-3-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid D23; 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-chlorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D25; 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-trifluoromethylphenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D26; 2-[(1Z)-5-fluoro-2-methyl-1-({3-[3-trifluoromethylphenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D27; 2-[(1E)-5-fluoro-2-methyl-1-({4-[3,4-difluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E1; 2-[(1E)-5-fluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E2; 2-[(1E)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid E3; 2-[(1E)-5,7-difluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E4; or 2-[(1E)-5,7-difluoro-1-(3-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid E6; Or its medically acceptable salt.

2. A compound, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid A1; 2-[(1Z)-5-fluoro-1-{[4-(4-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A2; 2-[(1Z)-1-({2-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A3; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(4-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A4; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid A5; 2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A6; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A7; (Z)-2-(5-fluoro-2-methyl-1-(4-(3-(trifluoromethyl)phenoxy)benzylidene)-1H-inden-3-yl)acetic acid A9; 2-[(1Z)-1-{[4-(4-ethylphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A10; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A11; 2-[(1Z)-1-{[2-chloro-4-(4-methoxyphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A12; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A14; 2-[(1Z)-1-({2-chloro-4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A15; 2-[(1Z)-1-{[4-(2,4-difluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A16; 2-[(1Z)-1-{[4-(2-bromo-4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A17; 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(2,4,5-trifluorophenoxy)phenyl]methylene}-1H-inden-3-yl]acetic acid A18; 3-[(1Z)-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]propionic acid A19; 2-[(1Z)-5-fluoro-1-({4-[(6-fluoro-5-methylpyridin-3-yl)oxy]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A21; (Z)-2-(5-fluoro-2-methyl-1-(4-(quinolin-5-yloxy)benzylidene)-1H-inden-3-yl)acetic acid A22; 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]-N-hydroxyacetamide A23; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A24; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetamide A25; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-methylacetamide A26; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-(2-hydroxyethyl)acetamide A27; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[methyl(phenyl)amino]phenyl}methylene)-1H-inden-3-yl]acetic acid A29; 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A30; 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(methyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A31; 2-[(1Z)-1-({4-[ethyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid A32; 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(propyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A33; (Z)-2-(5-fluoro-1-(4-((4-fluorophenyl)(2-hydroxyethyl)amino)benzylidene)-2-methyl-1H-inden-3-yl)acetic acid A34; 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(4-formylphenyl)amino]phenyl}-methylene)-2-methyl-1H-inden-3-yl]acetic acid A35; 2-[(1Z)-5-fluoro-1-({4-[(4-formylphenyl)(phenyl)amino]phenyl}methylene)-2-methyl-1H-inden-3-yl]acetic acid A36; 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A38; 5-{[(1Z)-2-methyl-1-[(3-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazole A39; 5-{[(1Z)-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazolium A40; 5-{2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A42; 5-{2-[(1Z)-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A43; 5-{2-[(1Z)-2-methyl-1-({4-[4-(trifluoromethyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A45; 5-{2-[(1Z)-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A46; 3-(4-{[(1Z)-2-methyl-3-[2-(1H-1,2,3,4-tetrazo-5-yl)ethyl]-1H-indene-1-yl]methyl}phenoxy)benzylnitrile A47; 5-{2-[(1Z)-1-{[4-(3-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A48; 5-{2-[(1Z)-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-inden-3-yl]ethyl}-1H-1,2,3,4-tetrazole A51; 5-{[(1E)-1-[(3-phenoxyphenyl)methylene]-1H-inden-3-yl]methyl}-1H-1,2,3,4-tetrazole A54; 2-[(1Z)-4,5-difluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]acetic acid A68; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2,4-dimethyl-1H-inden-3-yl]acetic acid A69; or 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(2-hydroxyethyl)amino]phenyl}-methylene)-2-methyl-1H-inden-3-yl]-N-hydroxyacetamide A85; Or its medically acceptable salt.

3. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-indene-3-yl]acetic acid A1 or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-{[4-(4-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]acetic acid A2 or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-({2-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A3 or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(4-methylphenoxy)phenyl]methylene}-1H-indene-3-yl]acetic acid A4 or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-indene-3-yl]acetic acid A5 or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A6 or a pharmaceutically acceptable salt thereof.

9. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-indene-3-yl]acetic acid A7 or a pharmaceutically acceptable salt thereof.

10. The compound of claim 2, wherein the compound is (Z)-2-(5-fluoro-2-methyl-1-(4-(3-(trifluoromethyl)phenoxy)benzyl)-1H-inden-3-yl)acetic acid A9 or a pharmaceutically acceptable salt thereof.

11. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-{[4-(4-ethylphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A10 or a pharmaceutically acceptable salt thereof.

12. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]acetic acid Al11 or a pharmaceutically acceptable salt thereof.

13. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-{[2-chloro-4-(4-methoxyphenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A12 or a pharmaceutically acceptable salt thereof.

14. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-indene-3-yl]acetic acid A14 or a pharmaceutically acceptable salt thereof.

15. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-({2-chloro-4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A15 or a pharmaceutically acceptable salt thereof.

16. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-{[4-(2,4-difluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A16 or a pharmaceutically acceptable salt thereof.

17. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-{[4-(2-bromo-4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A17 or a pharmaceutically acceptable salt thereof.

18. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-{[4-(2,4,5-trifluorophenoxy)phenyl]methylene}-1H-indene-3-yl]acetic acid A18 or a pharmaceutically acceptable salt thereof.

19. The compound of claim 2, wherein the compound is: 3-[(1Z)-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]propionic acid A19 or a pharmaceutically acceptable salt thereof.

20. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-({4-[(6-fluoro-5-methylpyridin-3-yl)oxy]phenyl}-methylene)-2-methyl-1H-indene-3-yl]acetic acid A21 or a pharmaceutically acceptable salt thereof.

21. The compound of claim 2, wherein the compound is (Z)-2-(5-fluoro-2-methyl-1-(4-(quinolin-5-yloxy)benzylidene)-1H-indene-3-yl)acetic acid A22 or a pharmaceutically acceptable salt thereof.

22. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-indene-3-yl]-N-hydroxyacetamide A23 or a pharmaceutically acceptable salt thereof.

23. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]-N-hydroxyacetamide A24 or a pharmaceutically acceptable salt thereof.

24. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]acetamide A25 or a pharmaceutically acceptable salt thereof.

25. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]-N-methylacetamide A26 or a pharmaceutically acceptable salt thereof.

26. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]-N-(2-hydroxyethyl)acetamide A27 or a pharmaceutically acceptable salt thereof.

27. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-({4-[methyl(phenyl)amino]phenyl}methylene)-1H-indene-3-yl]acetic acid A29 or a pharmaceutically acceptable salt thereof.

28. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A30 or a pharmaceutically acceptable salt thereof.

29. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(methyl)amino]phenyl}methylene)-2-methyl-1H-indene-3-yl]acetic acid A31 or a pharmaceutically acceptable salt thereof.

30. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-({4-[ethyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-indene-3-yl]acetic acid A32 or a pharmaceutically acceptable salt thereof.

31. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(propyl)amino]phenyl}methylene)-2-methyl-1H-indene-3-yl]acetic acid A33 or a pharmaceutically acceptable salt thereof.

32. The compound of claim 2, wherein the compound is (Z)-2-(5-fluoro-1-(4-((4-fluorophenyl)(2-hydroxyethyl)amino)benzylidene)-2-methyl-1H-indene-3-yl)acetic acid A34 or a pharmaceutically acceptable salt thereof.

33. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(4-formylphenyl)amino]phenyl}-methylene)-2-methyl-1H-indene-3-yl]acetic acid A35 or a pharmaceutically acceptable salt thereof.

34. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-({4-[(4-formylphenyl)(phenyl)amino]phenyl}methylene)-2-methyl-1H-indene-3-yl]acetic acid A36 or a pharmaceutically acceptable salt thereof.

35. The compound of claim 2, wherein the compound is: 2-[(1Z)-1-({4-[benzyl(4-fluorophenyl)amino]phenyl}methylene)-5-fluoro-2-methyl-1H-indene-3-yl]-N-hydroxyacetamide A38 or a pharmaceutically acceptable salt thereof.

36. The compound of claim 2, wherein the compound is: 5-{[(1Z)-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-indene-3-yl]methyl}-1H-1,2,3,4-tetrazolium A40 or a pharmaceutically acceptable salt thereof.

37. The compound of claim 2, wherein the compound is: 5-{2-[(1Z)-1-{[4-(4-bromophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]ethyl}-1H-1,2,3,4-tetraazole A42 or a pharmaceutically acceptable salt thereof.

38. The compound of claim 2, wherein the compound is: 5-{2-[(1Z)-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-indene-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A43 or a pharmaceutically acceptable salt thereof.

39. The compound of claim 2, wherein the compound is: 5-{2-[(1Z)-2-methyl-1-({4-[4-(trifluoromethyl)phenoxy]phenyl}methylene)-1H-indene-3-yl]ethyl}-1H-1,2,3,4-tetraazole A45 or a pharmaceutically acceptable salt thereof.

40. The compound of claim 2, wherein the compound is: 5-{2-[(1Z)-2-methyl-1-{[4-(3-methylphenoxy)phenyl]methylene}-1H-indene-3-yl]ethyl}-1H-1,2,3,4-tetraazole A46 or a pharmaceutically acceptable salt thereof.

41. The compound of claim 2, wherein the compound is: 3-(4-{[(1Z)-2-methyl-3-[2-(1H-1,2,3,4-tetrazo-5-yl)ethyl]-1H-indene-1-yl]methyl}phenoxy)benzylnitrile A47 or a pharmaceutically acceptable salt thereof.

42. The compound of claim 2, wherein the compound is: 5-{2-[(1Z)-1-{[4-(3-methoxyphenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]ethyl}-1H-1,2,3,4-tetrazolium A48 or a pharmaceutically acceptable salt thereof.

43. The compound of claim 2, wherein the compound is: 5-{2-[(1Z)-2-methyl-1-{[4-(naphthyl-2-yloxy)phenyl]methylene}-1H-indene-3-yl]ethyl}-1H-1,2,3,4-tetraazole A51 or a pharmaceutically acceptable salt thereof.

44. The compound of claim 2, wherein the compound is: 5-{[(1E)-1-[(3-phenoxyphenyl)methylene]-1H-indene-3-yl]methyl}-1H-1,2,3,4-tetraazole A54 or a pharmaceutically acceptable salt thereof.

45. The compound of claim 2, wherein the compound is: 2-[(1Z)-4,5-difluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-indene-3-yl]acetic acid A68 or a pharmaceutically acceptable salt thereof.

46. ​​The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2,4-dimethyl-1H-indene-3-yl]acetic acid A69 or a pharmaceutically acceptable salt thereof.

47. The compound of claim 2, wherein the compound is: 2-[(1Z)-5-fluoro-1-({4-[(4-fluorophenyl)(2-hydroxyethyl)amino]phenyl}-methylene)-2-methyl-1H-indene-3-yl]-N-hydroxyacetamide A85 or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]-N-hydroxy-N-methylacetamide C1; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-methyl-1H-inden-3-yl]-N-hydroxy-N-methylacetamide C2; ​​or (Z)-2-(5-fluoro-2-methyl-1-(3-phenoxybenzyl)-1H-inden-3-yl)-N-hydroxy-N-methylacetamide C3; Or its medically acceptable salt.

49. The compound of claim 1, wherein the compound is: 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(propane-2-yl)phenoxy]phenyl}methylene)-1H-inden-3-yl]-N-hydroxyacetamide D1; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(tert-butyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D2; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3-(tert-butyl)phenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D3; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[3,4-difluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D5; 2-[(1Z)-5-fluoro-2-methyl-1-({4-[4-(trifluoromethyl)phenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D7; 2-[(1Z)-5-fluoro-1-{[4-(4-fluorophenoxy)phenyl]methylene}-2-(2-methyl-propyl)-1H-inden-3-yl]acetic acid D8; 2-[(1Z)-5-methoxy-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D10; 2-[(1Z)-5-methoxy-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid D11; 2-[(1Z)-1-{[2-methyl-4-(4-fluorophenoxy)phenyl]methylene}-5-fluoro-2-methyl-1H-inden-3-yl]acetic acid D14; 2-[(1Z)-5,7-difluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D15; (Z)-2-(5-fluoro-2-methyl-1-(3-phenoxybenzylidene)-1H-inden-3-yl)acetic acid D18; 2-[(1Z)-5,7-difluoro-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D20; 2-[(1Z)-4,6-difluoro-1-(3-(phenoxy)benzyl)-2-methyl-1H-inden-3-yl]-acetic acid D21; 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-methoxyphenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D22; 2-[(1Z)-5-fluoro-1-(4-fluoro-3-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid D23; 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-chlorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid D25; 2-[(1Z)-5-fluoro-2-methyl-1-({3-[4-trifluoromethylphenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D26; or 2-[(1Z)-5-fluoro-2-methyl-1-({3-[3-trifluoromethylphenoxy]phenyl}-methylene)-1H-inden-3-yl]acetic acid D27; Or its medically acceptable salt.

50. The compound of claim 1, wherein the compound is: 2-[(1E)-5-fluoro-2-methyl-1-({4-[3,4-difluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E1; 2-[(1E)-5-fluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E2; 2-[(1E)-5-fluoro-2-methyl-1-[(4-phenoxyphenyl)methylene]-1H-inden-3-yl]acetic acid E3; 2-[(1E)-5,7-difluoro-2-methyl-1-({4-[4-fluorophenoxy]phenyl}methylene)-1H-inden-3-yl]acetic acid E4; or 2-[(1E)-5,7-difluoro-1-(3-(phenoxy)benzylidene)-2-methyl-1H-inden-3-yl]-acetic acid E6; Or its medically acceptable salt.

51. A pharmaceutical composition for treating liver fibrosis, comprising a compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

52. Use of the compound of any one of claims 1 to 50 in the preparation of a medicament for treating, preventing or alleviating liver fibrosis in a subject.

53. The application according to claim 52, wherein the liver fibrosis disease is non-alcoholic fatty liver disease (NAFLD).

54. The application according to claim 52, wherein the liver fibrosis disease is non-alcoholic steatohepatitis (NASH).

55. The application according to claim 52, wherein the subject is a human.

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