Hormone receptor modulators for the treatment of metabolic conditions and disorders

Abstract

This invention relates to an activator of FXR, which can be used to treat autoimmune diseases, liver diseases, intestinal diseases, kidney diseases, cancer, and other diseases in which FXR plays a role, and has the formula (I): wherein L1, A, X1, X2, R 1 R 2 and R 3 As described in this article.

Description

[0001] This application is a divisional application of Chinese patent application No. 201780065305.2, entitled "Hormonal Receptor Modulator for Treating Metabolic Disorders and Diseases", filed on August 23, 2017 (PCT application No. PCT / US2017 / 048281).

[0002] Related applications

[0003] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 378,625, filed August 23, 2016; and U.S. Provisional Application No. 62 / 532,983, filed July 14, 2017, the contents of each of which are hereby incorporated by reference in their entirety.

[0004] Description of the text file submitted electronically

[0005] The contents of the text file submitted electronically are incorporated herein by reference in full: a computer-readable copy of the sequence list (filename: ARDE_024_02WO_SeqList.txt, date of submission: August 23, 2017, file size: 4 kilobytes). Technical Field

[0006] This invention relates to modulators of the nuclear hormone receptor—farnesoid X receptor (FXR)—which can be used to treat diseases or conditions associated with the FXR protein. Specifically, this invention relates to compounds and compositions that modulate FXR, methods for treating diseases or conditions associated with FXR, and methods for synthesizing these compounds. Background Technology

[0007] FXRs are ligand-activated transcription factors. Upon ligand binding, FXRs either bind to DNA as monomers at FXR response elements (FXREs) or form heterodimers with retinoid X receptors (RXRs), subsequently binding to FXREs to regulate the transcription of a variety of target genes. To date, more than 40 FXR target genes have been identified, involved in a wide range of physiological functions, including bile acid homeostasis (i.e., BACS, BAAT, BSEP, FGF15 / 19, etc.), cholesterol and lipoprotein metabolism (i.e., apolipoproteins CI, II, IV, E, MDR3, human complement C3, ApoA-1, hepatic lipase, SREPB-1c), glucose metabolism (i.e., PEPCK, GSK3, AKR1B7, GLUT4, G6Pase), and xenobiotic metabolism (i.e., GSTα3, GSTα4, GSTμ1, GSTμ3, SULT1A1, SULT1A2). In addition to regulating metabolism-related genes, recent results have confirmed that FXR is a regulator of cellular inflammation and immune responses. FXR activation can provide anti-inflammatory effects by negatively regulating the nuclear factor κB (NFκB) pathway, reducing the expression of NFκB and many pro-inflammatory cytokines associated with this pathway (Matsubara, T. et al., “FXR signaling in the enterohepatic system,” Mol. Cell Endocrinol. 2013, 368, 17-29; Moschetta, A., “Deciphering the nuclear bile acid receptor FXR paradigm,” Nucl. Recept. Signal. 2010, 8, e005; Huang, W. et al., “FXR: a metabolic regulator and cell protector,” Cell Res. 2008, 1087-1095).

[0008] FXR plays a crucial role in the synthesis, transport, and metabolism of bile acids (BA), as well as in many physiological and pathophysiological conditions involving BA. In the liver, activation of FXR has been shown to lead to increased expression of short heterodimeric chaperones (SHPs), which in turn inactivates liver receptor homolog-1 (LRH-1) and inhibits cholesterol 7-α-hydroxylase (CYP7A1), the rate-limiting enzyme in the first step of primary bile acid biosynthesis from cholesterol, thereby reducing bile acid production. Activation of FXR in the liver has also been shown to downregulate transporters such as sodium taurocholate cotransport peptide (NTCP) and organic anion transport peptide (OATP), preventing bile acid uptake into the liver. BA accumulation in the liver plays a critical role in cholestasis-related liver injury, and pharmacological activation of FXR via synthetic ligands may provide a therapeutic intervention.

[0009] FXR has also been shown to play an important role in the control of inflammation in various liver and intestinal diseases (Shaik, FB et al., “Role of farnesoid X receptor in inflammation and resolution,” Inflamm. Res. 2015, 64, 9-20). Activation of FXR has been shown to inhibit the NFκB pathway, a typical pro-inflammatory signaling pathway, and suppress the expression of key cytokines such as TNFα, IL-1β, and IL-6. In the colon of FXR knockout mice, increased expression of pro-inflammatory cytokines (e.g., TNFα, IL-1β, IFNγ) and pro-fibrotic genes (i.e., collagen α1, TIMP-1, and αSMA) has been observed, indicating dysregulation of intestinal immunity and tissue remodeling. It has been shown that activating FXR with FXR activators in a TNBS-induced mouse model of inflammatory bowel disease can inhibit the aforementioned cytokines, prevent inflammation and fibrosis, and prevent subsequent colitis (Vavassori, P., "The bile acid receptor FXR is a modulator of intestinal innate immunity," J. Immunol. 2009, 183, 6251-6261). Furthermore, in a rat model of cholestatic liver injury (biliary duct ligation), treatment with FXR agonists reduced NK cell and INFγ expression, leading to decreased intestinal inflammation, reduced bacterial translocation, and overall improvement of intestinal barrier function (Verbeke, L., "The FXR agonistobeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats," Am. J. Pathol. 2015, 185, 409-419).

[0010] Activating FXR with small molecule activators has the potential to treat a range of diseases, including bile acid-related disorders, metabolic syndrome, type 2 diabetes, hyperlipidemia, hypertriglyceridemia, primary biliary cirrhosis (PBC), fatty liver disease, non-alcoholic steatohepatitis (NASH), inflammatory autoimmune diseases, Crohn's disease, multiple sclerosis, atherosclerosis, liver and colon cancer, and other conditions. However, known FXR activators have been shown to have toxicity, therapeutically limiting side effects, and other problems. For these reasons, the development of novel and effective small molecule FXR activators remains necessary. Summary of the Invention

[0011] One aspect of the invention provides a compound of formula I:

[0012]

[0013] or its salt,

[0014] in:

[0015] One of X1 or X2 is NR x or N + (O - )R x And the other is CHR y Or C(O);

[0016] R x yes

[0017] R y It is H, alkyl, cycloalkyl or cycloalkylalkyl, wherein the alkyl, cycloalkyl and cycloalkylalkyl are optionally substituted with halogen or alkoxy;

[0018] L1 is -(CH2) m (C=O)- or -(CH2) p -;

[0019] L2 is a bond or –S(O)2-;

[0020] A is a cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally composed of one or more R groups. 7 replace;

[0021] B is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally influenced by one or more R groups. 5 replace;

[0022] R 1 and R 2 Each is independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, wherein the cycloalkyl group is optionally influenced by one or more R groups. 9 replace;

[0023] Or when A is a cycloalkyl or heterocycloalkyl, R 1 and R 2 When bonded to the same carbon atom, they form together, optionally bound by one or more R atoms. 8 Substituted spirocycloalkyl ring; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 When bonded to the same atom, they form together, optionally bound by one or more R atoms. 8 Substituted spirochetal alkyl rings; or R 1 and R 2When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted cycloalkyl ring; or R 1 and R 2 When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted heterocyclic alkyl rings; or R 1 and R 2 When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted aryl ring; or R 1 and R 2 When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted heteroaryl ring; or when A is a cycloalkyl or heterocycloalkyl group, R 1 and R 2 When on non-adjacent atoms, together with the atoms they are connected to, they form an optional structure controlled by one or more R atoms. 8 Substituted cycloalkyl ring; or when cycloalkyl or heteroalkyl, R 1 and R 2 When on non-adjacent atoms, together with the atoms they are connected to, they form an optional structure controlled by one or more R atoms. 8 Substituted heterocyclic alkyl rings;

[0024] R 3 It is an alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl or cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and -OH.

[0025] R 4 It is COOR 6a -(CH2) n -COOR 6a CONR 6b OH, CONR 6b R 6c CO NH(CH2) n COOR 6a CONH(CH2) n R 6a -(CH2) n CONH(CH2) n R 6a CONR 6b SO2R 6d CONR 6b SO2(CH2) n R 6d -(CH2) n -CONR6b SO2R 6d CONR 6b SO2(CH2) n N(CO)R 6d CONH(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g )2、CO NR 6b (CH2) n PO(OR 6g )2. CONR 6b SO2(CH2) n N + (R 6f 3. COO(CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a SO2R 6e CN, -(CH2) n -NR 6b C(O)R 6c -(CH2) n -N(OH)-C(O)R 6c , oxo, alkyl, cycloalkyl, -(CH2) n -cycloalkyl, heterocycloalkyl, -(CH2) n -Heterocyclic alkyl, heteroaryl, or -(CH2) n -Heteroaryl; wherein the alkyl, cycloalkyl, -(CH2) n -cycloalkyl, heterocycloalkyl, -(CH2) n -Heterocyclic alkyl groups, heteroaryl groups, and -(CH2) n -Hybrid aryl groups are selectively controlled by COOR 6a -(CH2) n -COOR 6a CONR 6b OH, CONR 6b R 6c CONH(CH2) n COOR 6a CONH(CH2) n R 6a -(CH2) n CONH(CH2) n R 6a CONR 6b SO2R 6d CONR6b SO2(CH2) n R 6d -(CH2) n -CONR 6b SO2R 6d CON R 6b SO2(CH2) n N(CO)R 6d CONH(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g 2. COO(CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a SO2R 6e CN, -(CH2) n -NR 6b C(O)R 6c Or -(CH2) n -N(OH)-C(O)R 6c replace;

[0026] Each R 5 Each time it appears, it is independently a halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, spiroheteroalkyl, -O-cycloalkyl, -O-heteroalkyl, aryl, heteroalkyl or heteroaryl, wherein the cycloalkyl, aryl, heteroalkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, alkyl, haloalkyl, alkoxy and haloalkoxy;

[0027] R 6a It is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally selected by one or more of the following independently: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, NR. 6b R 6c SO2NR 6b R 6c Substitution with -OH substituents;

[0028] R 6b and R 6c Each of the following is independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally substituted by one or more substituents selected independently from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and -OH.

[0029] R 6d It is an alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally selected by one or more of the following independently: halogen, COOH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, -O-CO-alkyl, -O-COcycloalkyl, -O-CO-alkyl-COOH, NR 6b R 6c NR 6f CO-alkyl, NR 6f Substitution with CO-alkoxy, cycloalkyl, heterocycloalkyl and -OH substituents;

[0030] R 6e It is -OH, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and -OH;

[0031] R 6f It is an alkyl or haloalkyl group;

[0032] R 6g It is H or an alkyl group optionally substituted with -O-CO-alkyl;

[0033] Each R 7 Each time it appears, it is independently OH, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN;

[0034] Each R 8 Each time it appears, it is independently alkyl, alkoxy, haloalkyl, haloalkoxy, halogen or –OH;

[0035] Each R 9 Each time it appears, it is independently alkyl, alkoxy, haloalkyl, haloalkoxy, halogen or –OH;

[0036] m is 0, 1, or 2;

[0037] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0038] p is 1 or 2.

[0039] Another aspect of the invention relates to a method for treating a disease or condition in which FXR functions. The method comprises administering to a patient requiring treatment of a disease or condition in which FXR functions an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0040] Another aspect of the invention relates to a method for regulating FXR. The method involves administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer to a patient in need.

[0041] Another aspect of the invention relates to a method for activating FXR. The method comprises administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0042] Another aspect of the invention relates to a method for treating liver disease. The method comprises administering to a patient requiring treatment of liver disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0043] Another aspect of the invention relates to a method for treating enteropathy. The method comprises administering to a patient requiring treatment of enteropathy an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0044] Another aspect of the invention relates to a method for treating kidney disease. The method comprises administering to a patient requiring treatment of kidney disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0045] Another aspect of the invention relates to a method for treating autoimmune diseases. The method comprises administering to a patient requiring treatment for an autoimmune disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0046] Another aspect of the invention relates to a method for treating cancer. The method comprises administering to a patient requiring cancer treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0047] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0048] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating diseases associated with FXR activation.

[0049] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating diseases in which FXR functions.

[0050] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating liver diseases.

[0051] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating enteropathy.

[0052] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for the treatment of kidney disease.

[0053] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for the treatment of autoimmune diseases.

[0054] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating cancer.

[0055] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment of diseases associated with FXR activation.

[0056] Another aspect of the invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment of diseases in which FXR functions.

[0057] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment of liver diseases.

[0058] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment of enteropathy.

[0059] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment of kidney disease.

[0060] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment of autoimmune diseases.

[0061] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment of cancer.

[0062] The present invention further provides a method for treating diseases or conditions related to the regulation of FXR, including but not limited to liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof to a patient suffering from at least one of the diseases or conditions.

[0063] This invention provides activators of FXR, which are therapeutic agents used in the treatment of diseases such as liver disease, intestinal disease, kidney disease, autoimmune diseases, and cancer. Ultimately, this invention provides the medical community with new pharmacological strategies for treating diseases and conditions associated with the regulation of FXR. Attached Figure Description

[0064] Figure 1 Body weight of DSS colitis model mice measured 9 days before final necropsy. Mice were administered mediators containing and without the DSS and FXR agonist compounds OCA, FXR1, and FXR2.

[0065] Figure 2 DAI score measured 9 days prior to final autopsy. DSS significantly increased DAI scores compared to control mice without DSS. FXR1 significantly attenuated DSS-induced DAI score increases at 0.3 mg / kg and 1 mg / kg.

[0066] Figure 3 Measured values ​​of pro-inflammatory cytokines in the colon on day 9. Compared with control mice without DSS, DSS administration significantly increased the levels of the inflammatory cytokine IL-6 in the colon. Figure 3 A in IL-1β Figure 3 B), TNFα ( Figure 3 C in IFNγ Figure 3 D) and KC / Gro ( Figure 3The content of E in the FXR agonist compounds FXR1 and FXR2 of the present invention significantly reduced the levels of all these pro-inflammatory cytokines in the colon of DSS mice at 1 mg / kg.

[0067] Figure 4 Histological colitis score on day 9. At 1 mg / kg, DSS administration significantly increased the histological colitis score compared with control mice without DSS, while FXR1 significantly decreased the histological colitis score in control mice.

[0068] Figure 5 Histological presence of epithelial erosion in the colon on day 9. At 1 mg / kg, DSS administration significantly increased the presence of histologically observed epithelial erosion (mucosal defects), while FXR1 significantly prevented epithelial erosion (mucosal defects).

[0069] Figure 6 : Urinary sucralose excretion as a marker of colonic permeability in HFCC mice. A significant increase in urinary sucralose excretion indicates increased colonic permeability in HFCC-fed mice compared to NC control mice. FXR1 normalized urinary sucralose excretion in HFCC-fed mice in a dose-dependent manner, indicating restoration of colonic permeability. Detailed Implementation

[0070] This invention relates to compounds and compositions capable of modulating the activity of FXRs. The key point of this invention is a method for treating, preventing, or alleviating diseases or conditions in which FXRs play a role by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof to a patient in need. The methods of this invention can be used to treat a variety of FXR-dependent diseases and conditions by increasing the activity of the nuclear receptor FXR. Activation or modulation of FXR provides novel methods for treating, preventing, or alleviating diseases including (but not limited to) liver diseases, intestinal diseases, kidney diseases, autoimmune diseases, and cancer.

[0071] Compounds of formula (I) are described in the first aspect of the invention:

[0072]

[0073] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers, of which L1, A, X1, X2, R 1 R 2 and R 3 As described in this article.

[0074] The details of the invention are set forth in the appended specification. Evident methods and materials are now described, but similar or equivalent methods and materials may also be used to practice or test the invention. Other features, objects, and advantages of the invention will become apparent from the specification and claims. In the specification and appended claims, the singular form includes the plural unless the context clearly specifies otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety.

[0075] definition

[0076] The article “a (kind)” is used in this text to refer to one or more (e.g., at least one) grammatical objects. For example, “a element” means one element or more elements.

[0077] Unless otherwise stated, the term "and / or" is used herein to mean "and" or "or".

[0078] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., alkyl) may (but is not required to) be bonded with other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" indicates that a given chemical moiety may contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents for optionally replacing the groups include, but are not limited to, halogens, oxo groups, -OH groups, -CN groups, -COOH groups, -CH2CN groups, -O-(C1-C6)alkyl groups, (C1-C6)alkyl groups, (C1-C6)alkenyl groups, (C1-C6)ynyl groups, (C1-C6)hydroxyalkyl groups, (C1-C6)alkoxy groups, (C1-C6)haloalkyl groups, (C1-C6)haloalkoxy groups, (C3-C7)cycloalkyl groups, aryl groups, heterocycloalkyl groups, heteroaryl groups, -O-(C2-C6)alkenyl groups, -O-(C2-C6)ynyl groups, and (C2-C6)... Alkenyl, (C2-C6)alkynyl, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)2NH(C1-C6)alkyl, and S(O)2N((C1-C6)alkyl)2. As used herein, "optionally substituted" also refers to substituted or unsubstituted compounds in the following senses.

[0079] As used herein, the term “substituted” means that the specified group or portion has one or more suitable substituents, wherein the substituents may be attached to the specified group or portion at one or more positions. For example, an aryl group substituted with a cycloalkyl group may mean that the cycloalkyl group is attached to one atom of the aryl group by a bond or by fusion with the aryl group and sharing two or more common atoms.

[0080] As used herein, the term “unsubstituted” means that the specified group does not contain substituents.

[0081] Unless otherwise specifically defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. In the case of two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted at any connection point with one or more substituents (e.g., one to five substituents). Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)2NH(C1-C6)alkyl, and -S(O)2N((C1-C6)alkyl)2. Furthermore, when two fused rings are present, the aryl group defined herein may be fused with an unsaturated or partially saturated ring, or with a fully saturated ring. Exemplary cyclic systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, phenalenyl, phenanthyl, indanyl, indanyl, tetrahydronaphthyl, tetrahydrobenzoannulenyl, etc.

[0082] Unless otherwise specifically defined, “heteroaryl” refers to a monovalent monocyclic aromatic or polycyclic aromatic group with 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, and S, with the remaining ring atom being C. As defined herein, a heteroaryl also refers to a bicyclic heteroaryl group, wherein the heteroatoms are selected from N, O, and S. The aromatic group may optionally be independently substituted by one or more substituents described herein. Examples include, but are not limited to, furanyl, thiophene, pyrrole, pyridinyl, pyrazolyl, pyrimidinyl, imidazole, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophene-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazole[1,2-b]pyrazolyl, furan[2,3]... -c]pyridyl, imidazo[1,2-a]pyridyl, indazole, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indole, indolinyl, indolinone yl), dihydrobenzothiopheneyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthidyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazole Linolyl, tetrazo[1,5-a]pyridyl, [1,2,4]trizo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, furano[2,3-b]pyridyl, benzothiophenyl, 1,5-naphthidyl, furano[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyridyl [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl and their derivatives. Furthermore, when containing two fused rings, the heteroaryl groups defined herein may be fused with an unsaturated or partially saturated ring containing a heteroatom selected from N, O, and S; or with a fully saturated ring containing a heteroatom selected from N, O, and S. Exemplary ring systems of these heteroaryl groups include indololinyl, indololinone, dihydrobenzothio, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, indololinyl, indolyl, and dihydrobenzoxyl.

[0083] Halogens, or "halogenated" halogens, refer to fluorine, chlorine, bromine, or iodine.

[0084] "Alkyl" alone or in combination with other groups (e.g., alkoxy, haloalkyl, etc.) refers to a straight-chain or branched saturated or unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. In one embodiment, the "alkyl" is fully saturated.

[0085] "Alkoxy" refers to a straight-chain or branched saturated or unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms, such as -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy. In one embodiment, the "alkoxy" is fully saturated.

[0086] "Alkoxyalkoxy" refers to an alkoxy group as defined herein, which is substituted with an alkoxy group, such as -O(alkyl)-O-(alkyl). Examples of alkoxyalkoxy groups include, but are not limited to, methoxymethoxy, ethoxyethoxy, propoxymethoxy, or ethoxymethoxy.

[0087] "Alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An alkenyl contains at least one double bond in its chain. The double bond in an alkenyl can be unconjugated or conjugated with another unsaturated group. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Alkenyl groups can be unsubstituted or substituted. Alkenyl groups as defined herein can be straight-chain or branched.

[0088] "Alynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An alkynyl group contains at least one triple bond in its chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl. Alynyl groups can be unsubstituted or substituted.

[0089] "Cycloalkyl" or "carbocyclic" refers to a monocyclic or polycyclic saturated or unsaturated (fully or partially) non-aromatic carbocyclic ring containing 3 to 18 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, bicyclo[2.2.2]octyl or bicyclo[2.2.2]octenyl and their derivatives. C3-C8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. Cycloalkyl can be fused (e.g., decahydronaphthalene) or bridged (e.g., norbornane). In one embodiment, "cycloalkyl" is fully saturated.

[0090] "Heterocyclic group" or "heterocyclic alkyl group" is a monocyclic or polycyclic ring containing a carbon and a heteroatom selected from oxygen, nitrogen, or sulfur, wherein there is no shared delocalized π electron (aromaticity) between the ring carbons or heteroatoms. In one embodiment, the heterocyclic alkyl group comprises one or two 4- to 7-membered rings and 1-4 heteroatoms or heteroaryl groups selected from N, O, and S. The heterocyclic alkyl ring structure may be substituted by one or more substituents. Examples of heterocyclic rings include, but are not limited to, oxacyclobutane, azacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolinyl, thiazolinyl, thiazolinyl, pyranyl, thiaranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazine, aza... azepinyl, oxo oxepinyl, diaza The compounds include tropanyl, oxazolidinone, and homotropanyl. In one embodiment, the "heterocyclic" or "heterocyclic alkyl" is fully saturated.

[0091] The term "hydroxyalkyl" refers to an alkyl group as defined above, wherein the alkyl group is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2-, and CH3-CH(OH)-. In one embodiment, the "hydroxyalkyl" is fully saturated.

[0092] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, which is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. In one embodiment, the "haloalkyl" is fully saturated.

[0093] As used herein, the term "haloalkoxy" refers to an alkoxy group as defined herein, which is substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. In one embodiment, the "haloalkoxy" is fully saturated.

[0094] As used herein, the term "cyano" refers to a substituent having a carbon atom connected to a nitrogen atom via a triple bond, such as C≡N.

[0095] As used in this article, the term "oxo" refers to the "=O" group.

[0096] "Spirocycloalkyl" or "spirocycloyl" indicates a bicyclic ring system of two carbon sources linked by a single atom. The rings can differ in size and properties, or they can be the same in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spiroctane, spirononane, or spirodecane. One or both rings of the spirocycle may be fused with another ring of carbocyclic, heterocyclic, aromatic, or heteroaromatic rings. One or more carbon atoms in the spirocycle may be substituted with heteroatoms (e.g., O, N, S, or P). (C3-C) 12 Spirocycloalkyl is a spirocyclic ring containing between 3 and 12 carbon atoms. One or more carbon atoms may be substituted with heteroatoms. In one embodiment, "spirocycloalkyl" or "spirocyclic" is fully saturated.

[0097] The term "spiroheteroalkyl" or "spiroheterocyclic" is understood to mean a spirocycle in which at least one ring is a heterocycle (e.g., at least one ring is furanyl, morpholinyl, or piperidinyl). In one embodiment, "spiroheteroalkyl" or "spiroheterocyclic" is fully saturated.

[0098] As defined herein, “GW4064” is an FXR agonist compound having the following structure.

[0099]

[0100] The term "solvate" refers to a complex with variable stoichiometry formed by a solute and a solvent. For the purposes of this invention, such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water as well as compositions containing a variable amount of water.

[0101] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. Structural differences may lie in their configuration (geometric isomers) or ability to rotate the plane of polarization (stereoisomers). Regarding stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0102] The present invention also includes pharmaceutical compositions comprising an effective amount of the disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts such as acetates, 4,4-diaminostilbene-2,2-disulfonate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium salt, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, estolate, ethanesulfonate, fumarate, fiunarate, gluconate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, and hydrochloric acid. Salts, hydroxynaphthates, iodides, isothiosulfates, lactates, lacturonates, laurates, magnesium salts, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucilages, napsylates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthate, oleates, oxalates, palmitates, bis(hydroxynaphthate) (1,1-methylene-bis-2-hydroxy-3-naphthate, ibuprofen), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, subacetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, teoclates, triethiodide, and valerates.

[0103] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0104] "Effective amount" is, when used in combination with a compound, an effective amount for the treatment or prevention of a disease in a subject as described in this article.

[0105] As used herein, the term “carrier” encompasses carriers, excipients, and diluents, and refers to a substance, composition, or medium relating to the transport or delivery of a pharmaceutical agent from one organ or part of a subject’s body to another organ or part of a subject’s body, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance.

[0106] The term "treatment" in relation to a subject refers to the improvement of at least one symptom of the subject's condition. Treatment includes curing, improving, or at least partially alleviating the condition.

[0107] Unless otherwise stated, the term “symptom” is used in this document to mean the term disease, symptom or patient, and may be used interchangeably with them.

[0108] As used herein, “administer” means the direct administration of a disclosed compound or a pharmaceutically acceptable salt or composition of a disclosed compound to a subject, or the administration of a prodrug derivative or analog or composition of a compound or a pharmaceutically acceptable salt of a compound to a subject, which may form an equivalent amount of the active compound in the subject’s body.

[0109] As used herein, the term "prodrug" refers to a compound that can be converted into a known compound in vivo via metabolism (e.g., through hydrolysis).

[0110] The term "autoimmune disease" includes, but is not limited to, the following autoimmune diseases: amyotrophic lateral sclerosis (ALS), autoimmune atherosclerosis, autoimmune diabetes insipidus, autoimmune gastritis, autoimmune hepatitis, autoimmune interstitial cystitis, autoimmune uveitis, autoimmune vasculitis, Behcet's disease, celiac disease, chronic fatigue syndrome, Crohn's disease, chronic active hepatitis, diabetes, multiple sclerosis, PBC, primary biliary cirrhosis, primary glomerulonephritis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, ulcerative colitis, and vasculitis.

[0111] The term "nephropathy" includes, but is not limited to, the following kidney diseases: fibrotic nephropathy and diabetic nephropathy.

[0112] The term "liver disease" includes, but is not limited to, the following liver diseases: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, intra- and extra-cholestasis, portal hypertension (PAH), obesity, and type 2 diabetes.

[0113] The term "intestinal disease" includes, but is not limited to, the following intestinal diseases: inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, celiac disease, and bile acid diarrhea.

[0114] The term "cancer" includes, but is not limited to, the following cancers: hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, esophageal cancer, gastric cancer / gastriccarcinoma, colon cancer, gastrointestinal stromal carcinoma, cholangiocarcinoma, renal carcinoma, breast cancer, and Barrett's esophagus and combinations thereof.

[0115] This invention relates to compounds capable of activating FXR, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which may be used to treat diseases and conditions related to the regulation of FXR proteins or receptors. The invention further relates to compounds that can be used to activate FXR, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0116] This invention relates to compounds capable of activating FXR, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which can be used to treat diseases and conditions related to the regulation of FXR proteins. The invention further relates to compounds that can be used to activate FXR, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0117] In one embodiment, the compound of the present invention has the structure of formula (I):

[0118]

[0119] or its salt, wherein:

[0120] One of X1 or X2 is NR x or N + (O - )R x And the other is CHR y Or C(O);

[0121] R x yes

[0122] R y It is H, alkyl, cycloalkyl or cycloalkylalkyl, wherein the alkyl, cycloalkyl and cycloalkylalkyl are optionally substituted with halogen or alkoxy;

[0123] L1 is -(CH2) m (C=O)- or -(CH2) p -;

[0124] L2 is a bond or –S(O)2-;

[0125] A is a cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally composed of one or more R groups. 7 replace;

[0126] B is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally influenced by one or more R groups. 5 replace;

[0127] R 1 and R 2 Each is independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, wherein the cycloalkyl group is optionally influenced by one or more R groups. 9 replace;

[0128] Or when A is a cycloalkyl or heterocycloalkyl, R 1 and R 2 When bonded to the same carbon atom, they form together, optionally bound by one or more R atoms. 8 Substituted spirocycloalkyl ring; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 When bonded to the same atom, they form together, optionally bound by one or more R atoms. 8 Substituted spirochetal alkyl rings; or R 1 and R 2 When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted cycloalkyl ring; or R 1 and R 2 When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted heterocyclic alkyl rings; or R 1 and R 2 When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted aryl ring; or R 1 and R 2 When on adjacent atoms, together with the atoms they are connected to, they form an optional structure that can be formed by one or more R atoms. 8 Substituted heteroaryl ring; or when A is a cycloalkyl or heterocycloalkyl group, R 1 and R 2 When on non-adjacent atoms, together with the atoms they are connected to, they form an optional structure controlled by one or more R atoms. 8 Substituted cycloalkyl ring; or when cycloalkyl or heteroalkyl, R 1 and R 2 When on non-adjacent atoms, together with the atoms they are connected to, they form an optional structure controlled by one or more R atoms. 8 Substituted heterocyclic alkyl ring; optionally with one or more R 8Substituted cycloalkyl ring; or when cycloalkyl or heteroalkyl, R 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted heterocyclic alkyl rings;

[0129] R 3 It is an alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl or cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and -OH.

[0130] R 4 It is COOR 6a -(CH2) n -COOR 6a CONR 6b OH, CONR 6b R 6c CO NH(CH2) n COOR 6a CONH(CH2) n R 6a -(CH2) n CONH(CH2) n R 6a CONR 6b SO2R 6d CONR 6b SO2(CH2) n R 6d -(CH2) n -CONR 6b SO2R 6d CONR 6b SO2(CH2) n N(CO)R 6d CONH(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g 2. CO O(CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a SO2R 6e CN, -(CH2) n -NR 6b C(O)R 6c -(CH2) n -N(OH)-C(O)R6c , oxo, alkyl, cycloalkyl, -(CH2) n -cycloalkyl, heterocycloalkyl, -(CH2) n -Heterocyclic alkyl groups, heteroaryl groups, and -(CH2) n -Heteroaryl; wherein the alkyl, cycloalkyl, -(CH2) n -cycloalkyl, heterocycloalkyl, -(CH2) n -Heterocyclic alkyl groups, heteroaryl groups, and -(CH2) n -Hybrid aryl groups are selectively controlled by COOR 6a -(CH2) n -COOR 6a CONR 6b OH, CONR 6b R 6c CONH(CH2) n COOR 6a CONH(CH2) n R 6a -(CH2) n CONH(CH2) n R 6a CONR 6b SO2R 6d CONR 6b SO2(CH2) n R 6d -(CH2) n -CONR 6b SO2R 6d CONR 6b SO2(CH2) n N(CO)R 6d CONH(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g 2. COO(CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a SO2R 6e CN, -(CH2) n -NR 6b C(O)R 6c -(CH2) n -N(OH)-C(O)R 6c replace;

[0131] Each R 5Each time it appears, it is independently a halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, alkyl, haloalkyl, alkoxy and haloalkoxy.

[0132] R 6a It is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally selected by one or more of the following independently: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, NR. 6b R 6c Substitution with -OH substituents;

[0133] R 6b and R 6c Each of the following is independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally substituted by one or more substituents selected independently from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and -OH.

[0134] R 6d It is an alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally selected by one or more of the following independently: halogen, COOH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, -O-CO-alkyl, -O-COcycloalkyl, -O-CO-alkyl-COOH, NR 6b R 6c NR 6f CO-alkyl, NR 6f Substitution with CO-alkoxy, cycloalkyl, heterocycloalkyl and -OH substituents;

[0135] R 6e It is -OH, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and -OH;

[0136] R 6f It is an alkyl or haloalkyl group;

[0137] R 6g It is H or an alkyl group optionally substituted with -O-CO-alkyl;

[0138] Each R 7Each time it appears, it is independently alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN;

[0139] Each R 8 Each time it appears, it is independently alkyl, alkoxy, haloalkyl, haloalkoxy, halogen or –OH;

[0140] Each R 9 Each time it appears, it is independently alkyl, alkoxy, haloalkyl, haloalkoxy, halogen or –OH;

[0141] m is 0, 1, or 2;

[0142] n is 1, 2, 3, or 4; and

[0143] p is 1 or 2.

[0144] In another embodiment, the compound of the present invention has formula (I).

[0145]

[0146] in:

[0147] One of X1 or X2 is NR x And the other is CH2;

[0148] R x yes

[0149] L1 is -(CH2) m (C=O)- or -(CH2) p -;

[0150] L2 is a bond or –S(O)2-;

[0151] A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group, or a cycloalkyl group. 10 ) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), and wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally composed of one or more R 7 replace;

[0152] B is (C6-C) 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 replace;

[0153] R 1 and R2 Each of the following is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, (C3-C7)cycloalkyl, or CN, wherein the cycloalkyl is optionally surrounded by one or more R 9 replace;

[0154] Or R 1 and R 2 When bonded to the same carbon atom, they form together, optionally bound by one or more R atoms. 8 Substituted (C3-C8) spirocycloalkyl ring; or R 1 and R 2 When bonded to the same atom, they form an optional group consisting of one or more R atoms. 8 Substituted (C3-C8) spirochetal alkyl rings; or R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted (C3-C8) cycloalkyl rings; or R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted heterocyclic alkyl rings; or R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted aryl ring; or R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted heteroaryl ring; or when A is a cycloalkyl or heterocycloalkyl group, R 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted (C3-C8) cycloalkyl ring; or when cycloalkyl or heteroalkyl, R 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted heterocyclic alkyl rings;

[0155] R 3It is optionally substituted by one or more substituents selected independently from halogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl or (C3-C7) cycloalkyl;

[0156] R 4 It is COOR 6a CONR 6b R 6c CONH(CH2) n COOR 6a CONR 6b SO2R 6d CONH(CH2) n SO2R 6e CN, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S);

[0157] Each R 5 Each time it appears, it is independently a halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN, (C3-C8)cycloalkyl, (C6-C 10 ) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S), and wherein the cycloalkyl, aryl, heterocyclic alkyl or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy and (C1-C6)haloalkoxy;

[0158] R 6a It is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S), and wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH;

[0159] R 6b and R 6c Each of the following is independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10 ) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S), and wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH;

[0160] R 6d It is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10 ) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S), and wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH;

[0161] R 6e It is -OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S), and wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH;

[0162] Each R 7 Each time it appears, it is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen or CN;

[0163] Each R 8 Each time it appears, it is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen or –OH;

[0164] Each R 9 Each time it appears, it is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen or –OH;

[0165] m is 0, 1, or 2; and

[0166] p is 1 or 2.

[0167] In one embodiment, the compound of formula (I) has the structure of formula (Ia) or (Ib):

[0168]

[0169] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0170] In another embodiment, the compound of formula (I) has the structure of formula (Ic) or (Id):

[0171]

[0172] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0173] In another embodiment, the compound of formula (I) has the structure of formula (Ie) or (If):

[0174]

[0175] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0176] In another embodiment, the compound of formula (I) has the structure of formula (Ig) or (Ih):

[0177]

[0178] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0179] In another embodiment, the compound of formula (I) has the structure of formula (Ii) or (Ij):

[0180]

[0181] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0182] In another embodiment, the compound of formula (I) has the structure of formula (Ik) or (Il):

[0183]

[0184] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0185] In another embodiment, the compound of formula (I) has the structure of formula (Im) or (In):

[0186]

[0187] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0188] In another embodiment, the compound of formula (I) has the structure of formula (Io) or (Ip):

[0189]

[0190] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0191] In another embodiment, the compound of formula (I) has the structure of formula (Iq) or (Ir):

[0192]

[0193] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0194] In another embodiment, the compound of formula (I) has the structure of formula (Is) or (It):

[0195]

[0196] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0197] In another embodiment, the compound of formula (I) has the structure of formula (Iu) or (Iv):

[0198]

[0199] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0200] In another embodiment, the compound of formula (I) has the structure of formula (Iw) or (Ix):

[0201]

[0202] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0203] In another embodiment, the compound of formula (I) has the structure of formula (Iy) or (Iz):

[0204]

[0205] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0206] In another embodiment, the compound of formula (I) has the structure of formula (Iaa) or (Ibb):

[0207]

[0208] And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0209] In some implementations of the above formula, X1 is CHR. y Or C(O), and X2 is NR x or N + (O - )R x In one implementation, X1 is a CHR. y And X2 is NRx or N + (O - )R x In one implementation, X1 is C(O) and X2 is NR. x or N + (O - )R x In one implementation, X1 is a CHR. y And X2 is NR x In one implementation, X1 is C(O) and X2 is NR. x In one implementation, X1 is a CHR. y And X2 is N + (O - )R x In one implementation, X1 is C(O) and X2 is N. + (O - )R x In one implementation, X1 is CH2 and X2 is NR. x In another embodiment, X1 is NR x or N + (O - )R x And X2 is CHR y Or C(O). In another embodiment, X1 is NR x And X2 is CHR y Or C(O). In another embodiment, X1 is N. + (O - )R x And X2 is CHR y Or C(O). In another embodiment, X1 is NR x And X2 is CHR y In another embodiment, X1 is NR x And X2 is C(O). In another embodiment, X1 is N. + (O - )R x And X2 is CHR y In another embodiment, X1 is N. + (O - )R x And X2 is C(O). In another embodiment, X1 is NR. x And X2 is CH2.

[0210] In some implementations of the above formula, L1 is -(CH2). m (C=O)-. In another embodiment, L1 is -(CH2).p In another embodiment, L1 is -CH2. In another embodiment, L1 is -CH2C(O)-. In another embodiment, L1 is -C(O)-.

[0211] In some embodiments of the above formula, L2 is a bond. In another embodiment, L2 is –S(O)2-.

[0212] In some implementations of the above formula, A is optionally controlled by one or more R. 7 Substituted (C3-C8) cycloalkyl. In another embodiment, A is a (C3-C8) cycloalkyl. In yet another embodiment, A is substituted with one or more R 7 Substituted (C3-C8) cycloalkyl. In another embodiment, optionally with one or more R 7 Replacement (C6-C) 10 )Aryl. In yet another embodiment, A is (C6-C 10 )Aryl. In another embodiment, A is a group consisting of one or more R 7 Replacement (C6-C) 10 ) aryl. In one embodiment, A is optionally composed of one or more R 7 Substituted phenyl group. In another embodiment, A is untreated by R. 7 Substituted phenyl, while R 1 and R 2 Both are halogens. In another embodiment, A is not R 7 Substituted phenyl, while R 1 and R 2 Both are Cl atoms in the ortho position relative to the isoxazole ring. In yet another embodiment, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R atoms. 7 Replacement. In another embodiment, A is a heterocyclic alkyl group comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S. In yet another embodiment, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, and is replaced by one or more R... 7 Substitution. In another embodiment, A is a heteroaryl group, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally replaced by one or more R atoms. 7 Substitution. In yet another embodiment, A is a heteroaryl group, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S.

[0213] In another embodiment, A is a heteroaryl group, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, which are influenced by one or more R groups. 7 Replacement. In yet another embodiment, A is a (C3-C8) cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally replaced by one or more R 7 Replacement. In another embodiment, A is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally surrounded by one or more R 7 Substitution. In yet another embodiment, A is a (C3-C8)cycloalkyl, (C6-C... 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution. In another embodiment, A is a (C3-C8) cycloalkyl or (C6-C8) cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement. In yet another implementation, A is (C6-C 10 aryl or heterocyclic alkyl groups, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heterocyclic alkyl group is optionally surrounded by one or more R groups. 7 replace.

[0214] In some implementations of the above formula, B is optionally controlled by one or more R. 5 Replacement (C6-C) 10 aryl. In another embodiment, B is a heteroaryl group comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 5 Replacement. In yet another implementation, B is (C6-C 10 )Aryl. In another embodiment, B is a group consisting of one or more R 5 Replacement (C6-C) 10 ) aryl. In another embodiment, B is a heteroaryl. In yet another embodiment, B is a heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, which is irradiated by one or more R 5 Replacement. In another embodiment, B is (C6-C 10)aryl or heteroaryl, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S. In another embodiment, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is determined by one or more R 5 replace.

[0215] In some implementations of the above formula, R 1 It is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In another embodiment, R 1 It is halogen, CN, or optionally oxidized by one or more R 9 Substituted (C3-C7) cycloalkyl. In yet another embodiment, R 1 It is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, or (C3-C7)cycloalkyl, optionally distilled by one or more R 9 Replacement. In another implementation, R 1 It is H, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or (C3-C7)cycloalkyl, optionally with one or more R 9 Replacement. In yet another implementation, R 1 It is (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or (C3-C7)cycloalkyl, optionally bonded by one or more R 9 Replacement. In another implementation, R 1 It is H, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R 1 It is a (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In another embodiment, R 1 It is H, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R 1 It is a (C1-C6)alkoxy, a (C1-C6)haloalkoxy, or a halogen. In another embodiment, R 1 It is H, a (C1-C6) haloalkyl, a (C1-C6) haloalkoxy, or a halogen. In yet another embodiment, R 1 It is a (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or halogen. In another embodiment, R 1It is a (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, or (C3-C7)cycloalkyl, optionally bonded by one or more R 9 Replacement. In yet another implementation, R 1 It is H, a (C1-C6) haloalkyl group, or a halogen. In another embodiment, R... 1 It is a (C1-C6) haloalkyl or halogen.

[0216] In some implementations of the above formula, R 2 It is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In another embodiment, R 2 It is halogen, CN, or optionally oxidized by one or more R 9 Substituted (C3-C7) cycloalkyl. In yet another embodiment, R 2 It is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, or (C3-C7)cycloalkyl, optionally distilled by one or more R 9 Replacement. In another implementation, R 2 It is H, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or (C3-C7)cycloalkyl, optionally with one or more R 9 Replacement. In yet another implementation, R 2 It is (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or (C3-C7)cycloalkyl, optionally bonded by one or more R 9 Replacement. In another implementation, R 2 It is H, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R 2 It is a (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In another embodiment, R 2 It is H, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In yet another embodiment, R 2 It is a (C1-C6)alkoxy, a (C1-C6)haloalkoxy, or a halogen. In another embodiment, R 2 It is H, a (C1-C6) haloalkyl, a (C1-C6) haloalkoxy, or a halogen. In yet another embodiment, R 2 It is a (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or halogen. In another embodiment, R 2It is a (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, or (C3-C7)cycloalkyl, optionally bonded by one or more R 9 Replacement. In yet another implementation, R 2 It is H, a (C1-C6) haloalkyl group, or a halogen. In another embodiment, R... 2 It is a (C1-C6) haloalkyl or halogen.

[0217] In some implementations of the above formula, R 1 and R 2 When bonded to the same carbon atom, they form together, optionally bound by one or more R atoms. 8 Substituted (C3-C8) spirocyclic alkyl ring. In another embodiment, R 1 and R 2 When bonded to the same carbon atom, they form an optional group consisting of one to three R atoms. 8 A substituted (C3-C8) spirocyclic alkyl ring. In yet another embodiment, R 1 and R 2 When bonded to the same carbon atom, they together form a (C3-C8) spirocyclic alkyl ring. In another embodiment, R 1 and R 2 When bonded to the same carbon atom, they form a group consisting of one to three R atoms. 8 Substituted (C3-C8) spiroalkyl rings.

[0218] In some implementations of the above formula, R 1 and R 2 When bonded to the same atom, they form an optional group consisting of one or more R atoms. 8 Substituted (C3-C8) spiroheterocyclic alkyl ring. In another embodiment, R 1 and R 2 When bonded to the same atom, they form an optional group consisting of one to three R atoms. 8 A substituted (C3-C8) spiroheterocyclic alkyl ring. In yet another embodiment, R 1 and R 2 When bonded to the same atom, they together form a (C3-C8) spiroheterocyclic alkyl ring. In another embodiment, R 1 and R 2 When bonded to the same atom, they form a group consisting of one to three R atoms. 8 Substituted (C3-C8) spiroheterocyclic alkyl rings.

[0219] In some implementations of the above formula, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8Substituted (C3-C8) cycloalkyl ring. In another embodiment, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one to three R atoms. 8 Substituted (C3-C8) cycloalkyl ring. In yet another embodiment, R on adjacent atoms... 1 and R 2 Together with the atoms they are attached to, they form (C3-C8) cycloalkyl rings. In another embodiment, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form a structure consisting of one to three R atoms. 8 Substituted (C3-C8) cycloalkyl rings.

[0220] In some implementations of the above formula, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted heterocyclic alkyl ring. In another embodiment, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one to three R atoms. 8 Substituted heterocyclic alkyl ring. In yet another embodiment, R on adjacent atoms... 1 and R 2 Together with the atoms they are attached to, they form a heterocyclic alkyl ring. In another embodiment, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form a structure consisting of one to three R atoms. 8 Substituted heterocyclic alkyl rings.

[0221] In some implementations of the above formula, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted aryl ring. In another embodiment, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one to three R atoms. 8 Substituted aryl ring. In yet another embodiment, R on adjacent atoms... 1 and R 2 Together with the atoms they are attached to, they form an aryl ring. In another embodiment, the R on adjacent atoms... 1 and R 2 Together with the atoms they are attached to, they form a structure consisting of one to three R atoms. 8 Substituted aryl ring.

[0222] In some implementations of the above formula, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted heteroaryl ring. In another embodiment, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form optional groups of one to three R atoms. 8 Substituted heteroaryl ring. In yet another embodiment, R on adjacent atoms... 1 and R 2 Together with the atoms they are attached to, they form a heteroaryl ring. In another embodiment, R on adjacent atoms 1 and R 2 Together with the atoms they are attached to, they form a structure consisting of one to three R atoms. 8 Substituted heteroaryl rings.

[0223] In some embodiments of the above formula, when A is a cycloalkyl or heterocycloalkyl, R 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted (C4-C8) cycloalkyl ring. In another embodiment, when A is a cycloalkyl or heterocycloalkyl ring, R 1 and R 2 Together with the atoms they are attached to, they form optional groups of one to three R atoms. 8 Substituted (C4-C8) cycloalkyl ring. In yet another embodiment, when A is a cycloalkyl or heterocycloalkyl ring, R 1 and R 2 Together with the atoms they are attached to, they form (C4-C8) cycloalkyl rings. In another embodiment, when A is a cycloalkyl or heterocycloalkyl, R... 1 and R 2 Together with the atoms they are attached to, they form a structure consisting of one to three R atoms. 8 Substituted (C4-C8) cycloalkyl rings.

[0224] In some embodiments of the above formula, when cycloalkyl or heterocycloalkyl, R 1 and R 2 Together with the atoms they are attached to, they form optional groups of one or more R 8 Substituted heterocyclic alkyl ring. In another embodiment, when cycloalkyl or heterocyclic alkyl, R 1 and R 2 Together with the atoms they are attached to, they form optional groups of one to three R atoms. 8 Substituted heterocyclic alkyl ring. In yet another embodiment, when cycloalkyl or heterocyclic alkyl, R 1 and R 2Together with the atoms they are attached to, they form a heterocyclic alkyl ring. In another embodiment, when cycloalkyl or heterocyclic alkyl, R 1 and R 2 Together with the atoms they are attached to, they form a structure consisting of one to three R atoms. 8 Substituted heterocyclic alkyl rings.

[0225] In some implementations of the above formula, R 3 It is optionally substituted with one or more substituents selected independently from halogen, (C1-C6) alkyl, (C2-C4) alkenyl, (C2-C4) alkoxy, (C1-C4) haloalkyl, (C1-C6) haloalkoxy, (C1-C4) hydroxyalkyl, or (C3-C7) cycloalkyl. In another embodiment, R 3 It is (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, or (C1-C4)alkoxy. In yet another embodiment, R 3 It is a (C1-C4) haloalkyl, (C1-C4) haloalkoxy, or (C1-C4) hydroxyalkyl. In another embodiment, R 3 It is optionally substituted with one or more substituents selected independently from halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C4) hydroxyalkyl, or (C3-C7) cycloalkyl. In yet another embodiment, R 3 It is optionally substituted with one or more substituents selected independently from halogens, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, and –OH, and is a (C1-C4)alkyl or (C3-C7)cycloalkyl. In another embodiment, R 3 It is optionally substituted with one or more substituents selected independently from halogens and (C1-C6) alkyl groups, which are either (C1-C4) alkyl or (C3-C7) cycloalkyl groups. In yet another embodiment, R 3 It is an optional (C3-C7) cycloalkyl group substituted with one or more substituents, each independently selected from halogens, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, and –OH. In another embodiment, R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C6) alkyl groups.

[0226] In some implementations of the above formula, R 4 It is COOR 6a -(CH2) n -COOR 6a CO NR 6b OH, CONR 6b R 6c CONH(CH2) n COOR 6a CONH(CH2) n R 6a -(CH2) n CONH(CH2) n R 6a CONR 6b SO2R 6d CONR 6b SO2(CH2) n R 6d -(CH2) n -CONR 6b SO2R 6d CONR 6b SO2(CH2) n N(CO)R 6d CONH(CH2) n SO2R 6e C OR 6f (CH2) n PO(OR 6g 2. COO(CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a SO2R 6e CN, -(CH2) n -NR 6b C(O)R 6c -(CH2) n -N(OH)-C(O)R 6c , oxo, alkyl, cycloalkyl, -(CH2) n -cycloalkyl, heterocycloalkyl, -(CH2) n -Heterocyclic alkyl groups, heteroaryl groups, and -(CH2) n -Heteroaryl; wherein the heterocyclic alkyl group and -(CH2) n - Heterocyclic alkyl groups independently comprise one or two 5- to 7-membered rings and 1-4 heteroatoms or heteroaryl groups selected from N, O, and S, wherein the heteroaryl group and -(CH2) n- Heteroaryl groups comprise one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S; and the alkyl, cycloalkyl, -(CH2) group... n -cycloalkyl, heterocycloalkyl, -(CH2) n -Heterocyclic alkyl groups, heteroaryl groups, and -(CH2) n -Hybrid aryl groups are selectively controlled by COOR 6a -(CH2) n -COOR 6a CONR 6b OH, CONR 6b R 6c CONH(CH2) n C OOR 6a CONH(CH2) n R 6a -(CH2) n CONH(CH2) n R 6a CONR 6b SO2R 6d CONR 6b SO2(CH2) n R 6d -(CH2) n -CONR 6b SO2R 6d CONR 6b SO2(CH2) n N(CO)R 6d CONH(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g 2. COO(CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a SO2R 6e CN, -(CH2) n -NR 6b C(O)R 6c -(CH2) n -N(OH)-C(O)R 6c replace.

[0227] In one implementation, R 4 It is COOR 6a In one implementation, R 4 It is -alkyl-COOR 6aIn another implementation, R 4 It is -(CH2) n -COOR 6a In one implementation, R 4 It is CONR 6b OH. In another embodiment, R 4 It is CONR 6b R 6c In yet another implementation scheme, R 4 It is CONH(CH2) n COOR 6a In another implementation, R 4 It is CONH(CH2) n SO2R 6e In yet another implementation scheme, R 4 It is CONH(CH2) n C OOR 6a CONH(CH2) n R 6a -(CH2) n CONH(CH2) n R 6a In yet another implementation scheme, R 4 It is CONH(CH2) n R 6a In yet another implementation scheme, R 4 It is -(CH2) n CONH(CH2) n R 6a In yet another implementation scheme, R 4 It is CONR 6b SO2R 6d In yet another implementation scheme, R 4 It is -(CH2) n -NR 6b C(O)R 6c In yet another implementation scheme, R 4 It is -(CH2) n -N(OH)-C(O)R 6c In yet another implementation scheme, R 4 It is -alkyl-CONR 6b SO2R 6d In yet another implementation scheme, R 4 It is COR 6f (CH2) n PO(OR 6g )2. In yet another implementation scheme, R 4 It is COO(CH2) n PO(OR6g )2. In yet another implementation scheme, R 4 It is SO2NR 6b (CH2) n COOR 6a In yet another implementation scheme, R 4 It is SO2R 6e In yet another implementation scheme, R 4 It is an oxidation. In yet another implementation, R 4 It is optional (CH2) n COOR 6a COOR 6a CONR 6b OH, CONR 6b R 6c CONH(CH2) n COOR 6a CONR 6b SO2R 6d CO NH(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g 2. COO(CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a SO2R 6e Substituted (C3-C8) cycloalkyl. In another embodiment, R 4 It is a heterocyclic alkyl group comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S; and the heterocyclic alkyl group is optionally (CH2). n COOR 6a COOR 6a , C ONR 6b OH, CONR 6b R 6c CONH(CH2) n COOR 6a CONR 6b SO2R 6d CO NH(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g 2. COO(CH2) n PO(OR 6g 2. SO2NR 6b(CH2) n COOR 6a SO2R 6e Replacement. In yet another implementation, R 4 It is a heteroaryl group, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S; and the heteroaryl group is optionally (CH2). n COOR 6a COOR 6a CO NR 6b OH, CONR 6b R 6c CONH(CH2) n COOR 6a CONR 6b SO2R 6d CON H(CH2) n SO2R 6e COR 6f (CH2) n PO(OR 6g 2. COO(CH2) n PO(OR 6g )2、SO2NR 6b (CH2) n COOR 6a SO2R 6 Replacement. In another implementation, R 4 It is COOR 6a CONR 6b SO2R 6d or CONR 6b R 6c In yet another implementation scheme, R 4 It is COOR 6a CONR 6b SO2R 6d Or CONH(CH2) n SO2R 6e In another implementation, R 4 It is COOR 6a CONR 6b SO2R 6d Or CONH(CH2) n COOR 6a In yet another implementation scheme, R 4 It is COOR 6a CONR 6b SO2R 6d Or it may be a heterocyclic alkyl group comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S. In another embodiment, R 4Yes CO OR 6a CONR 6b SO2R 6d CONR 6b R 6c Or it may be a heterocyclic alkyl group comprising a 5- to 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In another embodiment, R 4 It is COO R 6a CONR 6b SO2R 6d Or it may be a heterocyclic alkyl group comprising a 5- to 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In another embodiment, R 4 It is CONH(CH2) n COOR 6a Or CONH(CH2) n SO2R 6e In yet another implementation scheme, R 4 It is CONR 6b R 6c Or C ONH(CH2) n COOR 6a In another implementation, R 4 It is CONR 6b SO2R 6d Or CO NH(CH2) n SO2R 6e .

[0228] In some implementations, n is 1. In another implementation, n is 2. In another implementation, n is 3. In another implementation, n is 4.

[0229] In some implementations of the above formula, R 5 It is halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, CN, (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy. In another embodiment, R 5It is a halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, or (C3-C8)cycloalkyl, optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy. In another embodiment, R 5 It is (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy. In another embodiment, R 5 It is a halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, or (C3-C8)cycloalkyl. In another embodiment, R 5 It is a halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or (C1-C4)haloalkoxy.

[0230] In some implementations of the above formula, R y It is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In one embodiment, R y It is H. In one implementation scheme, R y It is methyl. In one embodiment, R y It is ethyl. In one embodiment, R y It is CF3. In one implementation, R y It is a (C1-C6) alkyl group. In one embodiment, R y It is a (C1-C6) haloalkyl. In one embodiment, R y It is an alkoxyalkyl group. In some embodiments of the above formula, R... 6a It is H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally selected, one or more of which are independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, NR 6b R 6c Substituents of –OH and OH. In another embodiment, R 6a It is H, a (C1-C4) alkyl, or a (C1-C4) haloalkyl. In yet another embodiment, R... 6a It is H, (C1-C4) haloalkyl, or (C1-C4) alkyl, optionally substituted by one or more substituents each independently selected from halogens, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, and –OH. In another embodiment, R 6a It is (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH. In yet another embodiment, R 6a It is H or (C1-C4) alkyl.

[0231] In some implementations of the above formula, R 6b It is H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH. In yet another embodiment, R 6bIt is H, (C1-C4)alkyl, or (C1-C4)haloalkyl. In another embodiment, R 6b It is H, (C1-C4) haloalkyl, or (C1-C4) alkyl, optionally substituted by one or more substituents each independently selected from halogens, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, and –OH. In yet another embodiment, R 6b It is (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH. In another embodiment, R 6b It is H or (C1-C4) alkyl. In yet another embodiment, R... 6b It's H.

[0232] In some implementations of the above formula, R 6c It is H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH. In another embodiment, R 6c It is H, a (C1-C4) alkyl, or a (C1-C4) haloalkyl. In yet another embodiment, R... 6c It is H, (C1-C4) haloalkyl, or (C1-C4) alkyl, optionally substituted by one or more substituents each independently selected from halogens, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, and –OH. In another embodiment, R 6c It is (C3-C8)cycloalkyl, (C6-C 10)aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH. In yet another embodiment, R 6c It is H or (C1-C4) alkyl. In another embodiment, R 6c It's H.

[0233] In some implementations of the above formula, R 6d It is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10 ) aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- or 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), and wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally selected, one or more of which are independently selected from halogen, COOH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkoxyalkoxy, -O-CO-(C1-C6)alkyl, -O-CO-(C3-C8)cycloalkyl, -O-CO-(C1-C6)alkyl-COOH, NR 6b R 6c NR 6f CO-(C1-C6)alkyl, NR 6f Substituents of CO-(C1-C6)alkoxy, cycloalkyl, heterocycloalkyl, and -OH groups. In one embodiment, R... 6d It is (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH. In another embodiment, R 6dIt is a (C1-C4) alkyl or a (C1-C4) haloalkyl. In yet another embodiment, R 6d It is optionally substituted with one or more substituents selected independently from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH, and is a (C1-C4)haloalkyl or (C1-C4)alkyl. In yet another embodiment, R 6d It is (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and –OH. In another embodiment, R 6d It is a (C1-C4) alkyl or (C3-C8) cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by one or more substituents, each independently selected from halogens, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, and –OH. In yet another embodiment, R 6d It is a (C1-C4) alkyl or (C3-C8) cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more –OH groups. In another embodiment, R 6d It is (C1-C4)alkyl or (C3-C8)cycloalkyl.

[0234] In some implementations of the above formula, R 6e It is -OH, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and -OH. In another embodiment, R 6eIt is -OH, (C1-C4)haloalkyl, (C1-C4)alkyl, optionally substituted by one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH. In another embodiment, R 6e It is (C3-C8)cycloalkyl, (C6-C 10 )aryl, heterocyclic alkyl (wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S) or heteroaryl (wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, aryl, heterocyclic alkyl, or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and -OH. In another embodiment, R 6e It is an (C3-C8) cycloalkyl group optionally substituted with one or more substituents, each independently selected from halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, and -OH. In another embodiment, R 6e It is optionally substituted with one or more substituents selected independently from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH. 10 )Aryl. In another embodiment, R 6e It is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted by one or more substituents each independently selected from halogens, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and -OH. In another embodiment, R 6e It is a heteroaryl group, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, which are optionally substituted by one or more substituents selected independently from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH.

[0235] In another implementation, R 6eIt is a (C3-C8) cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents, each independently selected from halogens, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, and -OH. In another embodiment, R 6e It is (C6-C) 10 ) aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted by one or more substituents, each independently selected from halogens, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and -OH. In another embodiment, R 6e It is a (C1-C4) alkyl or (C3-C8) cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by one or more substituents, each independently selected from halogens, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, and –OH. In yet another embodiment, R 6e It is a (C1-C4) alkyl or (C3-C8) cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more –OH groups. In another embodiment, R 6e It is a (C1-C4) alkyl or a (C3-C8) cycloalkyl. In another embodiment, R 6e It is –OH, (C1-C4)alkyl or (C3-C8)cycloalkyl.

[0236] In some implementation schemes, R 6f It is a (C1-C6) alkyl or a (C1-C6) haloalkyl. In another embodiment, R 6f It is a (C1-C6) alkyl group. In another embodiment, R 6f It is methyl. In another embodiment, R 6f It is a (C1-C6) haloalkyl. In another embodiment, R 6f Trifluoromethyl

[0237] In some implementation schemes, R 6g It is H or optionally a (C1-C6) alkyl group substituted with -O-CO-(C1-C6)alkyl. In one embodiment, R 6g It is H. In one implementation, R 6g It is an (C1-C6) alkyl group optionally substituted with -O-CO-(C1-C6)alkyl. In one embodiment, R 6gIt is -CH2-OC(O)-C(CH3)3.

[0238] In some implementations of the above formula, R 7 It is (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or CN. In another embodiment, R 7 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or CN. In yet another embodiment, R 7 It is (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, R 7 It is (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, or (C1-C4)alkoxy. In yet another embodiment, R 7 It is (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, or halogen. In another embodiment, R 7 It is a (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or halogen. In yet another embodiment, R 7 It is a (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or halogen. In another embodiment, R 7 It is a (C1-C4) haloalkyl, (C1-C4) haloalkoxy, or halogen.

[0239] In some implementations of the above formula, R 8 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or –OH. In another embodiment, R 8 It is a (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or halogen. In yet another embodiment, R 8 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, R 8 It is a (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, or –OH. In yet another embodiment, R 8 It is (C1-C4)alkyl, (C1-C4)alkoxy, halogen, or –OH. In another embodiment, R8 It is a halogen or –OH. In yet another embodiment, R 8 It is (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or –OH. In another embodiment, R 8 It is a (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or –OH. In yet another embodiment, R… 8 It is a (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, or –OH. In another embodiment, R… 8 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, halogen, or –OH. In yet another embodiment, R 8 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or –OH.

[0240] In some implementations of the above formula, R 9 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or –OH. In another embodiment, R 9 It is a (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or halogen. In yet another embodiment, R 9 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, R 9 It is a (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, or –OH. In yet another embodiment, R 9 It is (C1-C4)alkyl, (C1-C4)alkoxy, halogen, or –OH. In another embodiment, R 9 It is a halogen or –OH. In yet another embodiment, R 9 It is (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or –OH. In another embodiment, R 9 It is a (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, or –OH. In yet another embodiment, R… 9 It is a (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, or –OH. In another embodiment, R… 9It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, halogen, or –OH. In yet another embodiment, R 9 It is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or –OH.

[0241] In some embodiments of the above formula, m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is either 1 or 2. In another embodiment, m is either 0 or 1.

[0242] In some embodiments of the above formula, p is 1. In another embodiment, p is 2.

[0243] In some implementations of the above formula, A is (C6-C 10 Aryl, (C3-C8)cycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S. In another embodiment, A is (C6-C8)cycloalkyl. 10 Aryl or (C3-C8)cycloalkyl. In yet another embodiment, A is (C6-C8) aryl or (C3-C8) cycloalkyl. 10 A is an aryl or heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S. In another embodiment, A is a (C3-C8)cycloalkyl or heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S. In yet another embodiment, A is a phenyl or (C3-C8)cycloalkyl. In yet another embodiment, A is a phenyl or heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S. In yet another embodiment, A is a phenyl. In yet another embodiment, A is cyclohexyl, bicyclo[2.2.2.]octyl, or spiro[2.5]octyl. In yet another embodiment, A is cyclohexyl or bicyclo[2.2.2.]octyl. In yet another embodiment, A is bicyclo[2.2.2.]octyl or spiro[2.5]octyl. In yet another embodiment, A is cyclohexyl, bicyclo[2.2.2.]octyl, or tetrahydropyranyl. In another embodiment, A is cyclohexyl. In yet another embodiment, A is bicyclo[2.2.2.]octyl. In another embodiment, A is tetrahydropyranyl.

[0244] In some implementations of the above formula, R 1 and R 2 Each is independently H, halogen, (C1-C6)alkoxy, or (C1-C6) haloalkoxy. In another embodiment, R 1 and R 2Each is independently H, a halogen, or a (C1-C6) haloalkyl group. In yet another embodiment, R 1 and R 2 Each is independently a halogen or a (C1-C6) haloalkyl group. In another embodiment, R 1 It is H, and R 2 It is a halogen, a (C1-C6) haloalkyl, or a (C1-C6) haloalkoxy. In yet another embodiment, R 1 It is H, and R 2 It is a (C1-C6) haloalkyl or (C1-C6) haloalkoxy. In another embodiment, R 1 It is H, and R 2 It is a (C1-C6) haloalkyl. In yet another embodiment, R 1 It is H, and R 2 It is a (C1-C6) haloalkoxy group. In another embodiment, R 1 It is halogen, and R 2 It is a halogen, a (C1-C6) haloalkyl, or a (C1-C6) haloalkoxy. In yet another embodiment, R 1 It is halogen, and R 2 It is a (C1-C6) haloalkoxy group. In another embodiment, R 1 It is halogen, and R 2 It is a (C1-C6) haloalkyl. In yet another embodiment, R 1 It is halogen, and R 2 It is halogen.

[0245] In some embodiments of the above formula, B is an unsubstituted heteroaryl group comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S.

[0246] In some embodiments of the above formula, B is a heteroaryl group comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, which is substituted with one or more halogens, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or (C3-C8)cycloalkyl.

[0247] In some implementations of the above formula, B is unsubstituted (C6-C). 10 )aryl. In some embodiments of the above formula, B is optionally substituted with (C1-C6)alkyl, halogen, (C1-C6)alkoxy, (C1-C6)haloalkoxy or (C3-C8)cycloalkyl. 10 Aryl.

[0248] In some embodiments of the above formula, B is pyrimidinyl, furanyl, benzo[d]thiazolyl, 1-methyl-1H-benzo[d]imidazolyl, 1-methyl-1H-indolyl, benzo[d]isoxazolyl, 2,2-difluoro-1-methylindololin-3-one or 7-fluoro-1-methyl-1H-benzo[d]imidazolyl, wherein each B is optionally substituted by one or more halogens, (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)haloalkyl.

[0249] In some implementations of the above formula, R 3 It is optionally a (C3-C8) cycloalkyl group substituted with a halogen or a (C1-C6) alkyl group. In another embodiment, R 3 It is an optional (C3-C8) cycloalkyl group substituted with a halogen. In another embodiment, R 3 It is an unsubstituted (C3-C8) cycloalkyl group.

[0250] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, and L2 is a bond. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, and A is a (C3-C8) cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0251] In another implementation, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 H, halogen or (C1-C4) haloalkyl substitution, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0252] In another implementation, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0253] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, and L2 is a bond. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, and A is a (C3-C8) cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0254] In another implementation, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0255] In another implementation, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl or (C1-C4) haloalkoxy. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0256] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, L2 is the bond, and A is arbitrarily bounded by one or more R 7 Substituted (C3-C8) cycloalkyl groups. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Substituted (C3-C8) cycloalkyl, and B is (C6-C8) cycloalkyl. 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 It can be substituted with H, halogens, or (C1-C4) haloalkyl groups.

[0257] In another implementation, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0258] In another implementation, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2).m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0259] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, L2 is the bond, and A is arbitrarily bounded by one or more R 7 Replacement (C6-C) 10 aryl. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Replacement (C6-C) 10 ) aryl, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0260] In another implementation, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0261] In another implementation, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is the bond, A is arbitrarily bounded by one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0262] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, L2 is a bond, and A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0263] In another implementation, L1 is -(CH2). m(C=O)-, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0264] In another implementation, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0265] In some implementations of the above formula, L1 is -(CH2). p - and L2 is a bond. In another embodiment, L1 is -(CH2). p -, L2 is a bond, and A is a (C3-C8) cycloalkyl, (C6-C8) cycloalkyl, (C6-C8) cycloalkyl 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0266] In another implementation, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 H, halogen or (C1-C4) haloalkyl substitution, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0267] In another implementation, L1 is -(CH2). p-, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group, (C6-C8) cycloalkyl group. 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0268] In some implementations of the above formula, L1 is -(CH2). p - and L2 is a bond. In another embodiment, L1 is -(CH2). p -, L2 is a bond, and A is a (C3-C8) cycloalkyl or (C6-C8) cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 ) aryl, wherein the cycloalkyl or (C6-C 10 )Aryl is optionally influenced by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0269] In another implementation, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0270] In another implementation, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl or (C1-C4) haloalkoxy. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a (C3-C8) cycloalkyl group or (C6-C8) cycloalkyl group. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0271] In some implementations of the above formula, L1 is -(CH2). p -, L2 is the key, and A is arbitrarily assigned to one or more Rs. 7 Substituted (C3-C8) cycloalkyl groups. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Substituted (C3-C8) cycloalkyl, and B is (C6-C8) cycloalkyl. 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 It can be substituted with H, halogens, or (C1-C4) haloalkyl groups.

[0272] In another implementation, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0273] In another implementation, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0274] In some implementations of the above formula, L1 is -(CH2). p -, L2 is the key, and A is arbitrarily assigned to one or more Rs. 7 Replacement (C6-C) 10 aryl. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Replacement (C6-C) 10 ) aryl, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0275] In another implementation, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0276] In another implementation, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). p -, L2 is the key, A is optional and can be assigned to one or more Rs 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0277] In some implementations of the above formula, L1 is -(CH2). p -, L2 is a bond, and A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0278] In another implementation, L1 is -(CH2). p -, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). p -, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0279] In another implementation, L1 is -(CH2). p -, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). p-, L2 is a bond, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally separated by one or more R atoms. 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0280] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, and L2 is –S(O)2-. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, and A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0281] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 H, halogen or (C1-C4) haloalkyl substitution, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0282] In another implementation, L1 is -(CH2).m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0283] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, and A is (C3-C8)cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0284] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0285] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl or (C1-C4) haloalkoxy. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0286] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, and A is arbitrarily controlled by one or more R 7 Substituted (C3-C8) cycloalkyl groups. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8) cycloalkyl, and B is (C6-C8) cycloalkyl. 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m(C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 It can be substituted with H, halogens, or (C1-C4) haloalkyl groups.

[0287] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0288] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0289] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, and A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 aryl. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 ) aryl, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0290] In another implementation, L1 is -(CH2). m(C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0291] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0292] In some implementations of the above formula, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, and A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0293] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0294] In another implementation, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). m (C=O)-, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0295] In some implementations of the above formula, L1 is -(CH2). p - and L2 is –S(O)2-. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, and A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Replacement, and B is (C6-C10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0296] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5H, halogen or (C1-C4) haloalkyl substitution, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0297] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl, (C6-C 10 aryl or heterocyclic alkyl, wherein the heterocyclic alkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, aryl, or heterocyclic alkyl is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0298] In some implementations of the above formula, L1 is -(CH2). p - and L2 is –S(O)2-. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, and A is (C3-C8)cycloalkyl or (C6-C 10aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C8)cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C8)cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, or (C1-C4) haloalkyl.

[0299] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C8)cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C8)cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0300] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C8)cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl or (C1-C4) haloalkoxy. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is (C3-C8)cycloalkyl or (C6-C8)cycloalkyl. 10 aryl, wherein the cycloalkyl or aryl group is optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0301] In some implementations of the above formula, L1 is -(CH2). p -, L2 is –S(O)2-, and A is arbitrarily controlled by one or more R 7 Substituted (C3-C8) cycloalkyl groups. In another embodiment, L1 is -(CH2). p-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8) cycloalkyl, and B is (C6-C8) cycloalkyl. 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 It can be substituted with H, halogens, or (C1-C4) haloalkyl groups.

[0302] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is H, a halogen, or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is H, halogen, or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0303] In another implementation, L1 is -(CH2). p-, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, and R 2 It is a halogen or a (C1-C4) haloalkyl group. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Substituted (C3-C8)cycloalkyl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, or (C1-C4) haloalkyl, R 2 It is a halogen or (C1-C4) haloalkyl, and R 3 It is a (C3-C7) cycloalkyl group that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0304] In some implementations of the above formula, L1 is -(CH2). p -, L2 is –S(O)2-, and A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 aryl. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 ) aryl, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0305] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0306] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is arbitrarily controlled by one or more R 7 Replacement (C6-C) 10 )Aryl, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0307] In some implementations of the above formula, L1 is -(CH2). p -, L2 is –S(O)2-, and A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Replacement. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Replacement, and B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replacement. In another embodiment, L1 is -(CH2). p-, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, and R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy.

[0308] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is H, a halogen, a (C1-C4)alkoxy group, a (C1-C4)haloalkyl group, or a (C1-C4)haloalkoxy group. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0309] In another implementation, L1 is -(CH2). p -, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy. In another embodiment, L1 is -(CH2). p -, L2 is –S(O)2-, A is a heterocyclic alkyl group, wherein the heterocyclic alkyl group comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally surrounded by one or more R 7 Substitution, B is (C6-C 10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the aryl or heteroaryl is optionally surrounded by one or more R 5 Replace, R 1 It is H, halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, R 2 It is a halogen, (C1-C4)alkoxy, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy, and R 3 It is a (C1-C4) alkyl or (C3-C7) cycloalkyl that is optionally substituted by one or more substituents selected independently from halogens or (C1-C4) alkyl groups.

[0310] Non-limiting exemplary compounds of the present invention include:

[0311] 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-1);

[0312] 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-2);

[0313] 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-methyl-1,3-benzothiazol-6-carboxylic acid (I-3);

[0314] 4-Cyclopropyl-2-[(1S,4S,5R)-5-[5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-4);

[0315] 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethyl)-1,3-benzothiazol-6-carboxylic acid (I-5);

[0316] 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazol-6-carboxylic acid (I-6);

[0317] 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-(2,2,2-trifluoroethoxy)-1,3-benzothiazol-6-carboxylic acid (I-7);

[0318] 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-ethoxy-1,3-benzothiazol-6-carboxylic acid (I-8);

[0319] 2-[(1S,4S,5R)-5-{5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-carbonyloxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazol-6-carboxylic acid (I-9);

[0320] 2-[(1S,4S,5R)-5-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-10);

[0321] 2-[(1S,4S,5R)-5-(3-{bicyclo[2.2.2]octan-1-yl}-5-cyclopropyl-1,2-oxazol-4-carbonyloxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-11);

[0322] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-12);

[0323] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-methyl-1,3-benzothiazol-6-carboxylic acid (I-13);

[0324] 4-Cyclopropyl-2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-14);

[0325] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethyl)-1,3-benzothiazol-6-carboxylic acid (I-15);

[0326] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazol-6-carboxylic acid (I-16);

[0327] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(2,2,2-trifluoroethoxy)-1,3-benzothiazol-6-carboxylic acid (I-17);

[0328] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-ethoxy-1,3-benzothiazol-6-carboxylic acid (I-18);

[0329] 2-[(1S,4S,5R)-5-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methoxy)-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-19);

[0330] 2-[(1S,4S,5R)-5-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methoxy)-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazol-6-carboxylic acid (I-20);

[0331] 2-[(1S,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazol-6-carboxylic acid (I-21);

[0332] 2-[(1S,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-22);

[0333] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(oxan-4-yl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazol-6-carboxylic acid (I-23);

[0334] 2-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-24);

[0335] 2-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazol-6-carboxylic acid (I-25);

[0336] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1,3-benzothiazole (I-26);

[0337] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-6-(2H-1,2,3,4-tetrazol-5-yl)-4-(trifluoromethoxy)-1,3-benzothiazole (I-27);

[0338] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-N-methanesulfonyl-1,3-benzothiazol-6-carboxamide (I-28);

[0339] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-N-(propane-1-sulfonyl)-1,3-benzothiazol-6-carboxamide (I-29);

[0340] N-(cyclopropanesulfonyl)-2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxamide (I-30);

[0341] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-[4-fluoro-6-(methanesulfonylcarbamoyl)-1,3-benzothiazol-2-yl]-2-azabicyclo[2.2.1]heptane-5-yl ester (I-31);

[0342] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-{4-fluoro-6-[(propane-1-sulfonyl)carbamoyl]-1,3-benzothiazolyl-2-yl}-2-azabicyclo[2.2.1]heptane-5-yl ester (I-32);

[0343] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-{6-[(cyclopropanesulfonyl)carbamoyl]-4-fluoro-1,3-benzothiazolyl-2-yl}-2-azabicyclo[2.2.1]heptane-5-yl ester (I-33);

[0344] 2-[(1S,4S,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-34);

[0345] 2-[(1S,4S,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-35);

[0346] 2-[(1S,4S,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid methyl ester (I-36);

[0347] 2-[(1S,4S,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-37);

[0348] 2-[(1R,4R,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-38);

[0349] 2-[(1R,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-39);

[0350] 2-[(1R,4R,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-40);

[0351] 2-[(1R,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-41);

[0352] 4-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-42);

[0353] 4-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-43);

[0354] 4-[(1S,4S,5R)-5-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-44);

[0355] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-[4-(methanesulfonylcarbamoyl)phenyl]-2-azabicyclo[2.2.1]heptane-5-yl ester (I-45);

[0356] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-{4-[(propane-1-sulfonyl)carbamoyl]phenyl}-2-azabicyclo[2.2.1]heptane-5-yl ester (I-46);

[0357] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-{4-[(cyclopropanesulfonyl)carbamoyl]phenyl}-2-azabicyclo[2.2.1]heptane-5-yl ester (I-47);

[0358] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-[2-fluoro-4-(methanesulfonylcarbamoyl)phenyl]-2-azabicyclo[2.2.1]heptane-5-yl ester (I-48);

[0359] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-{2-fluoro-4-[(propane-1-sulfonyl)carbamoyl]phenyl}-2-azabicyclo[2.2.1]heptane-5-yl ester (I-49);

[0360] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-[4-(2H-1,2,3,4-tetrazol-5-yl)phenyl]-2-azabicyclo[2.2.1]heptane-5-yl ester (I-50);

[0361] 5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carboxylic acid (1S,4S,5R)-2-[2-fluoro-4-(2H-1,2,3,4-tetrazol-5-yl)phenyl]-2-azabicyclo[2.2.1]heptane-5-yl ester (I-51);

[0362] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-52);

[0363] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-53);

[0364] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3,5-difluorobenzoic acid (I-54);

[0365] 6-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-3-carboxylic acid (I-55);

[0366] 4-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-56);

[0367] 4-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-57);

[0368] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-methanesulfonylbenzamide (I-58);

[0369] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(propane-1-sulfonyl)benzamide (I-59);

[0370] N-(cyclopropanesulfonyl)-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzamide (I-60);

[0371] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluoro-N-(propane-1-sulfonyl)benzamide (I-61);

[0372] N-(cyclopropanesulfonyl)-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzamide (I-62);

[0373] 2-[(1R,4S,6R)-6-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-63);

[0374] 2-[(1R,4S,6S)-6-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-64);

[0375] 2-[(1R,4S,6R)-6-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-65);

[0376] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3,5-difluorobenzonitrile (I-54a)

[0377] 2-Cyano-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-101);

[0378] 3-Cyano-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-102);

[0379] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (I-103);

[0380] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2,6-difluorobenzoic acid (I-104);

[0381] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2,5-difluorobenzoic acid (I-105);

[0382] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-(trifluoromethyl)benzoic acid (I-106);

[0383] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-methylbenzoic acid (I-107);

[0384] 3-Cyclopropyl-4-((1S,4S,5R)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzoic acid (I-108);

[0385] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-ethylbenzoic acid (I-109);

[0386] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-2,3-difluorobenzoic acid (I-110);

[0387] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-2-methylbenzoic acid (I-111);

[0388] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-2-methoxybenzoic acid (I-112);

[0389] 4-[(1S,4S,5R)-5-{[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-113);

[0390] 4-[(1S,4S,5R)-5-{[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-114);

[0391] 4-[(1S,4S,5R)-5-{[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (I-115);

[0392] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-116);

[0393] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-117);

[0394] 4-[(1S,4S,5R)-5-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-118);

[0395] 4-[(1S,4S,5R)-5-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-119);

[0396] 4-[(1S,4S,5R)-5-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methoxy)-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-120);

[0397] 4-[(1S,4S,5R)-5-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methoxy)-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-121);

[0398] 4-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (I-122);

[0399] 2-Cyano-4-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-123);

[0400] 4-[(1S,4S,5R)-5-{[3-(2-chloro-6-methylphenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (I-124);

[0401] 4-[(1S,4S,5R)-5-[(5-cyclopropyl-3-{spiro[2.5]octane-6-yl}-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-125);

[0402] 4-[(1S,4S,5R)-5-[(5-cyclopropyl-3-{spiro[2.5]octane-6-yl}-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-126);

[0403] (1S,4S,5R)-2-(4-carboxyphenyl)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-onthium-2-ol (I-127);

[0404] 5-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-2-carboxylic acid (I-128);

[0405] 6-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-5-fluoropyridine-3-carboxylic acid (I-129);

[0406] 6-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-5-fluoropyridine-3-carboxylic acid (I-130);

[0407] 4-[(1R,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-131);

[0408] 4-[(1R,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-132);

[0409] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2,6-difluorobenzonitrile (I-133) (1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-[2-fluoro-4-(2H-1,2,3,4-tetrazol-5-yl)phenyl]-2-azabicyclo[2.2.1]heptane (I-134);

[0410] 5-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2,3-dihydro-1H-isoindol-1-one (I-135);

[0411] 6-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,2,3,4-tetrahydroisoquinoline-1-one (I-136);

[0412] (2R)-6-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (I-137) and (2S)-6-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (I-138);

[0413] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-hydroxy-3-methylbenzamide (I-139);

[0414] 5-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2,3-dihydro-1,3-benzoxazol-2-one (I-140);

[0415] 5-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-dihydro-2-benzofuran-1-one (I-141);

[0416] 1-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}-2,2,2-trifluoroethyl-1-one (I-142);

[0417] 2-{N-methyl4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzenesulfonamide}acetic acid (I-143);

[0418] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzene-1-sulfonic acid (I-144);

[0419] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]pyrimidine-5-carboxylic acid (I-145);

[0420] 2-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}acetic acid (I-146);

[0421] 3-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}propionic acid (I-147);

[0422] 4-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}butyric acid (I-148);

[0423] 1-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}cyclopropane-1-carboxylic acid (I-149);

[0424] 1-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}cyclobutane-1-carboxylic acid (I-150);

[0425] 3-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}cyclobutane-1-carboxylic acid (I-151);

[0426] 3-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}butyric acid (I-152);

[0427] 2-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}acetic acid (I-153);

[0428] 3-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}propionic acid (I-154);

[0429] 3-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorophenyl}propionic acid (I-155);

[0430] 3-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorophenyl}-2,2-dimethylpropionic acid (I-156);

[0431] 4-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}butyric acid (I-157);

[0432] 3-{3-cyano-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}propionic acid (I-158);

[0433] 3-{4-[(1S,4S,5R)-5-{[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}propionic acid (I-159);

[0434] 1-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}methyl)azacyclobutane-3-carboxylic acid (I-160);

[0435] N-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}methyl)-N-hydroxyformamide (I-161);

[0436] (1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-{2-fluoro-4-[2-(2H-1,2,3,4-tetrazol-5-yl)ethyl]phenyl}-2-azabicyclo[2.2.1]heptane (I-162);

[0437] 3-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}propionic acid 2-[bis(2-hydroxyethyl)amino]ethyl ester (I-163);

[0438] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)benzamide (I-164);

[0439] 2-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)acetic acid (I-165);

[0440] 2-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)ethane-1-sulfonic acid (I-166);

[0441] 2-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorophenyl}carbamoyl)acetic acid (I-167);

[0442] 2-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorophenyl}carbamoyl)ethane-1-sulfonic acid (I-168);

[0443] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(2-methanesulfonylethyl)benzamide (I-169);

[0444] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-(2-methanesulfonylethyl)benzamide (I-170);

[0445] N-[2-(cyclopropanesulfonyl)ethyl]-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzamide (I-171);

[0446] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-[2-(oxane-4-sulfonyl)ethyl]benzamide (I-172);

[0447] [2-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-methylphenyl}formamido)ethyl]phosphonic acid (I-173);

[0448] 2,2-Dimethylpropionic acid ({[2-({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-methylphenyl}carbamoyl)ethyl]({[(2,2-dimethylpropionyl)oxy]methoxy})phosphoryl}oxy)methyl ester (I-174);

[0449] (2-{4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}ethyl)phosphonic acid (I-175);

[0450] ({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}methyl)phosphonic acid (I-176);

[0451] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoate (I-177);

[0452] 5-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3,4-thiadiazole-2-carboxylic acid (I-178);

[0453] 3-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,2-oxazol-5-carboxylic acid (I-179);

[0454] 5-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1-methyl-1H-pyrazole-3-carboxylic acid (I-180);

[0455] N-(cyclohexanesulfonyl)-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]benzamide (I-181);

[0456] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)benzamide (I-182);

[0457] N-(cyclobutylsulfonyl)-4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzamide (I-183);

[0458] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(oxetane-3-ylsulfonyl)benzamide (I-184);

[0459] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-((tetrahydrofuran-3-yl)sulfonyl)benzamide (I-185);

[0460] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(((tetrahydrofuran-3-yl)methyl)sulfonyl)benzamide (I-186);

[0461] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-((1-methylpiperidin-4-yl)sulfonyl)benzamide (I-187);

[0462] N-((1H-pyrazol-4-yl)sulfonyl)-4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzamide (I-188);

[0463] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(phenylsulfonyl)benzamide (I-189);

[0464] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluoro-N-(isopentylsulfonyl)benzamide (I-190);

[0465] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluoro-N-(pentylsulfonyl)benzamide (I-191);

[0466] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluoro-N-(octylsulfonyl)benzamide (I-192);

[0467] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-((2-(2-ethoxyethoxy)ethyl)sulfonyl)-3-fluorobenzamide (I-193);

[0468] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-2-fluoro-N-(propylsulfonyl)benzamide (I-194);

[0469] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)-2-fluorobenzamide (I-195);

[0470] N-(cyclopropylsulfonyl)-4-((1S,4S,5R)-5-((3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzamide (I-196);

[0471] N-(cyclopropylsulfonyl)-4-((1S,4S,5R)-5-((3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorobenzamide (I-197);

[0472] 4-((1S,4S,5R)-5-((3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluoro-N-(propylsulfonyl)benzamide (I-198);

[0473] 3-(2,6-Dichlorophenyl)-5-(1-fluorocyclopropyl)isoxazole-4-carboxylic acid (1S,4S,5R)-2-(4-((cyclopropylsulfonyl)carbamoyl)-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane-5-yl ester (I-199);

[0474] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluoro-N-(propylsulfonyl)benzamide (I-200);

[0475] N-(Butylsulfonyl)-4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorobenzamide (I-201);

[0476] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)-3-fluorobenzamide (I-202);

[0477] 4-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide (I-203);

[0478] 6-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(propylsulfonyl)nicotinamide (I-204);

[0479] 6-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)nicotinamide (I-205);

[0480] 6-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-5-fluoro-N-(propylsulfonyl)nicotinamide (I-206);

[0481] 6-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)-5-fluoronicotinamide (I-207);

[0482] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)benzamide (I-208);

[0483] N-(cyclopropanesulfonyl)-6-[(1S,4S,5R)-5-{[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-3-carboxamide (I-209);

[0484] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(2-hydroxyethanesulfonyl)benzamide (I-210);

[0485] 2-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)sulfonyl]ethyl ester (I-211);

[0486] Cyclopropanecarboxylic acid 2-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)sulfonyl]ethyl ester (I-212);

[0487] 2-Methylpropionic acid 2-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)sulfonyl]ethyl ester (I-213);

[0488] 3-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)sulfonyl]propyl acetate (I-214);

[0489] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(3-hydroxypropanesulfonyl)benzamide (I-215);

[0490] Acetic acid 4-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)sulfonyl]butane-2-yl ester (I-216);

[0491] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(3-hydroxybutyryl)benzamide (I-217);

[0492] 4-({4-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}carbamoyl)sulfonyl]butane-2-yl}oxy)-4-oxobutyric acid (I-218);

[0493] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(3,4-dihydroxybutyryl)benzamide (I-219);

[0494] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-{[(1s,4s)-4-hydroxycyclohexyl]sulfonyl}benzamide (I-220) and 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-{[(1r,4r)-4-hydroxycyclohexyl]sulfonyl}benzamide (I-221);

[0495] 4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-N-(dodecane-1-sulfonyl)-3-fluorobenzamide (I-222);

[0496] (2R,3S,4R,5R)-N-{10-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}carbamoyl)sulfonyl]decyl}-2,3,4,5,6-pentahydroxyhexamamide (I-223);

[0497] N-{10-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}carbamoyl)sulfonyl]decyl}acetamide (I-224);

[0498] N-{10-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}carbamoyl)sulfonyl]decyl}-2-methoxyacetamide (I-225);

[0499] {10-[({4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}carbamoyl)sulfonyl]decyl}diethylmethylazaium (I-226);

[0500] N-[10-(azacyclobutan-1-yl)decylsulfonyl]-4-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzamide (I-227);

[0501] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)benzamide (I-228);

[0502] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)-3-fluorobenzamide (I-229);

[0503] 4-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluoro-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide (I-230);

[0504] 4-((1R,4R,5S)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)-3-fluorobenzamide (I-231);

[0505] 4-((1R,4R,5S)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)benzamide (I-232);

[0506] N-(cyclopropanesulfonyl)-5-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1-methyl-1H-pyrazole-3-carboxamide (I-233);

[0507] (1S,4S,5R)-2-{4-[(cyclopropanesulfonyl)carbamoyl]phenyl}-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-onthium-2-ol (I-234);

[0508] 3-{4-[(1S,4S,5R)-5-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}-N-(oxane-4-sulfonyl)propionamide (I-235);

[0509] 3-(4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-(methylsulfonyl)propionamide (I-236);

[0510] 3-(4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-(cyclopropylsulfonyl)propionamide (I-237);

[0511] 3-(4-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)propionamide (I-238);

[0512] 3-(4-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-(methylsulfonyl)propionamide (I-239);

[0513] 3-(4-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-(cyclopropylsulfonyl)propionamide (I-240);

[0514] 3-(4-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-(methylsulfonyl)propionamide (I-241);

[0515] 3-(4-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-(cyclopropylsulfonyl)propionamide (I-242);

[0516] 3-(4-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)propionamide (I-243);

[0517] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-244);

[0518] 4-[(1S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-245);

[0519] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-ethyl-1,3-benzothiazol-6-carboxylic acid (I-246);

[0520] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(propane-2-yl)-1,3-benzothiazol-6-carboxylic acid (I-247);

[0521] 4-tert-butyl-2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-248);

[0522] 4-Cyclobutyl-2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-249);

[0523] 4-Cyclopentyl-2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-250);

[0524] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(oxacyclopentane-3-yl)-1,3-benzothiazol-6-carboxylic acid (I-251);

[0525] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(3S)-oxacyclopentane-3-yl]-1,3-benzothiazol-6-carboxylic acid (I-252);

[0526] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(3R)-oxacyclopentane-3-yl]-1,3-benzothiazol-6-carboxylic acid (I-253);

[0527] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(oxane-4-yl)-1,3-benzothiazol-6-carboxylic acid (I-254);

[0528] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(1R,3R,5S)-8-azabicyclo[3.2.1]octane-3-yl]-1,3-benzothiazol-6-carboxylic acid (I-255);

[0529] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(1R,3S,5S)-8-azabicyclo[3.2.1]octane-3-yl]-1,3-benzothiazol-6-carboxylic acid (I-256);

[0530] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-{7-oxaspiro[3.5]nonane-2-yl}-1,3-benzothiazol-6-carboxylic acid (I-257);

[0531] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-(oxacycloheptane-4-yl)-1,3-benzothiazol-6-carboxylic acid (I-258);

[0532] 4-Cyclopropoxy-2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-259);

[0533] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(3S)-oxacyclopentane-3-yloxy]-1,3-benzothiazol-6-carboxylic acid (I-260);

[0534] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(3R)-oxacyclopentane-3-yloxy]-1,3-benzothiazol-6-carboxylic acid (I-261);

[0535] 2-[(1S,4S,5R)-5-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-methyl-1,3-benzothiazol-6-carboxylic acid (I-262);

[0536] 2-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-cyclopropoxybenzo[d]thiazol-6-carboxylic acid (I-263);

[0537] 2-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-6-carboxylic acid (I-264);

[0538] 2-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-((R)-tetrahydrofuran-3-yl)benzo[d]thiazol-6-carboxylic acid (I-265);

[0539] 2-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-((S)-tetrahydrofuran-3-yl)benzo[d]thiazol-6-carboxylic acid (I-266);

[0540] 2-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(((S)-tetrahydrofuran-3-yl)oxy)benzo[d]thiazol-6-carboxylic acid (I-267);

[0541] 2-((1S,4S,5R)-5-((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]thiazol-6-carboxylic acid (I-268);

[0542] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-methylbenzo[d]thiazol-6-carboxylic acid (I-269);

[0543] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-cyclopropoxybenzo[d]thiazol-6-carboxylic acid (I-270);

[0544] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-6-carboxylic acid (I-271);

[0545] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-((R)-tetrahydrofuran-3-yl)benzo[d]thiazol-6-carboxylic acid (I-272);

[0546] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-((S)-tetrahydrofuran-3-yl)benzo[d]thiazol-6-carboxylic acid (I-273);

[0547] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(((S)-tetrahydrofuran-3-yl)oxy)benzo[d]thiazol-6-carboxylic acid (I-274);

[0548] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]thiazol-6-carboxylic acid (I-275);

[0549] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-methyl-1,3-benzothiazol-6-carboxylic acid (I-276);

[0550] 2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-{spiro[2.5]octane-6-yl}-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-277);

[0551] 4-Cyclopropoxy-2-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzo[d]thiazol-6-carboxylic acid (I-278);

[0552] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-6-carboxylic acid (I-279):

[0553] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-((R)-tetrahydrofuran-3-yl)benzo[d]thiazol-6-carboxylic acid (I-280);

[0554] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-((S)-tetrahydrofuran-3-yl)benzo[d]thiazol-6-carboxylic acid (I-281);

[0555] 4-Cyclobutyl-2-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzo[d]thiazol-6-carboxylic acid (I-282);

[0556] 4-Cyclopentyl-2-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octane-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzo[d]thiazol-6-carboxylic acid (I-283);

[0557] 4-Cyclobutyl-2-[(1R,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-284);

[0558] 4-Cyclopentyl-2-[(1R,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid (I-285);

[0559] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichloro-4-methoxyphenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-286);

[0560] 2-[(1S,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichloro-4-hydroxyphenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptane-2-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (I-287);

[0561] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(2-methoxyphenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-fluorobenzo[d]thiazol-6-carboxylic acid (I-288);

[0562] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(3-methoxyphenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-fluorobenzo[d]thiazol-6-carboxylic acid (I-289);

[0563] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(4-methoxyphenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-fluorobenzo[d]thiazol-6-carboxylic acid (I-290);

[0564] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(2-hydroxyphenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-fluorobenzo[d]thiazol-6-carboxylic acid (I-291);

[0565] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(3-hydroxyphenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-fluorobenzo[d]thiazol-6-carboxylic acid (I-292);

[0566] 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(4-hydroxyphenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-fluorobenzo[d]thiazol-6-carboxylic acid (I-293);

[0567] 2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-4-ethyl-1,3-benzothiazol-6-carboxylic acid (I-294);

[0568] 4-Cyclopropyl-2-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)benzo[d]thiazol-6-carboxylic acid (I-295);

[0569] 4-Cyclobutyl-2-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)benzo[d]thiazol-6-carboxylic acid (I-296);

[0570] 4-Cyclopropoxy-2-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)benzo[d]thiazol-6-carboxylic acid (I-297);

[0571] 2-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-4-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-6-carboxylic acid (I-298);

[0572] 2-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-4-(tetrahydrofuran-3-yl)benzo[d]thiazol-6-carboxylic acid (I-299);

[0573] 2-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-4-(7-oxaspiro[3.5]nonane-2-yl)benzo[d]thiazol-6-carboxylic acid (I-300);

[0574] 2-((1S,4S,5R)-5-((3-(2-chloro-6-methylphenyl)-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)-4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]thiazol-6-carboxylic acid (I-301);

[0575] 2-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-4-(((S)-tetrahydrofuran-3-yl)oxy)benzo[d]thiazol-6-carboxylic acid (I-302);

[0576] 3-{4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}propionic acid (I-303);

[0577] 3-{4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}propionic acid (I-304);

[0578] 3-{4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorophenyl}propionic acid (I-305);

[0579] 4-[(1S,4R,5R)-5-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-306);

[0580] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-307);

[0581] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-308);

[0582] 4-[(1S,4R,5R)-5-{[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-309);

[0583] 4-[(1S,4R,5R)-5-({5-cyclopropyl-3-[2-fluoro-6-(propane-2-yl)phenyl]-1,2-oxazol-4-yl}methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-310);

[0584] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2-cyclopropyl-6-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-311);

[0585] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2,3-dihydro-1H-indene-1-carboxylic acid (I-312)

[0586] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2,3-dihydro-1H-indene-2-carboxylic acid (I-313);

[0587] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (I-314);

[0588] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-315);

[0589] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-methylbenzoic acid (I-316);

[0590] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-methylbenzoic acid (I-317);

[0591] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-ethylbenzoic acid (I-318);

[0592] 2-Cyclopropyl-4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-319);

[0593] 4-Cyclopropyl-2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-320);

[0594] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-2-carboxylic acid (I-321);

[0595] 6-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-3-carboxylic acid (I-322);

[0596] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyrimidine-2-carboxylic acid (I-323);

[0597] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyrazine-2-carboxylic acid (I-324);

[0598] 6-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridazine-3-carboxylic acid (I-325);

[0599] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluoropyridine-2-carboxylic acid (I-326);

[0600] 3-{5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridin-2-yl}propionic acid (I-327);

[0601] 3-{5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluoropyridin-2-yl}propionic acid (I-328);

[0602] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-[(2,2-dimethyloxane-4-yl)sulfonyl]benzamide (I-329);

[0603] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-[(2,2-dimethyloxane-4-yl)sulfonyl]-2-fluorobenzamide (I-330);

[0604] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)-2-fluorobenzamide (I-331);

[0605] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-2-fluoro-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide (I-332);

[0606] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-2-fluoro-N-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)benzamide (I-333);

[0607] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-2-fluoro-N-((tetrahydrofuran-3-yl)sulfonyl)benzamide (I-334);

[0608] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-2-fluoro-N-(((tetrahydrofuran-3-yl)methyl)sulfonyl)benzamide (I-335);

[0609] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-2-fluoro-N-((2-(tetrahydrofuran-3-yl)ethyl)sulfonyl)benzamide (I-336);

[0610] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)benzamide (I-337);

[0611] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide (I-338);

[0612] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)benzamide (I-339);

[0613] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-((tetrahydrofuran-3-yl)sulfonyl)benzamide (I-340);

[0614] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-(((tetrahydrofuran-3-yl)methyl)sulfonyl)benzamide (I-341);

[0615] 4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-((2-(tetrahydrofuran-3-yl)ethyl)sulfonyl)benzamide (I-342);

[0616] N-(cyclopentylsulfonyl)-4-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)benzamide (I-343);

[0617] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-{[(1R,2R)-2-hydroxycyclopentyl]sulfonyl}benzamide (I-344)

[0618] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (1R,2R)-2-aminosulfonylcyclopentyl ester (I-345);

[0619] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-{[(1R,2R)-2-hydroxycyclopentyl]sulfonyl}benzamide (I-346);

[0620] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (1R,2R)-2-aminosulfonylcyclopentyl ester (I-347)

[0621] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluoro-N-{[(1R,2R)-2-methoxycyclopentyl]sulfonyl}pyridine-2-carboxamide (I-348);

[0622] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluoro-N-{[(1R,2R)-2-hydroxycyclopentyl]sulfonyl}pyridine-2-carboxamide (I-349);

[0623] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-{[(1R,2R)-2-hydroxycyclopentyl]sulfonyl}pyridine-2-carboxamide (I-350);

[0624] 5-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)pyridineamide (I-351);

[0625] 5-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyridineamide (I-352);

[0626] N-(cyclopentylsulfonyl)-5-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)pyridineamide (I-353);

[0627] 5-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)sulfonyl)pyridineamide (I-354);

[0628] 5-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-(cyclopropylsulfonyl)-3-fluoropyridineamide (I-355);

[0629] N-(cyclopentylsulfonyl)-5-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-3-fluoropyridine amide (I-356);

[0630] 5-((1S,4R,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazo-4-yl)methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)sulfonyl)-3-fluoropyridineamide (I-357);

[0631] 2-({4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)acetic acid (I-358);

[0632] 2-({4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)ethane-1-sulfonic acid (I-359);

[0633] 4-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-360);

[0634] 4-[(1R,3S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-361);

[0635] 4-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (I-362);

[0636] 4-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-363);

[0637] 4-[(1R,3S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid (I-364);

[0638] 4-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-ethyl-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-365);

[0639] -[(1R,3S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-ethyl-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (I-366);

[0640] 5-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-2-carboxylic acid (I-367);

[0641] 5-[(1R,3S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-2-carboxylic acid (I-368);

[0642] 6-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-3-carboxylic acid (I-369);

[0643] 6-[(1R,3S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-3-carboxylic acid (I-370);

[0644] 5-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)pyridine-2-carboxamide (I-371);

[0645] 5-[(1R,3S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)pyridine-2-carboxamide (I-372);

[0646] 6-[(1S,3R,4S,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)pyridine-3-carboxamide (I-373); and

[0647] 6-[(1R,3S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-methyl-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)pyridine-3-carboxamide (I-374).

[0648] In another embodiment, the compound is selected from:

[0649] 6-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridazine-3-carboxylic acid;

[0650] 4-[(1S,4R,5R)-5-{[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-(oxane-4-sulfonyl)benzamide;

[0651] 3-{4-[(1S,4R,5R)-5-{[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}propionic acid;

[0652] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyrazine-2-carboxylic acid;

[0653] 3-{5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridin-2-yl}propionic acid;

[0654] 4-[(1S,4R,5R)-5-{[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0655] 4-[(1S,4R,5R)-5-{[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid;

[0656] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)pyridine-2-carboxamide;

[0657] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyrimidine-2-carboxylic acid;

[0658] 6-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-3-carboxylic acid;

[0659] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]pyridine-2-carboxylic acid;

[0660] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-{[(1R,2R)-2-hydroxycyclopentyl]sulfonyl}benzamide;

[0661] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid (1R,2R)-2-aminosulfonylcyclopentyl ester;

[0662] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-{[(1R,2R)-2-hydroxycyclopentyl]sulfonyl}benzamide;

[0663] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid (1R,2R)-2-aminosulfonylcyclopentyl ester;

[0664] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-[2-(oxacyclopentane-3-yl)ethanesulfonyl]benzamide;

[0665] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-[2-(oxacyclopentan-3-yl)ethanesulfonyl]benzamide;

[0666] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-[(oxane-4-yl)methanesulfonyl]benzamide;

[0667] 4-Cyclopropyl-2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0668] 2-Cyclopropyl-4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0669] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-[(oxane-4-yl)methanesulfonyl]benzamide;

[0670] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-methylbenzoic acid;

[0671] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-[(2,2-dimethyloxane-4-yl)sulfonyl]-2-fluorobenzamide;

[0672] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-[(2,2-dimethyloxane-4-yl)sulfonyl]benzamide;

[0673] 2-({4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)ethane-1-sulfonic acid;

[0674] 2-({4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}formamido)acetic acid;

[0675] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2,3-dihydro-1H-indene-2-carboxylic acid;

[0676] 4-[(1S,4R,5R)-5-({5-cyclopropyl-3-[2-fluoro-6-(propane-2-yl)phenyl]-1,2-oxazol-4-yl}methoxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0677] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-ethylbenzoic acid;

[0678] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-methylbenzoic acid;

[0679] 5-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2,3-dihydro-1H-indene-1-carboxylic acid;

[0680] 4-Cyclopropoxy-2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid;

[0681] 2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-4-{7-oxaspiro[3.5]nonane-2-yl}-1,3-benzothiazol-6-carboxylic acid;

[0682] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2-cyclopropyl-6-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0683] N-(cyclopropanesulfonyl)-4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzamide;

[0684] 2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-4-(oxacyclopentane-3-yl)-1,3-benzothiazol-6-carboxylic acid;

[0685] 2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-4-ethyl-1,3-benzothiazol-6-carboxylic acid;

[0686] 4-[(1S,4R,5R)-5-{[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0687] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0688] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0689] N-(cyclopropanesulfonyl)-4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzamide;

[0690] 4-[(1S,4R,5R)-5-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0691] N-(cyclopentanesulfonyl)-4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzamide;

[0692] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-[(oxacyclopentane-3-yl)methanesulfonyl]benzamide;

[0693] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-(oxacyclopentane-3-sulfonyl)benzamide;

[0694] 4-Cyclobutyl-2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid;

[0695] 4-Cyclopropyl-2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-1,3-benzothiazol-6-carboxylic acid;

[0696] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorobenzoic acid;

[0697] 2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-4-(oxane-4-yl)-1,3-benzothiazol-6-carboxylic acid;

[0698] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-[(oxacyclopentane-3-yl)methanesulfonyl]benzamide;

[0699] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxacyclopentane-3-sulfonyl)benzamide;

[0700] 3-{4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorophenyl}propionic acid;

[0701] 2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(3S)-oxacyclopentane-3-yloxy]-1,3-benzothiazol-6-carboxylic acid;

[0702] 2-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-4-[(3R)-oxacyclopentane-3-yloxy]-1,3-benzothiazol-6-carboxylic acid;

[0703] 3-{4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-3-fluorophenyl}propionic acid;

[0704] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-N-(oxane-4-sulfonyl)benzamide;

[0705] 3-{4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]phenyl}propionic acid;

[0706] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluoro-N-(oxane-4-sulfonyl)benzamide;

[0707] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]-2-fluorobenzoic acid;

[0708] 4-[(1S,4R,5S)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0709] 4-[(1S,4R,5R)-5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl]benzoic acid;

[0710] In another embodiment of the invention, the compound of formula (I) is an enantiomer. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In still other embodiments, the compound of formula (I) may be a (+) or (-) enantiomer.

[0711] In another embodiment of the invention, the compound of formula (I) is a diastereomer.

[0712] It should be understood that all isomers are included within the scope of this invention, including mixtures thereof. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomers are also intended to be included.

[0713] The compounds of the present invention, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are considered part of the present invention herein.

[0714] The compounds of this invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of this invention, as well as mixtures thereof (including racemic mixtures), are intended to form part of this invention. Furthermore, this invention covers all geometric and positional isomers. For example, if the compounds of this invention incorporate double bonds or fused rings, the cis and trans forms, as well as mixtures thereof, are covered within the scope of this invention. Each compound disclosed herein includes all enantiomers conforming to the general structure of that compound. Compounds may be in racemic or enantiomerically pure forms, or in any other form for stereochemical purposes. Measurement results may reflect data collected for the racemic form, the enantiomerically pure form, or any other form for stereochemical purposes.

[0715] A mixture of diastereomers can be separated into their individual diastereomers based on physicochemical differences using methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Diastereomers can also be separated by reacting with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher acyl chloride) and converting (e.g., hydrolyzing) individual diastereomers into their corresponding pure enantiomers. Additionally, some compounds of the present invention can be transisomers (e.g., substituted biaryl groups) and are considered part of the invention. Enantiomers can also be separated by utilizing a chiral HPLC column.

[0716] The compounds of the present invention may also exist in different tautomeric forms, and all such forms are covered within the scope of the present invention. Additionally, the present invention includes, for example, all keto-enol and imine-enamine forms of the compounds.

[0717] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the present invention (including salts, solvates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of the prodrugs), such as those that may exist due to asymmetric carbons on various substituents, including enantiomers (even in the absence of asymmetric carbons), rotational isomers, trans-blocking isomers, and diastereomeric isomers, are considered to be within the scope of the present invention, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, if the compound of formula (I) incorporates a double bond or a fused ring, the cis and trans forms, as well as mixtures thereof, are covered within the scope of the present invention. Additionally, the present invention includes, for example, all keto-enol and imine-enamine forms of the compounds). Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may, for example, be racemic or mixed with all other or other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined in IUPAC 1974 Recommendations. The use of the terms “salt,” “solvent,” “ester,” “prodrug,” etc., is intended to equally apply to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the present invention.

[0718] Compounds of Formula I can form salts that are also within the scope of this invention. Unless otherwise stated, references to chemical formulas herein are understood to include references to their salts.

[0719] This invention relates to compounds that act as modulators of FXR. In one embodiment, the compounds of this invention are activators (agonists) of FXR.

[0720] This invention relates to compounds as described herein and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers, as well as pharmaceutical compositions comprising one or more compounds as described herein or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers.

[0721] Methods for synthesizing compounds

[0722] The compounds of this invention can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are described in the schemes given below.

[0723] As illustrated in part by the following synthetic scheme, compounds of formula (I) can be prepared by methods known in the field of organic synthesis. It is well known in the schemes described below that...

[0724] The protection of sensitive or reactive groups is used when necessary, according to general or chemical principles. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PGM Uts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods obvious to those skilled in the art. The selection of procedures, reaction conditions, and their sequence of execution should be consistent with the preparation of compounds of formula (I).

[0725] Those skilled in the art will recognize the presence of a stereocenter in the compound of formula (I). Therefore, the present invention includes two possible stereoisomers (unless specified in the synthesis), and includes not only racemic compounds, but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereooriented synthesis or by resolving the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be achieved by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E.L. Leel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0726] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic methods.

[0727] Preparation of compounds

[0728] The compounds of the present invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof as understood by those skilled in the art. These methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to the steps outlined in general embodiments 1, 2, 3, and 4, which constitute different sequences of combinatorial intermediates. The starting materials are commercially available or prepared by known procedures in reported literature or as illustrated.

[0729] General Scheme 1

[0730]

[0731] Among them, A, B and R 1 -R 4 As defined in equation (I), R 3bX is an alkyl group, X is a halogen (i.e., Cl, F, etc.) or other suitable leaving group (i.e., methanesulfonate), and PG is a protecting group (i.e., tert-butyl carbonate (BOC)).

[0732] The general method for preparing the target compound of formula (I) using intermediates 2a-2f, 2g1, 2g2, 2h1, 2h2, 2i1, 2i2, 2j, 2k1, and 2k2 is outlined above in General Scheme 1. Optionally, at high temperature, aldehyde 2a is condensed with hydroxylamine hydrochloride in the presence of a base (i.e., sodium hydroxide (NaOH)) and in a solvent (i.e., water (H2O) and / or ethanol (EtOH)) to give intermediate 2b. Intermediate 2c is then prepared by treating 2b in a solvent (i.e., N,N-dimethylformamide (DMF)) with a chlorinating agent (i.e., N-chlorosuccinimide). 2c is cyclized with β-keto ester 2d in the presence of a base (i.e., NET3, NaOMe, and / or tBuOK) and in a solvent (i.e., dichloromethane) to give intermediate 2e. Optionally, at high temperature, 2e is hydrolyzed in the presence of a base (i.e., lithium hydroxide monohydrate) and in a solvent (i.e., EtOH / H2O) to produce acid 2f. Acid 2f is treated with an activating agent (i.e., 1,1'-carbonyldiimidazole (CDI)) and then optionally reacted at high temperature in a solvent (i.e., DMF) with a protected 3-hydroxy-aza-bicycloheptane intermediate 2g1 or 2g2 to form ester 2h1 or 2h2. Alternatively, acid 2f can be converted to an acyl chloride in a solvent (i.e., DMF) using a chlorinating agent (i.e., chlorothiophene), and then reacted with a protected 3-hydroxy-aza-bicycloheptane intermediate 2g1 or 2g2 in the presence of DMAP and a base (i.e., triethylamine (Et3N)) and in a solvent (i.e., DMF) to form ester 2h1 or 2h2.

[0733] Intermediate 2h1 or 2h2 (i.e., when PG is an acid-labile group, i.e., BOC) is deprotected in a strong acid (i.e., trifluoroacetic acid (TFA)) and in a solvent (i.e., dichloromethane (DCM)) to give intermediate 2i1 or 2i2. At high temperature in a solvent (e.g., DMF), 2i1 or 2i2 is coupled to 2j using a catalytic amount of palladium catalyst and ligands (i.e., palladium(II) acetate (Pd(OAc)2) and 1,1'-ferrocene di-bis(diphenylphosphine) (dppf)) and acetic anhydride, wherein R in reagent 2j... 4 Optional protection, when R 4 When not protected, the desired product of formula (I) is obtained, or when R... 4 When protected, the higher intermediate 2k1 or 2k2 is obtained. Alternatively, 2i1 or 2i2 and 2j are treated with a base in a solvent and optionally at high temperature, wherein R in reagent 2j... 4 Optional protection, when R 4When not protected, the desired product of formula (I) is obtained, or when R... 4 When protected, the advanced intermediate 2k1 or 2k2 is obtained. The intermediate 2k1 or 2k2 is deprotected to obtain the desired product of formula (I).

[0734] General Option 2

[0735]

[0736] Among them, A, B, R 1 -R 4 And L1 is as defined in equation (I).

[0737] The general method for preparing the target compound of formula (I) using intermediates 2f and 3a to 3i, as outlined above in General Scheme 2, is -(CH2) m (C=O)-, X1 is CH2, and X2 is NR. x Intermediate 2f is reduced in a solvent (i.e., tetrahydrofuran (THF)) using a reducing agent (i.e., lithium aluminum hydride (LAH)) to give alcohol 3a. Alcohol 3a is treated with chlorothiophene in a solvent (i.e., DCM) to give chloride 3b. Optionally, 3b is cyaninated in a solvent (i.e., water) at high temperature in the presence of potassium cyanide or sodium cyanide to give intermediate 3c. Nitrile 3c is hydrolyzed using a base (i.e., sodium hydroxide (NaOH)) in a solvent (i.e., H2O and / or EtOH) and optionally at high temperature to give 3d. Alternatively, alcohol 3a can be oxidized to aldehyde 3e, which is further converted to a two-carbon-extended α,β-unsaturated ester 3f via standard Wittig reaction conditions (i.e., (carboxymethyl)triphenylphosphonium bromide, base (i.e., potassium tert-butoxide), and solvent (i.e., THF)). 3f is hydrogenated in the presence of a metal catalyst (i.e., carbon-supported palladium) and in a solvent (i.e., DCM), followed optionally by hydrolysis of the resulting ester at high temperature in the presence of a base (i.e., lithium hydroxide monohydrate) and in a solvent (i.e., EtOH / H2O) to give acid 3g. 3d or 3h and 2g1 are coupled to the 3-hydroxy-aza-bicycloheptane intermediate 2g1 under standard acylation conditions (i.e., treatment with DMAP and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in a solvent (i.e., DCM) for 3h and 2g1) to form ester 3i. Intermediate 3i can be converted to the desired product of formula (I) as described above in steps 6 to 8 of general scheme 1. The compound of formula (I) can also be synthesized from the hydroxy-aza-bicycloheptane intermediate 2g2 as described above in steps 1 to 8 of general scheme 2 and steps 6 to 8 of general scheme 1.

[0738] General Scheme 3

[0739]

[0740] Among them, A, B and R 1 -R 4 As defined in equation (I)

[0741] Alternatively, as outlined above in General Scheme 3, intermediates 2i1, 2i2, 4a, 4b1, and 4b2 can be used to prepare a compound of formula (I), wherein L1 is (C=O) and L2 is -S(O)2-, X1 is CH2, and X2 is NR. x The ester-substituted intermediate 2i1 or 2i2 is sulfonated with a substituted sulfonyl chloride 4a in the presence of a base (i.e., N,N-diisopropylethylamine (DIEA)) and in a solvent (i.e., DCM) to give sulfonamide intermediate 4b1 or 4b2. Intermediate 4b1 is deprotected to give the desired product of formula (I). Alternatively, intermediate 4b2 is deprotected to give the desired product of formula (I).

[0742] General Scheme 4

[0743]

[0744] Among them, A, B and R 1 -R 4 As defined in equation (I)

[0745] Alternatively, compounds of formula (I) can be prepared using intermediates 2e, 2g2, 2j, 3a, 3b, 4a, 4b, and 4c, as outlined above in General Scheme 4, where L1 is –(CH2). p - The intermediate 2e is reduced in a solvent (i.e., tetrahydrofuran (THF)) using a reducing agent (i.e., lithium aluminum hydride (LAH)) to give alcohol 3a. Alcohol 3a is treated with chlorothiophene in a solvent (i.e., DCM) to give chloride 3b. Nucleophilic addition of 2g1 to 3b in the presence of a base (i.e., sodium hydride (NaH)) and in a solvent (i.e., THF) gives 4a. Intermediate 4a (i.e., when PG is an acid-labile group, i.e., BOC) is deprotected in a strong acid (i.e., trifluoroacetic acid (TFA)) and in a solvent (i.e., dichloromethane (DCM)) to give intermediate 4b. Alternatively, when PG is a benzyloxycarbamate (Cbz), intermediate 4a is also deprotected in a solvent (i.e., dichloromethane (DCM)) in the presence of a palladium catalyst (i.e., carbon-supported palladium) to give intermediate 4b. At high temperature in a solvent (e.g., DMF), catalytic amounts of a palladium catalyst and ligands (i.e., palladium(II) acetate (Pd(OAc)2) and 1,1'-ferrocene di-bis(diphenylphosphine) (dppf)) and acetic anhydride are used to couple 4b to 2j, wherein R in reagent 2j... 4Optionally protected, intermediate 4c is obtained. Deprotection of intermediate 4c yields the desired product of formula (I). Alternatively, the compound of formula (I) can be synthesized from the hydroxy-aza-bicycloheptane intermediate 2g2 as described above in steps 1 to 6 of general scheme 4.

[0746] It should be understood that in the description and chemical formulas shown above, the various groups L1, L2, A, B, R... 1 R 2 R 3 R 4 R 5 R 6a R 6b R 6c R 6d R 6e R 7 R 8 R 9 m and n, and other variables, are as defined above, unless otherwise stated. Furthermore, for synthetic purposes, the compounds of general schemes 1, 2, and 3 are merely representative, illustrating the general synthetic methods for compounds of formula (I) as defined herein, using selected functional groups.

[0747] Method using the disclosed compounds

[0748] Another aspect of the invention relates to a method for modulating FXR. The method comprises administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0749] Another aspect of the invention relates to a method for regulating FXR. The method comprises administering to a patient in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0750] In another aspect, the present invention relates to a method for activating FXR. The method involves administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0751] In another aspect, the present invention relates to a method for activating FXR. The method involves administering to a patient in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

[0752] Another aspect of the invention relates to methods for treating, preventing, inhibiting, or eliminating diseases or conditions in which FXRs function. The method comprises administering to a patient requiring treatment of a disease or condition in which FXRs function an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0753] Another aspect of the invention relates to a method for treating, preventing, inhibiting, or eliminating a disease or condition in which FXR functions. The method comprises administering to a patient requiring treatment of a disease or condition in which FXR functions an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0754] Another aspect of the invention relates to a method for modulating FXR. The method comprises administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0755] Another aspect of the invention relates to a method for regulating FXR. The method comprises administering to a patient in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0756] Another aspect of the invention relates to a method for treating, preventing, inhibiting, or eliminating a disease or condition in a patient associated with the activation of FXR, the method comprising administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0757] Another aspect of the invention relates to a method for treating, preventing, inhibiting, or eliminating a disease or condition in a patient associated with FXR activation, the method comprising administering to a patient in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0758] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating liver disease. The methods include administering to a patient requiring treatment of liver disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0759] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating liver disease. The methods include administering to a patient requiring treatment of liver disease an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0760] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating enteropathy. The methods include administering to a patient requiring treatment of enteropathy an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0761] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating enteropathy. The methods include administering to a patient requiring treatment of enteropathy an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0762] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating kidney disease. The methods include administering to a patient requiring treatment of kidney disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0763] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating kidney disease. The methods include administering to a patient requiring treatment of kidney disease an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0764] In another aspect, the present invention relates to methods for treating, preventing, suppressing, or eliminating autoimmune diseases. The methods include administering to a patient requiring treatment for an autoimmune disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0765] In another aspect, the present invention relates to methods for treating, preventing, suppressing, or eliminating autoimmune diseases. The methods include administering to a patient requiring treatment for an autoimmune disease an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0766] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating cancer. The methods include administering to a patient requiring cancer treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0767] In another aspect, the present invention relates to methods for treating, preventing, inhibiting, or eliminating cancer. The methods include administering to a patient requiring cancer treatment an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0768] Another aspect of the invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for the treatment, prevention, inhibition, or elimination of diseases or conditions in which FXR functions. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0769] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for the treatment, prevention, inhibition or elimination of a disease or condition in which FXR functions. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0770] In another aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment, prevention, inhibition or elimination of liver disease.

[0771] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment, prevention, inhibition or elimination of diseases associated with FXR activation.

[0772] In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for the treatment, prevention, inhibition or elimination of liver disease.

[0773] In another aspect, the present invention relates to compounds of formula (I) or (Ia) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment, prevention, inhibition or elimination of enteropathy.

[0774] In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier thereof, for the treatment, prevention, inhibition or elimination of enteropathy.

[0775] In another aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment, prevention, inhibition or elimination of kidney disease.

[0776] In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for the treatment, prevention, inhibition or elimination of kidney disease.

[0777] In another aspect, the present invention relates to compounds of formula (I) or (Ia) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment, prevention, inhibition or elimination of autoimmune diseases.

[0778] In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier thereof, for the treatment, prevention, inhibition or elimination of autoimmune diseases.

[0779] In another aspect, the present invention relates to compounds of formula (I) or (Ia) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for the treatment, prevention, inhibition or elimination of cancer.

[0780] In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier thereof, for the treatment, prevention, inhibition or elimination of cancer.

[0781] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition in which FXR functions. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0782] Another aspect of the invention relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for treating, preventing, inhibiting or eliminating a disease or condition in which FXR functions. In one embodiment, the disease or condition is a liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0783] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the preparation of a medicament for the treatment, prevention, inhibition or elimination of liver disease.

[0784] In another aspect, the present invention relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for treating, preventing, inhibiting or eliminating liver disease.

[0785] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the preparation of a medicament for the treatment, prevention, inhibition or elimination of enteropathy.

[0786] In another aspect, the present invention relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for treating, preventing, inhibiting or eliminating enteropathy.

[0787] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the preparation of a medicament for the treatment, prevention, inhibition or elimination of kidney disease.

[0788] In another aspect, the present invention relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for treating, preventing, inhibiting or eliminating kidney disease.

[0789] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the preparation of a medicament for the treatment, prevention, inhibition or elimination of autoimmune diseases.

[0790] In another aspect, the present invention relates to the use of pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for treating, preventing, inhibiting or eliminating autoimmune diseases.

[0791] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the preparation of a medicament for the treatment, prevention, inhibition or elimination of cancer.

[0792] In another aspect, the present invention relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for treating, preventing, inhibiting or eliminating cancer.

[0793] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating diseases associated with FXR activation.

[0794] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the preparation of a medicament for treating diseases associated with activation of FXR.

[0795] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating diseases in which FXR functions.

[0796] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the preparation of a medicament for treating a disease in which FXR functions.

[0797] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating liver diseases.

[0798] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the preparation of a medicament for treating liver diseases.

[0799] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating enteropathy.

[0800] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the preparation of a medicament for treating enteropathy.

[0801] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for the treatment of kidney disease.

[0802] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the preparation of a medicament for treating kidney disease.

[0803] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for the treatment of autoimmune diseases.

[0804] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the preparation of a medicament for treating an autoimmune disease.

[0805] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, for use in the preparation of medicaments for treating cancer.

[0806] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the preparation of a medicament for treating cancer.

[0807] In other embodiments, the present invention relates to the use of FXR activators in the preparation of medicaments for the treatment, prevention, inhibition or elimination of liver disease.

[0808] In other embodiments, the present invention relates to the use of FXR activators in the preparation of medicaments for the treatment, prevention, inhibition or elimination of intestinal diseases.

[0809] In other embodiments, the present invention relates to the use of FXR activators in the preparation of medicaments for the treatment, prevention, inhibition or elimination of kidney disease.

[0810] In other embodiments, the present invention relates to the use of FXR activators in the preparation of medicaments for the treatment, prevention, suppression or elimination of autoimmune diseases.

[0811] In other embodiments, the present invention relates to the use of FXR activators in the preparation of medicaments for treating, preventing, inhibiting or eliminating cancer.

[0812] The present invention also relates to the use of FXR activators in the preparation of medicaments for treating, preventing, inhibiting or eliminating diseases or symptoms in which FXR plays a role, wherein the medicament comprises a compound of formula (I).

[0813] In another aspect, the present invention relates to a method for preparing a medicament for treating, preventing, inhibiting or eliminating diseases or symptoms mediated by FXR, wherein the medicament comprises a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0814] In some embodiments of the methods described herein, the disease or symptom is selected from liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer. In other embodiments, the disease may be any disease including but not limited to Alagille syndrome (ALGS), atherosclerosis, biliary atresia, Byler's disease, gallstones, hyperlipidemia, hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, kidney cancer, esophageal cancer, obesity, type 2 diabetes, and gastric cancer.

[0815] In any embodiment of the invention, the liver disease can be any liver disease, including but not limited to primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, intrahepatic and extrahepatic cholestasis, biliary atresia, portal hypertension (PAH), spontaneous bacterial peritonitis (SBP), acute decompensated liver failure, hepatorenal syndrome, and hepatic encephalopathy. In one embodiment, the liver disease is NASH. In one embodiment, the liver disease is NAFLD. In one embodiment, the liver disease is NASH, and the compounds of the invention are administered in combination with anti-inflammatory or antifibrotic agents.

[0816] In any embodiment of the invention, the enteropathy can be any enteropathy, including but not limited to inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, celiac disease, and bile acid diarrhea.

[0817] In one embodiment, the disease is a bowel permeability disorder, condition, or symptom mediated by tight junction dysfunction. In one embodiment, the disease, condition, or symptom is a gastric ulcer, infectious diarrhea, irritable bowel syndrome, functional GI disorders (IBS, IBS-C, IBS-D, IBS-M, post-infectious IBS), inflammatory bowel disease (CD, UC), celiac disease, cancer (colorectal), leaky gut syndrome, clinical manifestations of cystic fibrosis GI, multiple organ failure, microscopic colitis, or necrotizing enterocolitis.

[0818] In another embodiment, the compounds of the present invention are used to treat one of the following diseases, conditions, or symptoms: allergies, such as atopic dermatitis or food allergies; infections, such as respiratory infections; acute inflammation, such as sepsis, SIRS, or MOF; chronic inflammation, such as arthritis; metabolic diseases induced by obesity, such as NASH, diabetes, type 1 diabetes / type 2 diabetes, or CVD; kidney diseases, such as chronic kidney disease or diabetic nephropathy; heart diseases, such as heart failure or congestive heart failure; and liver diseases, such as cirrhosis, NASH, NAFLD, or steatosis. PSC, PBC, portal hypertension; autoimmune diseases such as type 1 diabetes, celiac disease, multiple sclerosis, IBD, ankylosing spondylitis, RA, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, multiple sclerosis, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, Crohn's disease, ulcerative colitis, urticaria (measles), and Raynaud's syndrome; neurological disorders such as schizophrenia, autism spectrum disorder, multiple sclerosis, hepatic encephalopathy; and chronic alcoholism.

[0819] In any embodiment of the invention, the kidney disease can be any kidney disease, including but not limited to fibrotic nephropathy and diabetic nephropathy.

[0820] In any embodiment of the present invention, the autoimmune disease can be any autoimmune disease, including but not limited to inflammatory bowel disease, autoimmune hepatitis, autoimmune liver disease (primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)) and multiple sclerosis.

[0821] In any embodiment of the present invention, the cancer can be any cancer, including but not limited to, selected from hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, esophageal cancer, or gastric cancer.

[0822] In another embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for the treatment of diseases including but not limited to liver disease, enteropathy, kidney disease, autoimmune disease or cancer.

[0823] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0824] One implementation provides a method for treating a disease or condition in which FXR is active, including liver disease, intestinal disease, kidney disease, or autoimmune disease, comprising administering a compound of formula (I) to a patient suffering from at least one of said diseases or conditions.

[0825] One therapeutic use of the compounds or compositions of the present invention that activate FXR is to provide treatment to patients or subjects suffering from liver disease, intestinal disease, kidney disease, autoimmune disease, or cancer.

[0826] The compound...

Claims

1. A compound of formula (Ik): Or its pharmaceutically acceptable salt, stereoisomer, or tautomer. in: L2 is the key; A is a cycloalkyl or aryl group, wherein the cycloalkyl or aryl group is optionally influenced by one or more R groups. 7 replace; B is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally influenced by one or more R groups. 5 The substitution, wherein the heteroaryl group comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O and S, or comprises two 5- or 6-membered rings and 1-4 heteroatoms selected from N and O; R 1 and R 2 Each is independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen or cycloalkyl; R 3 It is a cycloalkyl group that is optionally substituted with one or more halogens; R 4 It is COOR 6a -(CH2) n -COOR 6a CONR 6b R 6c CONR 6b SO2R 6d -(CH2) n -CONR 6b SO2R 6d COR 6f (CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n CO OR 6a SO2R 6e , oxo, alkyl, cycloalkyl, -(CH2) n -cycloalkyl, -(CH2) n -Heterocyclic alkyl, heteroaryl, or -(CH2) n -Heteroaryl; wherein the alkyl, cycloalkyl, -(CH2) n -cycloalkyl, -(CH2) n -Heterocyclic alkyl groups, heteroaryl groups, and -(CH2) n -Hybrid aryl groups are selectively controlled by COOR 6a -(CH2) n -COOR 6a CONR 6b R 6c CONR 6b SO2R 6d -(CH2) n -CONR 6b SO2R 6d COR 6f (CH2) n PO(OR 6g 2. SO2NR 6b (CH2) n COOR 6a or SO2R 6e Substitution, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S; Each R 5 Each time it appears, it is independently a halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, -O-cycloalkyl or -O-heterocyclic alkyl; R 6a It is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally selected by one or more of the following independently: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, NR. 6b R 6c SO2NR 6b R 6c Substitution with -OH groups, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S; R 6b and R 6c Each of the following is independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one or more substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and -OH, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S; R 6d It is an alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is optionally selected by one or more of the following independently: halogen, COOH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, -O-CO-alkyl, -O-COcycloalkyl, -O-CO-alkyl-COOH, NR 6b R 6c NR 6f CO-alkyl, NR 6f The substituents CO-alkoxy, cycloalkyl, heterocycloalkyl and -OH are used, wherein the heteroaryl group comprises one or two 5 or 6-membered rings and 1-4 heteroatoms selected from N, O and S; R 6e It is -OH, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more substituents each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and -OH, wherein the heteroaryl comprises one or two 5 or 6-membered rings and 1 to 4 heteroatoms selected from N, O and S; R 6f It is an alkyl or haloalkyl group; R 6g It is H or an alkyl group optionally substituted with -O-CO-alkyl; Each R 7 Each time it appears, it is independently OH, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. in: The term "cycloalkyl" refers to C3-C8 cycloalkyl groups; The term "aryl" refers to C6-C 10 Aryl; The term "alkyl" refers to C1-C6 alkyl groups; The term "alkoxy" refers to C1-C6 alkoxy groups; The term "haloalkyl" refers to C1-C6 haloalkyl; The term "haloalkoxy" refers to C1-C6 haloalkoxy groups; and The term "heterocyclic alkyl" contains one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein A is optionally composed of one or more R 7 Replacement C6-C 10 Aryl.

3. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein A is optionally composed of one or more R 7 Substituted phenyl groups.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 and R 2 Each is independently H, halogen, or C1-C6 haloalkyl.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein A is not R 7 Substituted phenyl, and R 1 and R 2 Both are relative to the Cl in the ortho position of the isoxazole ring.

6. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein B is a C6-C compound optionally substituted with a C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, or CN. 10 Aryl.

7. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein B is optionally R 5 Substituted phenyl groups.

8. The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 5 It is F.

9. The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein B is an unsubstituted phenyl group.

10. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 It is a C3-C8 cycloalkyl group.

11. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 It is cyclopropyl.

12. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 It is a C3-C8 cycloalkyl group that has been substituted with halogen.

13. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 It is a cyclopropyl group that has been replaced by a halogen.

14. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 4 It is COOR 6a -(CH2) n -COOR 6a or CONR 6b SO2R 6d .

15. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 4 It is COOR 6a .

16. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 4 It is -(CH2) n -COOR 6a And n is 2.

17. The compound of claim 14 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6a It's H.

18. The compound of claim 17 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 2.

19. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 4 It is CONR 6b SO2R 6d .

20. The compound of claim 19 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6b It's H.

21. The compound of claim 19 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6d It is a heterocyclic alkyl group.

22. The compound of claim 19 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6d It is an oxalyl group.

23. Use of the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in the preparation of a medicament for modulating farnesoid X receptor (FXR), wherein the medicament is formulated for administration to a subject.

24. Use of the compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, for the preparation of a medicament for activating a farnesoid X receptor (FXR), wherein the medicament is formulated for administration to a subject.

25. The use of any compound of claims 1 to 22 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in the preparation of a medicament for treating or preventing diseases in which farnesoid X receptors (FXR) function, wherein an effective amount of the medicament is formulated for administration to a subject in need.

26. The use as described in claim 25, wherein the disease is a liver disease, intestinal disease, kidney disease, or autoimmune disease.

27. The use as claimed in claim 26, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, intrahepatic or extrahepatic cholestasis, biliary atresia, or portal hypertension (PAH).

28. The use as claimed in claim 27, wherein the liver disease is non-alcoholic steatohepatitis (NASH).

29. The use as claimed in claim 26, wherein the enteropathy is inflammatory bowel disease, proctitis, colitis, celiac disease, or bile acid diarrhea.

30. The use as claimed in claim 29, wherein the enteropathy is Crohn's disease.

31. The use as claimed in claim 29, wherein the enteropathy is ulcerative colitis.

32. The use as claimed in claim 26, wherein the kidney disease is fibrotic nephropathy or diabetic nephropathy.

33. The use as described in claim 26, wherein the autoimmune disease is inflammatory bowel disease, autoimmune hepatitis, or multiple sclerosis.

34. The use as described in claim 26, wherein the autoimmune disease is an autoimmune liver disease (PBC, PSC).

35. The use as described in claim 25, wherein the disease is Alagille syndrome (ALGS), atherosclerosis, biliary atresia, Byler's disease, gallstones, hyperlipidemia, hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, esophageal cancer, obesity, type 2 diabetes, or gastric cancer.

36. A pharmaceutical composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier.

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