Benzoimidazoyl GLP-1 receptor agonists, pharmaceutical compositions containing same, and methods of use thereof

Abstract

Provided herein are GLP-1 receptor modulator compounds, pharmaceutical compositions, methods for their preparation, and methods of their use in treatment and / or diagnosis.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a PCT international application claiming the benefit of U.S. Provisional Application No. 63 / 282,686, filed November 24, 2021, and U.S. Provisional Application No. 63 / 183,612, filed May 3, 2021, the entire contents of each of which are incorporated herein by reference.

[0002] Provided herein are GLP-1 receptor modulator compounds, pharmaceutical compositions containing the compounds, methods for making the compounds, and methods of using the compounds and compositions for therapy. The compounds and compositions are useful, for example, in methods for treating and preventing metabolic diseases or conditions, detecting metabolic diseases or conditions, and diagnosing metabolic diseases or conditions. [Background technology]

[0003] Diabetes is a serious chronic disease that occurs when the pancreas does not produce enough insulin or when the body is unable to effectively use the insulin it produces. Diabetes complications include damage to the heart, blood vessels, eyes, kidneys, and nerves. Diabetes can increase the risk of heart disease and stroke. The consequences include serious impacts on quality of life, health, and mortality. WHO Global Report on Diabetes, 2016, World Health Organization. As of 2017, approximately 462 million people worldwide, or approximately 6.28% of the population, had type 2 diabetes, and this prevalence is increasing significantly. Khan et al., 2020, J. Epidemiol. Glob. Health 10(1):107-111. The global economic burden of diabetes was estimated at $1.3 trillion in 2015 and is estimated to increase to $2.1 trillion by 2030. Bommer et al., 2018, Diabetes Care 41(5):963-970. Approximately 90-95% of all diabetes cases are type 2 diabetes. Tripathi & Srivastava, 2016, Med. Sci. Monit. 12(7):RA130-147.

[0004] The glucagon-like peptide-1 receptor (GLP-1 receptor, or GLP1R) has emerged as a potential target for treating type 2 diabetes. Its ligand, glucagon-like peptide-1 (GLP-1), promotes glucose-induced insulin secretion and increases insulin synthesis, among many other effects. (Doyle and Egan, 2007, Pharmacol. Ther. 113(3):546-593) GLP-1 is known to delay gastric emptying, suppress food intake, increase satiety, and reduce body weight in humans. (Shah and Vella, 2014 Rev Endocr Metab Disord. 15(3):181-187) Activation of the GLP-1 receptor has been shown to have beneficial effects on insulin secretion and on maintaining beta-cell glucose sensing, transcription, synthesis, proliferation, and survival. (Doyle and Egan, 2007, supra) Although the GLP-1 receptor is a promising therapeutic target, only a handful of GLP-1 receptor drugs have been approved to date, and most or all of these are peptide or polypeptide drugs. Additional therapies are needed to treat metabolic diseases and conditions, such as type 2 diabetes. Small molecules that target the GLP-1 receptor should provide safe, stable, and easily administered therapeutic agents for metabolic diseases and conditions, such as type 2 diabetes. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Bommer et al.,2018,Diabetes Care 41(5):963-970 [Non-patent document 2] Tripathi & Srivastava,2016,Med.Sci.Monit.12(7):RA130-147 [Non-patent document 3] Doyle and Egan,2007,Pharmacol.Ther.113(3):546-593 [Non-patent document 4] Shah and Vella,2014 Rev Endocr Metab Disord.15(3):181-187 Summary of the Invention [Means for solving the problem]

[0006] Provided herein are GLP-1 receptor modulator compounds of Formulas (I)-(LVIII) and subformulae thereof, compositions comprising the compounds, methods of producing the compounds, and methods of using the compounds and crude products in therapy and diagnosis. The compounds of Formulas (I)-(LVIII) and subformulae, and embodiments thereof, are useful for modulating the activity of the GLP-1 receptor. In certain embodiments, the compounds can be used to agonize the activity of the GLP-1 receptor. In certain embodiments, the compounds can be used to treat diseases or conditions modulated by the GLP-1 receptor.

[0007] In one aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] wherein A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Ring B is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted bicyclic; Ring C is a substituted or unsubstituted C4-C6 heterocycloalkyl, or a substituted or unsubstituted C5 heterocycloalkenyl, or a substituted or unsubstituted phenyl, and the heterocycloalkyl and heterocycloalkenyl are each L as shown. 3 at least one N bonded to D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and; W is CR14 or C;W is CR 14 When W is C, the adjacent dashed line represents a double bond, or when L 2 is -C(H)=; L 1 is selected from the group consisting of a bond, —O—, —CH2—, and OCH2—; L 2 is selected from the group consisting of a bond, —CH—, —C(H)═, and —O—; L 3 is -CH2-, L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L 5 does not exist; L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist; R 4 is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; Each R 6 are independently alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11R 12 N-; R 11 is hydrogen or alkyl; R 12 is hydrogen or alkyl; R 13 is hydrogen or alkyl; R 14 is hydrogen, cyano, halo, hydroxyl, alkyl, haloalkyl, or methyl; In the formula, when ring C is C6 heterocycloalkyl, ring B is pyrazole or [ka] is.

[0008] In one aspect, there is provided a compound of formula (Ia), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] wherein A is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Ring B is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring C is further unsubstituted or further substituted and / or bridged; D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and; W is CH or C; when W is CH, the adjacent dashed line represents a single bond; When W is C, one adjacent dashed line indicates a double bond, e.g., L 2 is -C(H)=; L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, —C(H)═, and —O—; L 3 is -CH2-; L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L 5 does not exist; L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist; R 4 is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; Each R 6 is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11 R 12 N-, independently selected from the group consisting of: R 11 is hydrogen or alkyl; R 12 is hydrogen or alkyl; and R 13 is hydrogen or alkyl.

[0009] In one aspect, there is provided a compound of formula (Ib), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] wherein A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Ring B is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Ring C is further unsubstituted or further substituted and / or fused; D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and; L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, —C(H)═, and —O—; L 3 is -CH2-; L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L 5 does not exist; L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist; R 4 is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5-COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; Each R 6 is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11 R 12 N-, independently selected from the group consisting of: R 11 is hydrogen or alkyl; R 12 is hydrogen or alkyl; R 13 is hydrogen or alkyl.

[0010] In one aspect, there is provided a compound of formula (Ic), or a pharmaceutically acceptable salt, or stereoisomer thereof: [ka] wherein A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Ring B is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Ring C is further unsubstituted or further substituted and / or fused; C 1 , C 2 , C 3 , and C 4 0, 1, or 2 of these are N, and the rest are CH or CR 6 and; D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and; L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, —C(H)═, and —O—; L 3 is -CH2-; L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L 5 does not exist; L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist; R 4 is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; Each R 6 is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11 R 12 N-, independently selected from the group consisting of: R 11 is hydrogen or alkyl; R 12is hydrogen or alkyl; and R 13 is hydrogen or alkyl.

[0011] In one aspect, there is provided a compound selected from compounds 529, 530, 533, 534, 535, and 551, or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka]

[0012] In certain aspects, the compounds are useful in methods for treating and preventing metabolic diseases and conditions, detecting metabolic diseases and conditions, and diagnosing metabolic diseases and conditions.

[0013] In another aspect, provided herein is a composition comprising a compound of Formula (I), (Ia), (Ib), or (Ic). In some embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition may be used. In a further aspect, provided herein is a kit comprising a compound of Formula (I), (Ia), (Ib), or (Ic), or an embodiment thereof, or a pharmaceutical composition thereof.

[0014] In another aspect, provided herein are methods of using the compounds or compositions described herein. In some embodiments, the methods are for treatment. In some embodiments, the methods are diagnostic methods. In some embodiments, the methods are analytical methods. In some embodiments, the compounds or compositions described herein are used to treat a disease or condition. In some aspects, the disease or condition is selected from metabolic diseases or conditions. In certain embodiments, the disease is type 2 diabetes.

[0015] Also provided herein are uses of the compounds described herein and compositions thereof for the treatment of metabolic diseases or conditions. Also provided herein are uses of the compounds described herein and compositions thereof for the treatment of type 2 diabetes. DETAILED DESCRIPTION OF THE INVENTION

[0016] Described herein are GLP-1 receptor compounds that are useful in the treatment of metabolic diseases or conditions, such as type 2 diabetes.

[0017] definition Unless otherwise defined, all technical terms, notations, and other scientific terminology used herein shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for the sake of clarity and / or ready reference. The techniques and procedures described or referred to herein are generally well understood and commonly employed by those of ordinary skill in the art using conventional methodology. Where appropriate, procedures involving the use of commercially available kits and reagents are generally performed in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0018] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly indicates otherwise.

[0019] The term "about" denotes and encompasses the indicated value, as well as a range above and below that value. In certain embodiments, the term "about" denotes ±10%, ±5%, or ±1% of the specified value. In certain embodiments, the term "about" denotes the specified value ±1 standard deviation of that value. In certain embodiments, for example, on a logarithmic scale (e.g., pH), the term "about" denotes ±0.3, ±0.2, or ±0.1 of the specified value.

[0020] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise specified. 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. In the event that there are multiple definitions for terms herein, those in this section prevail unless stated otherwise.

[0021] "Alkoxy" and "alkoxyl" refer to the group -OR" where R" is alkyl or cycloalkyl. Alkoxy groups, in certain embodiments, include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0022] As used herein, the term "alkoxyamine" refers to an -alkylene-O-NH group, where alkylene is as defined herein. In some embodiments, an alkoxyamine group can react with an aldehyde to form an oxime residue. Examples of alkoxyamine groups include -CHCH-O-NH and -CH-O-NH.

[0023] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated, straight-chain or branched hydrocarbon. In certain embodiments, an alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkyl group contains 1 to 10 carbon atoms (i.e., C1 to C6). 10 In certain embodiments, alkyl is a lower alkyl, e.g., C 1-6and alkyl. In certain embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. In certain embodiments, "substituted alkyl" refers to an alkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkylalkylene. In some embodiments, the alkyl is unsubstituted.

[0024] The term "alkylene," as used herein, unless otherwise specified, refers to a divalent alkyl group, as defined herein. "Substituted alkylene" refers to an alkylene group substituted as described herein for alkyl. In some embodiments, the alkylene is unsubstituted.

[0025] "Alkenyl" refers, in certain embodiments, to an olefinically unsaturated hydrocarbon group which may be straight-chained or branched, having up to about 11 carbon atoms, or from 2 to 6 carbon atoms (e.g., "lower alkenyl"), and having at least 1, or from 1 to 2 sites of olefinic unsaturation. "Substituted alkenyl" refers to an alkenyl group substituted as described herein for alkyl.

[0026] "Alkenylene" refers to a divalent alkenyl as defined herein. Lower alkenylene is, for example, C2-C6 alkenylene.

[0027] "Alkynyl" refers, in certain embodiments, to an acetylenically unsaturated hydrocarbon group, which may be straight-chained or branched, having up to about 11 carbon atoms, or 2 to 6 carbon atoms (e.g., "lower alkynyl"), and having at least one, or 1 to 2, sites of acetylenic unsaturation. Non-limiting examples of alkynyl groups include acetylene (-C≡CH), propargyl (-CHC≡CH), and the like. "Substituted alkynyl" refers to an alkynyl group substituted as described herein for alkyl.

[0028] "Alkynylene" refers to a divalent alkynyl as defined herein. Lower alkenylene is, for example, C2-C6 alkynylene.

[0029] "Amino" refers to -NH2.

[0030] The term "alkylamino," as used herein, unless otherwise specified, refers to the group -NHR", where R is, for example, C, as defined herein. 1-10 In certain embodiments, alkylamino is C 1-6 It is alkylamino.

[0031] The term "dialkylamino," as used herein, unless otherwise specified, refers to the group -NR"R", where each R" is independently a C, as defined herein. 1-10 In certain embodiments, dialkylamino is di-C 1-6 It is alkylamino.

[0032] The term "aryl," as used herein, refers to phenyl, biphenyl, or naphthyl unless otherwise specified. The term includes both substituted and unsubstituted moieties. Aryl groups can be substituted with any of the listed moieties, including, but not limited to, one or more moieties (e.g., in some embodiments, one, two, or three moieties) selected from the group consisting of halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, where each moiety is independently unprotected or protected as needed, as understood by one of skill in the art (e.g., Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991); and the aryl in the arylamino and aryloxy substituents is not further substituted.

[0033] The term "arylamino", as used herein, unless otherwise specified, refers to the group -NR'R", where R' is hydrogen or C1-C6-alkyl; and R" is aryl as defined herein.

[0034] The term "arylene," as used herein, unless otherwise specified, refers to a divalent aryl group, as defined herein.

[0035] As used herein, unless otherwise specified, the term "aryloxy" means refers to an —OR group, where R is aryl as defined herein.

[0036] "Alkarylene" refers to an arylene group, as defined herein, in which the aryl ring is substituted with one or two alkyl groups. "Substituted alkarylene" refers to an alkarylene, as defined herein, in which the arylene group is further substituted as defined herein for aryl.

[0037] "Aralkylene" refers to an -alkyl-arylene- or arylene-alkyl, e.g., an -C-C alkyl-arylene-, -arylene-C-C alkyl-, or -C-C alkyl-arylene-C-C alkyl- group, where arylene is as defined herein. "Substituted alkarylene" refers to an aralkylene, as defined herein, in which the aralkylene group is substituted as defined herein for aryl. "Substituted C-C alkyl" refers to a C-C alkyl group that is substituted as defined herein for alkyl.

[0038] "Arylalkylene" refers to an -alkyl-arylene- or arylene-alkyl, e.g., an -C1-C2 alkyl-arylene-, -arylene-C1-C2 alkyl-, or -C1-C2 alkyl-arylene-C1-C2 alkyl- group, where arylene is as defined herein. "Substituted arylalkylene" refers to an arylalkylene, as defined herein, in which the arylalkylene group is substituted as defined herein for aryl. "Substituted C1-C2 alkyl" refers to a C1-C2 alkyl group that is substituted as defined herein for alkyl.

[0039] "Carboxyl" or "carboxy" refers to --C(O)OH or --COOH.

[0040] The term "cycloalkyl," as used herein, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, a cycloalkyl group can be saturated, and / or bridged, and / or unbridged, and / or fused bicyclic groups. In certain embodiments, a cycloalkyl group contains 3 to 10 carbon atoms (i.e., C3 to C6). 10 In some embodiments, cycloalkyl is a cycloalkyl group having 3 to 15 carbons (C 3~15 ), 3 to 10 carbons (C 3~10 ), 3 to 7 carbons (C 3~7 ), or 3 to 6 carbons (C3-C6) (i.e., "lower cycloalkyl"). In certain embodiments, a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl.

[0041] As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl group, as defined herein. In certain embodiments, a cycloalkylene group is [ka] etc. Lower cycloalkylene refers to C3-C6-cycloalkylene.

[0042] The term "cycloalkylalkyl," as used herein, unless otherwise specified, refers to an alkyl group, as defined herein, substituted with one or two cycloalkyl groups, as defined herein.

[0043] As used herein, the term "ester" refers to -C(O)OR, or -COOR, where R is alkyl as defined herein.

[0044] The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more independently selected halogen atoms (e.g., in some embodiments, 1, 2, 3, 4, or 5).

[0045] The term "heteroalkyl" refers to an alkyl, as defined herein, in which one or more carbon atoms are replaced by a heteroatom. As used herein, "heteroalkenyl" refers to an alkenyl, as defined herein, in which one or more carbon atoms are replaced by a heteroatom. As used herein, "heteroalkynyl" refers to an alkynyl, as defined herein, in which one or more carbon atoms are replaced by a heteroatom. Suitable heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted. Examples of heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl. "Substituted heteroalkyl" refers to a heteroalkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, a heteroalkyl group can contain one, two, three, or four heteroatoms. One of ordinary skill in the art will recognize that a 4-membered heteroalkyl typically contains one or two heteroatoms, a 5- or 6-membered heteroalkyl typically contains one, two, or three heteroatoms, and a 7- to 10-membered heteroalkyl typically can contain one, two, three, or four heteroatoms.

[0046] As used herein, the term "heteroalkylene" refers to a divalent heteroalkyl, as defined herein. "Substituted heteroalkylene" refers to a divalent heteroalkyl, as defined herein, that is substituted as described for heteroalkyl.

[0047] The term "heterocycloalkyl" refers to a monovalent, monocyclic, or polycyclic non-aromatic ring system where one or more of the ring atoms is a heteroatom independently selected from oxygen (O), sulfur (S), and nitrogen (N) (e.g., the nitrogen or sulfur atom may be optionally oxidized and the nitrogen atom may be optionally quaternized), and the remaining ring atoms of the non-aromatic ring are carbon atoms. In certain embodiments, a heterocycloalkyl is a monovalent, monocyclic, or polycyclic fully saturated ring system. In certain embodiments, a heterocycloalkyl group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, 4 to 11, or 5 to 6 ring atoms. A heterocycloalkyl can be attached to the core structure at any heteroatom or carbon atom that results in the creation of a stable compound. In certain embodiments, heterocycloalkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may include fused or bridged ring systems, the nitrogen or sulfur atoms may be optionally oxidized, and / or the nitrogen atoms may be optionally quaternized. In some embodiments, heterocycloalkyl radicals include, but are not limited to, 2,5-diazabicyclo[2.2.2]octanyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolyl, In certain embodiments, heterocycloalkyl may also be optionally substituted as described herein.In certain embodiments, heterocycloalkyl is substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, heterocycloalkyl groups can contain one, two, three, or four heteroatoms. One of ordinary skill in the art will recognize that 4-membered heterocycloalkyls typically contain one or two heteroatoms, 5- or 6-membered heterocycloalkyls typically contain one, two, or three heteroatoms, and 7- to 10-membered heterocycloalkyls can typically contain one, two, three, or four heteroatoms.

[0048] "Heterocycloalkylene" refers to a divalent heterocycloalkyl, as defined herein.

[0049] As used herein, a "heterocycloalkenyl" group refers to a monocyclic or bicyclic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, and one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heterocycloaliphatic rings are numbered according to standard chemical nomenclature.

[0050] The term "heteroaryl" refers to a monovalent monocyclic aromatic and / or polycyclic aromatic group in which at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen. Each ring of a heteroaryl group may contain one or two oxygen atoms, one or two sulfur atoms, and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. A heteroaryl may be attached to the remainder of the molecule through a nitrogen or carbon atom. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl can also be optionally substituted as described herein. "Substituted heteroaryl" refers to heteroaryl substituted as defined for aryl.

[0051] The term "heteroarylene" refers to a divalent heteroaryl group, as defined herein. A "substituted heteroarylene" is a heteroarylene substituted as defined for aryl.

[0052] The term "heteroarylalkylene" refers to an -alkyl-heteroarylene- or -heteroarylene-alkyl, such as a -C-C alkyl-heteroarylene-, -heteroarylene-C-C alkyl-, or -C-C alkyl-heteroarylene-C-C alkyl- group, where heteroarylene is as defined herein. "Substituted heteroarylalkylene" refers to a heteroarylalkylene group, as defined herein, in which the heteroarylalkylene group is substituted, where aryl is as defined herein. "Substituted C-C alkyl" refers to a C-C alkyl group that is substituted as defined herein for alkyl.

[0053] As used herein, unless otherwise specified, the term "protecting group" refers to a group attached to an oxygen, nitrogen, or phosphorus atom to prevent further reaction of the oxygen, nitrogen, or phosphorus atom, or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. (See, for example, Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Fourth Edition, 2006, incorporated herein by reference.)

[0054] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, (1) salts of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, and the like. Sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamido or (2) salts formed when an acidic proton present in the parent compound is replaced by (a) a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, including, but not limited to, ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0055] Pharmaceutically acceptable salts further include, by way of example and not limitation, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, and the like. Acid salts include hydroxysulfonates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, 1,2-ethanedisulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (besylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-toluenesulfonates, camphorates, camphorsulfonates, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonates, 3-phenylpropionates, trimethyl acetate, tert-butyl acetate, lauryl sulfate, gluconates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexylsulfamates, quinates, and muconates.

[0056] The terms "substantially free" or "substantially free," with respect to a composition, refer to a composition that contains at least 85%, or 90%, and in certain embodiments 95%, 98%, 99%, or 100% by weight; or in certain embodiments, 95%, 98%, 99%, or 100% of a specified enantiomer or diastereomer of a compound. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of one of the two enantiomers. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of one of the two diastereomers. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of an enantiomer (i.e., a racemate, or a 50:50 mixture of compounds).

[0057] Similarly, the term "isolated" with respect to a composition refers to a composition that contains at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of a compound, with the remainder containing other species, enantiomers, or diastereomers.

[0058] "Solvate" refers to a compound provided herein, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0059] "Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms with natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds described herein are meant to represent any stable isotope of that atom. For example, unless otherwise specified, if a position is specifically designated as hydrogen (H), it is understood that the position has hydrogen at its natural isotopic composition.

[0060] "Isotopic enrichment" refers to the proportion of a given atom in a molecule that incorporates a certain amount of a particular isotope, instead of the atom's natural isotopic abundance. For example, a deuterium (D) enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at that position. Since the distribution of naturally occurring deuterium is approximately 0.0156%, the deuterium enrichment at any position of a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0061] "Isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0062] As used herein, "alkyl," "alkylene," "alkylamino," "dialkylamino," "cycloalkyl," "aryl," "arylene," "alkoxy," "amino," "carboxyl," "heterocycloalkyl," "heteroaryl," "heteroarylene," "carboxyl," and "amino acid" groups optionally contain deuterium (D) at one or more positions where a hydrogen (H) atom would be present, and the deuterium composition of that atom(s) is other than the natural isotopic composition.

[0063] Also, as used herein, "alkyl," "alkylene," "alkylamino," "dialkylamino," "cycloalkyl," "aryl," "arylene," "alkoxy," "amino," "carboxyl," "heterocycloalkyl," "heteroaryl," "heteroarylene," "carboxyl," and "amino acid" groups optionally contain amounts of carbon-13( 13 C).

[0064] As used herein, "EC 50" refers to the dose, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximal expression of the particular response induced, elicited, or potentiated by the particular test compound.

[0065] As used herein, unless otherwise specified, "IC 50 The term "50% inhibition" refers to an amount, concentration, or dose of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures the maximal response.

[0066] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "subjects" refer to animals, e.g., mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys such as cynomolgus monkeys, chimpanzees, and humans), and in certain embodiments, humans. In certain embodiments, the subject is a farm animal (e.g., a horse, cow, pig, etc.) or a pet (e.g., a dog or cat). In certain embodiments, the subject is a human.

[0067] As used herein, the term "therapeutic agent(s)" refers to any agent(s) that can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In certain embodiments, a therapeutic agent is an agent that is known to be, has been used, or is currently being used to be useful in the treatment or prevention of a disorder or one or more symptoms thereof.

[0068] "Therapeutically effective amount" means the amount of a compound or composition that, when administered to a subject for treating a condition, is sufficient to effect such treatment for that condition. A "therapeutically effective amount" can vary depending, inter alia, on the compound, the disease or disorder and its severity, and the age, weight, etc., of the subject being treated.

[0069] "Treating" or "treatment" of any disease or disorder refers, in certain embodiments, to ameliorating the disease or disorder present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter, which may be difficult for a subject to discern. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physiological parameter), or both. In yet another embodiment, "treating" or "treatment" includes delaying or preventing the onset of the disease or disorder, or delaying or preventing the recurrence of the disease or disorder. In yet another embodiment, "treating" or "treatment" includes reducing or eliminating either the disease or disorder, or delaying the progression of the disease or disorder, or one or more symptoms of the disease or disorder, or reducing the severity of the disease or disorder, or the severity of one or more symptoms of the disease or disorder.

[0070] As used herein, the term "prophylactic agent(s)" refers to any agent(s) that can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes the compounds provided herein. In certain other embodiments, the term "prophylactic agent" does not refer to the compounds provided herein. For example, a prophylactic agent is an agent known to be useful for preventing or hindering the onset, development, progression, and / or severity of a disorder, or that has been used or is currently being used to arrest the onset, development, progression, and / or severity of a disorder.

[0071] As used herein, the phrase "prophylactically effective amount" refers to an amount of a therapy (e.g., a prophylactic agent) sufficient to prevent or reduce the onset, recurrence, or development of one or more symptoms associated with a disorder, or to enhance or improve the prophylactic effects of another therapy (e.g., another prophylactic agent).

[0072] Compounds of formula (I), (Ia-Ic), (IIe), (IIf), (IIi-IIo), (XIX)-(XXIV), (XXVIII), (XXIX), (XXXII-XXXVIII), and (XLVIII-LVI) Provided herein is a GLP-1 receptor compound that is useful for regulating one or more properties of GLP-1 receptor.This compound can be prepared as described herein and used for treatment or diagnosis.In certain embodiments, this treatment is the treatment of metabolic disease or metabolic condition.In certain embodiments, this treatment is the treatment of type 2 diabetes.

[0073] The embodiments described herein include the recited compounds, as well as pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, and / or mixtures thereof.

[0074] In certain embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] wherein A is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; ring B is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; ring C is further unsubstituted or further substituted and / or bridged; D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and;L 1 is selected from the group consisting of a bond, —O—, —CH—, and —OCH—; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2; L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L5 does not exist; and L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist;R 4 is an unsubstituted alkyl, a substituted alkyl, an unsubstituted arylalkylene, a substituted arylalkylene, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroarylalkylene, or a substituted heteroarylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11 R 12 N-; 11 is hydrogen or alkyl; R 12 is hydrogen or alkyl; and R 13 is hydrogen or alkyl.

[0075] In certain embodiments of Formula (I), L 1 is -OCH2- and L 4 does not exist and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-, or L 3 is —CH—, or both. In certain embodiments, L 1 is -OCH2- and L 4 does not exist and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-. In certain embodiments, L1 If is -OCH2-, L 4 L 1 and together with ring A and ring B form a fused tricyclic ring. 1 When is -OCH2-, L 5 L 2 and together with rings B and C form a fused tricyclic ring. 1 is -OCH2-, then Ring C is substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperidinyl.

[0076] In certain embodiments, A is a ring selected from phenyl. In certain embodiments, ring C is selected from piperidine and piperazine. In certain embodiments, ring B is selected from phenyl, furan, pyridine, pyrimidine, thiophene, oxazole, and benzofuran.

[0077] In certain embodiments, A is phenyl. In certain embodiments, Ring C is selected from substituted piperidine, azetidine, pyrrolidine, phenyl, and pyridine. In certain embodiments, Ring B is selected from phenyl, furan, pyridine, pyrimidine, thiophene, oxazole, and benzofuran. In certain embodiments, A is phenyl, and Ring C is azetidine. In certain embodiments, A is phenyl, and Ring C is pyrrolidine. In certain embodiments, A is phenyl, Ring C is azetidine, and Ring B is phenyl. In certain embodiments, A is phenyl, Ring C is azetidine, and Ring B is furan. In certain embodiments, A is phenyl, Ring C is pyrrolidine, and Ring B is phenyl. In certain embodiments, A is phenyl, Ring C is pyrrolidine, and Ring B is furan. In certain embodiments, A is phenyl, Ring C is phenyl, and Ring B is pyrimidine. In certain embodiments, A is phenyl, ring C is pyridine, and ring B is pyrimidine.

[0078] In certain embodiments, there is provided a compound of Formula (Ia), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] wherein A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; ring B is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; ring C is further unsubstituted or further substituted and / or bridged; D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 W is CH or C; when W is CH, adjacent dashed lines represent a single bond; when W is C, adjacent dashed lines represent a double bond, e.g., L 2 is -C(H)=;L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L 5 does not exist;L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist;R 4 is an unsubstituted alkyl, a substituted alkyl, an unsubstituted arylalkylene, a substituted arylalkylene, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroarylalkylene, or a substituted heteroarylalkylene; R 5-COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11 R 12 N-; 11 is hydrogen or alkyl; R 12 is hydrogen or alkyl; R 13 is hydrogen or alkyl.

[0079] In certain embodiments of Formula (Ia), L 1 is -OCH2- and L 4 does not exist and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-, or L 3 is —OCH2, or both. In certain embodiments, L 1 is -OCH2, and L 4 does not exist, and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-. In certain embodiments, L 1 is -OCH2- and L 4 does not exist and L 5 If does not exist, then L 3 is —C(O)—. In certain embodiments, L 1 If is -OCH2-, L 4 L 1 and together with ring A and ring B form a fused tricyclic ring. 1 When is -OCH2-, L 5 L2 and together with rings B and C form a fused tricyclic ring.

[0080] In certain embodiments, there is provided a compound of formula (Ib), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] wherein A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; ring B is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; ring C is further unsubstituted or further substituted and / or fused; D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 W is CH or C; when W is CH, adjacent dashed lines represent a single bond; when W is C, adjacent dashed lines represent a double bond, e.g., L2 is -C(H)=; L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L 5 does not exist;L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist;R 4 is an unsubstituted alkyl, a substituted alkyl, an unsubstituted arylalkylene, a substituted arylalkylene, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroarylalkylene, or a substituted heteroarylalkylene; R 5-COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11 R 12 N-; 11 is hydrogen or alkyl; R 12 is hydrogen or alkyl; and R 13 is hydrogen or alkyl.

[0081] In certain embodiments of Formula (Ib), L 1 is -OCH2- and L 4 does not exist and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-, or L 3 is —OCH2, or both. In certain embodiments, L 1 is -OCH2, and L 4 does not exist, and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-. In certain embodiments, L 1 is -OCH2- and L 4 does not exist, and L 5 If there is no L 3 is -CH-. In certain embodiments, L 1 If is -OCH2-, L 4 L 1 and together with rings A and B form a fused tricyclic ring. 1 If is -OCH2-, L 5 L 2and together with rings B and C form a fused tricyclic ring.

[0082] In certain embodiments, there is provided a compound of formula (Ic), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] wherein A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; ring B is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; ring C is further unsubstituted or further substituted and / or fused; C 1 , C 2 , C 3 , and C 4 0, 1, or 2 of these are N, and the rest are CH or CR 6 And ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 W is CH or C; when W is CH, adjacent dashed lines represent a single bond; when W is C, adjacent dashed lines represent a double bond, e.g., L 2 is -C(H)=;L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; L 4 does not exist or L 4 L 1 and together with rings A and B form a fused tricyclic ring, and L 5 does not exist;L 5 does not exist or L 5 L 2 and together with rings B and C form a fused tricyclic ring, and L 4 does not exist;R 4is an unsubstituted alkyl, a substituted alkyl, an unsubstituted arylalkylene, a substituted arylalkylene, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroarylalkylene, or a substituted heteroarylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R 11 R 12 NCO- and R 11 R 12 N-; 11 is hydrogen or alkyl; R 12 is hydrogen or alkyl; and R 13 is hydrogen or alkyl.

[0083] In certain embodiments of Formula (Ic), L 1 is -OCH2- and L 4 does not exist and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-, or L 3 is —OCH2, or both. In certain embodiments, L 1 is -OCH2, and L 4 does not exist, and L 5 If there is no L 2 is -CH2-, -C(H)=, or -O-. In certain embodiments, L 1 is -OCH2- and L 4 does not exist, and L 5 If there is no L 3 is -CH-. In certain embodiments, L 1 If is -OCH2-, L4 L 1 and together with rings A and B form a fused tricyclic ring. 1 If is -OCH2-, L 5 L 2 and together with rings B and C form a fused tricyclic ring.

[0084] In certain embodiments, A is a ring selected from phenyl. In certain embodiments, ring C is selected from piperidine and piperazine. In certain embodiments, ring B is selected from phenyl, furan, pyridine, pyrimidine, thiophene, oxazole, and benzofuran.

[0085] In certain embodiments, the compound of Formula (I) may be represented by Formula (IIe), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of which are N, and the rest are CH or CR 1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 wherein in formula IIe, B 4 does not exist ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is an unsubstituted alkyl, a substituted alkyl, an unsubstituted arylalkylene, a substituted arylalkylene, a heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroarylalkylene, or a substituted heteroarylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl, and each R 12 is hydrogen or alkyl, and each R 13 is hydrogen or alkyl; o is 1, 2, 3, or 4; p is 0 or 1; and q is 0 or 1.

[0086] In certain embodiments, the compound of Formula (I) may be represented by the formula (IIf), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of which are N, and the rest are CH or CR 1and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 wherein in formula IIf, B 4 does not exist ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is an unsubstituted alkyl, a substituted alkyl, an unsubstituted arylalkylene, a substituted arylalkylene, a heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroarylalkylene, or a substituted heteroarylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl, and each R 12 is hydrogen or alkyl, and each R 13is hydrogen or alkyl; o is 1, 2, 3, or 4; p is 0 or 1; and q is 0 or 1.

[0087] In certain embodiments, the compound of Formula (I) may be represented by Formula (IIi), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of which are N, and the rest are CH or CR 1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 wherein in formula IIi, B 4 does not exist ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5-COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0.

[0088] In certain embodiments, the compound of Formula (I) may be represented by Formula (IIj), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of which are N, and the rest are CH or CR 1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 wherein in formula IIj, B 4 does not exist ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer of 0 to 5; m is an integer of 0 to 4; and o is an integer of 0 to 4.

[0089] In certain embodiments, the compound of formula (I) is according to formula (IIk), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of these are N, and the rest are CH or CR1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 and in formula IIk, B 4 does not exist ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer of 0 to 5; m is an integer of 0 to 4; and o is an integer of 0 to 4.

[0090] In certain embodiments, the compound of Formula (I) is according to Formula (IIl), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of these are N, and the rest are CH or CR 1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 and in formula IIl, B 4 does not exist ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl, and each R 12 is hydrogen or alkyl, and each R 13 is hydrogen or alkyl; n is an integer of 0 to 5; m is an integer of 0 to 4; and o is an integer of 0 to 4.

[0091] In certain embodiments, the compound of Formula (I) is according to Formula (IIm), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of these are N, and the rest are CH or CR 1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 and in formula IIm, B 4 does not exist ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4. In certain embodiments, each R 3 are independently selected from the group consisting of F, alkyl, substituted alkyl, CHF, and CN.

[0092] In certain embodiments, the compound of formula (I) is according to formula (IIn), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of these are N, and the rest are CH or CR 1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 and in formula II n, B 4 does not exist ;D1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4. In certain embodiments, each R 3 are independently selected from the group consisting of F, alkyl, substituted alkyl, CHF, and CN.

[0093] In certain embodiments, the compound of Formula (I) is according to Formula (IIm), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka]

[0094] In the formula, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of these are N, and the rest are CH or CR 1 and;B 1 , B 2 , B 3 , and B 4 0, 1, or 2 of these are N, and the rest are CH or CR 2 and in formula IIo, B 4 does not exist;C 1 , C 2 , C 3 , and C 4 0, 1, or 2 of these are N, and the rest are CH or CR 6 And ;D 1 , D 2 , and D 3 0, 1, or 2 of these are N, and the rest are CH or CR 6 and each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5-COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4. In certain embodiments, each R 3 are independently selected from the group consisting of F, alkyl, substituted alkyl, CHF, and CN.

[0095] In certain embodiments, there is provided a compound of formula (XIX), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of Formula (XIX) is selected from compounds 172, 173, 184, 185, 201, and 209 in Table 1.

[0096] In certain embodiments, there is provided a compound of formula (XX), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of Formula (XX) is selected from compounds 119, 134, 192, 194-197, 210, 212, 222, 223, 228, 229, 233, 234, 237, 238, 350, 383, 387-389, 400, 401, 405, 406, 411, 412, 414, 415, 417-420, 426, 439, 443, and 446-448 in Table 1.

[0097] In certain embodiments, there is provided a compound of formula (XXI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, W is CR 14 or C;W is CR 14when W is C, the adjacent dashed line represents a double bond, or when L 2 is -C(H)=;L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4. In certain embodiments, the compound of Formula (XXI) is selected from compounds 127, 281, and 282 in Table 1.

[0098] In certain embodiments, there is provided a compound of formula (XXII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, --CH2-, --C(H)=, and --O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of Formula (XXII) is selected from compounds 147, 167, 191, 213, 225, and 474 in Table 1.

[0099] In certain embodiments, there is provided a compound of formula (XXIV), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5-COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of Formula (XXIV) is selected from compounds 175-177, 180, 181, 193, 211, 218, 219, 226, 236, 244, 245, 273, 289, 293, 298, 392, 399, 402-404, 431, 433, and 440 in Table 1.

[0100] In certain embodiments, there is provided a compound of formula (XXVIII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, the compound of Formula (XXVIII) is compound 235 in Table 1.

[0101] In certain embodiments, there is provided a compound of formula (XXIX), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, W is CR 14 or C;W is CR 14when W is C, the adjacent dashed line represents a double bond, or when L 2 is -C(H)=;L 1 is selected from the group consisting of a bond, —O—, —CH—, and —OCH—; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, the compound of formula (XXIX) is selected from compounds 360 and 395 in Table 1.

[0102] In certain embodiments, there is provided a compound of formula (XXXII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, the compound of Formula (XXXII) is selected from compounds 384, 385, 407-410, 422, 423, 429, 436, 437, 438, and 456, and 458 in Table 1.

[0103] In certain embodiments, there is provided a compound of formula (XXXIII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, the compound of formula (XXXIII) is selected from compounds 390, 391, 393, 394, 397, and 398 in Table 1.

[0104] In certain embodiments, there is provided a compound of formula (XXXIV), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, the compound of formula (XXXIV) is compound 396 in Table 1.

[0105] In certain embodiments, there is provided a compound of formula (XXXV), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, each R 3 is independently selected from the group consisting of F, alkyl, substituted alkyl, CHF, and CN. In certain embodiments, the compound of Formula (XXXV) is selected from compounds 462 and 466 in Table 1.

[0106] In certain embodiments, there is provided a compound of formula (XXXVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, each R 3 is independently selected from the group consisting of F, alkyl, substituted alkyl, CHF, and CN. In certain embodiments, the compound of Formula (XXXVI) is selected from compounds 460, 465, and 468 in Table 1.

[0107] In certain embodiments, there is provided a compound of formula (XXXVII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, each R 3 is independently selected from the group consisting of F, alkyl, substituted alkyl, CHF, and CN. In certain embodiments, the compound of Formula (XXXVII) is selected from compounds 386, 461, 463, and 464 in Table 1.

[0108] In certain embodiments, there is provided a compound of formula (XXXVIII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, W is CR 14 or C;W is CR 14 When W is C, the adjacent dashed line represents a double bond, or when L 2 is -C(H)=;L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is a bond, -C(O)-, -CH2-, -C(H)=, -SO2-, -O-, -CF2-, -CHF-, or -CH(OH)-, and [ka] In certain embodiments, the compound of formula (XXXVIII) is compound 435 in Table 1.

[0109] In certain embodiments, there is provided a compound of Formula (XLVIII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, and —O—; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is -CH2-. R 6 is F. In certain embodiments, the compound of formula (XLVIII) is selected from compounds 351, 444, 445, 449, and 450 in Table 1.

[0110] In certain embodiments, there is provided a compound of formula (XLIX), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, W is CR 14 or C;W is CR 14 When W is C, the adjacent dashed line represents a double bond, or when L 2 is -C(H)=;L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is -CH-. In certain embodiments, R 6 is F. In certain embodiments, the compound of formula (XLIX) is selected from compounds 361 and 546 in Table 1.

[0111] In certain embodiments, there is provided a compound of formula (L), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, and —O—; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is -CH-. In certain embodiments, R 6 is F. In certain embodiments, the compound of Formula (L) is a compound selected from compounds 427 and 428 in Table 1.

[0112] In certain embodiments, there is provided a compound of formula (LI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, -CH2-, -C(H)=, and -O-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is -CH-. In certain embodiments, R 6 is F. In certain embodiments, the compound of formula (LI) is a compound selected from compounds 459, 471, 537, 538, and 543 in Table 1.

[0113] In certain embodiments, there is provided a compound of formula (LII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, and —O—; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl. In certain embodiments, L 2 is -CH-. In certain embodiments, R 6is F. In certain embodiments, the compound of formula (LII) is a compound selected from compounds 467, 470, 539, and 540 in Table 1.

[0114] In certain embodiments, there is provided a compound of formula (LIII), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, and —O—; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl. In certain embodiments, L 2 is -CH-. In certain embodiments, R 6 is F. In certain embodiments, the compound of formula (LIII) is compound 469 in Table 1.

[0115] In certain embodiments, there is provided a compound of formula (LIV), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5-COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; R 6 is independently selected from the group consisting of F and methyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl. In certain embodiments, R 6 is F. In certain embodiments, the compound of formula (LIV) is a compound selected from compounds 522-525, 531, and 532 in Table 1.

[0116] In certain embodiments, there is provided a compound of formula (LV), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, and —O—; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl. In certain embodiments, the compound of formula (LV) is compound 542 in Table 1.

[0117] In certain embodiments, there is provided a compound of formula (LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof: [ka]

[0118] In the formula, L 1 is selected from the group consisting of -O-, -CH2-, and -OCH2-; L 2 is selected from the group consisting of a bond, —CH—, and —O—; L 3 is -CH2-; each R 1 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; each R 2 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R12 NCO-; each R 3 is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R 11 R 12 NCO-; 4 is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; R 5 -COOH, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, [ka] and tetrazolyl; each R 11 is hydrogen or alkyl; each R 12 is hydrogen or alkyl; each R 13 is hydrogen or alkyl. In certain embodiments, the compound of formula (LVI) is compound 544 in Table 1.

[0119] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein each R 2 and R 3 is H or F.

[0120] In certain embodiments, there is provided a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, wherein m is 0; and o is 0.

[0121] In certain embodiments, there is provided a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, wherein W is N or CH.

[0122] In certain embodiments, there is provided a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, wherein W is C.

[0123] In certain embodiments, there is provided a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, wherein W is CH.

[0124] In certain embodiments, there is provided a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, wherein W is CR 14 is.

[0125] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is selected from the group consisting of 1-(cyanomethyl)-cycloprop-1-yl-methyl, (1-ethyl-1H-imidazol-5-yl)-methyl, 1-(fluoromethyl)-cycloprop-1-yl-methyl, isoxazol-5-yl-methyl, oxetan-2-yl-methyl, (2S)-oxetan-2-yl-methyl, oxelan-3-yl-methyl, (3R)-oxelan-3-yl-methyl, 1,3-oxazol-2-yl-methyl, and tetrahydrofur-2-yl-methyl.

[0126] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4is selected from the group consisting of (1-ethyl-1H-imidazol-5-yl)-methyl, oxetan-2-yl-methyl, (2S)-oxetan-2-yl-methyl, oxelan-3-yl-methyl, (3R)-oxelan-3-yl-methyl, and 1,3-oxazol-2-yl-methyl.

[0127] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is selected from the group consisting of 1-(cyanomethyl)-cycloprop-1-yl-methyl, 1-(fluoromethyl)-cycloprop-1-yl-methyl, isoxazol-5-yl-methyl, and tetrahydrofur-2-yl-methyl.

[0128] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is selected from the group consisting of oxetan-2-yl-methyl, (1-ethyl-1H-imidazol-5-yl)-methyl, oxelan-3-yl-methyl, and 1,3-oxazol-2-yl-methyl.

[0129] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is selected from the group consisting of oxetan-2-yl-methyl and (1-ethyl-1H-imidazol-5-yl)-methyl.

[0130] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is oxetan-2-yl-methyl.

[0131] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is (2S)-oxetan-2-yl-methyl.

[0132] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is (1-ethyl-1H-imidazol-5-yl)-methyl.

[0133] In certain embodiments, a compound of formula (LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is H.

[0134] In certain embodiments, a compound of formula (LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is selected from the group consisting of oxelan-3-yl-methyl and 1,3-oxazol-2-yl-methyl.

[0135] In certain embodiments, a compound of formula (LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 4 is (3R)-oxelan-3-yl-methyl.

[0136] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 5 is -COOH or -COOMe.

[0137] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 5is -COOH.

[0138] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 5 is tetrazolyl.

[0139] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein R 5 is 1H-1,2,3,4-tetrazol-5-yl.

[0140] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L 2 is -CH2-.

[0141] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L 2 is a bond, -CH2-, or -C(H)=-O-.

[0142] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L 2 is -CH= or -O-.

[0143] In certain embodiments, a compound of formula (LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein L 2 is a bond.

[0144] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L3 is -CH2-.

[0145] In certain embodiments, there is provided a compound of formula (LIX), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, wherein L 1 is -OCH2-.

[0146] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L 1 is -OCH2-; and L 2 is -CH2-.

[0147] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L 1 is -O-.

[0148] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L 1 is -CH2-.

[0149] In certain embodiments, a compound of any of Formulas (I)-(LVI), or a pharmaceutical salt, tautomer, stereoisomer, and / or mixture of stereoisomers thereof, is provided, wherein: L 1 is -OCH2-.

[0150] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-; and L 2 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-; and L 2 is -C(H)=. In certain embodiments of any of formulas (I)-(LVI), L 1 is -O-;L 2is -CH2-; and L 3 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=; and L 3 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; and R 2 and R 3 and each is H. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; and R 2 and R 3 and each is H. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (2S)-oxetan-2-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (2S)-oxetan-2-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are each H; and R 4is (1-ethyl-1H-imidazol-5-yl)-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (1-ethyl-1H-imidazol-5-yl)-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1 may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0151] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; and L 2 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; and L 2 is -C(H)=. In certain embodiments of any of formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; and L 3 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -C(H)=; and L 3 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; and R 2 and R 3 and each is H. In certain embodiments of any of Formulas (I)-(LVI), L1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; and R 2 and R 3 and each is H. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (2S)-oxetan-2-yl-methyl. In certain embodiments of any of Formulas (I) through (LIX), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (2S)-oxetan-2-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -SO2-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (2S)-oxetan-2-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (1-ethyl-1H-imidazol-5-yl)-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3are each H; and R 4 is (1-ethyl-1H-imidazol-5-yl)-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0152] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is oxelan-3-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is oxelan-3-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is 1,3-oxazol-2-yl-methyl. In certain embodiments of any of Formulas (I) through (LIX), L 1 is -O-;L 2 is -C(H)=;L3 is -CH2-; R 2 and R 3 are each H; and R 4 is 1,3-oxazol-2-yl-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -C(O)-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -C(H)=;L3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4is 1,3-oxazol-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1 may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0153] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is oxelan-3-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is oxelan-3-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3are each H; and R 4 is 1,3-oxazol-2-yl-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is 1,3-oxazol-2-yl-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively.4 is 1,3-oxazol-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -CH2-; L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -C(H)=;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1 may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0154] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-; and L 2 In certain embodiments of any of formulas (I)-(LVI), L 1 is -O-;L 2 is -O-; and L 3 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; and R 2 and R 3 and each is H. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (2S)-oxetan-2-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (1-ethyl-1H-imidazol-5-yl)-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1 may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0155] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; and L 2 In certain embodiments of any of formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-; and L 3 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; and R 2 and R 3 and each is H. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (2S)-oxetan-2-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is (1-ethyl-1H-imidazol-5-yl)-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (2S)-oxetan-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is (1-ethyl-1H-imidazol-5-yl)-methyl; and R5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1 may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0156] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is oxelan-3-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is 1,3-oxazol-2-yl-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -O-;L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1 may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0157] In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is oxelan-3-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are each H; and R 4 is 1,3-oxazol-2-yl-methyl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 In certain embodiments of any of Formulas (I)-(LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R2 and R 3 are H and R, respectively. 4 is oxelan-3-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In certain embodiments of any of Formulas (I) through (LVI), L 1 is -OCH2-; L 2 is -O-;L 3 is -CH2-; R 2 and R 3 are H and R, respectively. 4 is 1,3-oxazol-2-yl-methyl; and R 5 is tetrazolyl, for example, 1H-1,2,3,4-tetrazol-5-yl. In any embodiment of this paragraph, R 1 may be selected from H, Cl, F, Me, —CF, —OMe, —CN, —C(O)NMe, alkyl, propyl, isopropyl, and cyclopropyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(cyanomethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is 1-(fluoromethyl)-cycloprop-1-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is isoxazol-5-yl-methyl. In certain embodiments of any of Formulas (I)-(LVI), R 4 is tetrahydrofur-2-yl-methyl.

[0158] In certain embodiments, there are provided compounds in Table 1 below, or pharmaceutical salts, tautomers, stereoisomers, and / or mixtures of stereoisomers thereof. [Table 1-1] [Table 1-2] [Table 1-3]

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

[0159] optically active compound In certain embodiments, the compounds provided herein may have several chiral centers and may exist and be isolated in optically active, racemic form. In certain embodiments, some compounds may exhibit polymorphism. Those of skill in the art will understand that the compounds provided herein can exist in any racemic, optically active, diastereomeric, polymorphic, or stereoisomeric form, and / or mixtures thereof. Those of skill in the art will also understand that such compounds described herein having the useful properties described herein are within the scope of the present disclosure. Those of skill in the art will further understand how to prepare optically active forms of the compounds described herein, for example, by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. Furthermore, most amino acids are chiral (i.e., designated L- or D-, with the L-enantiomer being the naturally occurring configuration) and may exist as separate enantiomers.

[0160] Examples of methods for obtaining optically active materials are known in the art and include at least the following: i) Physical separation of crystals - a technique in which macroscopic crystals of individual enantiomers are manually separated. This technique can be used when crystals of separate enantiomers exist (i.e., the material is a conglomerate and the crystals are visually distinct); ii) simultaneous crystallization - a technique in which individual enantiomers are crystallized separately from a solution of the racemate only if the racemate is a conglomerate in the solid state; iii) Enzymatic resolution - a technique that utilizes the different reaction rates of enantiomers in the presence of enzymes to achieve partial or complete separation of the racemate; iv) enzymatic asymmetric synthesis - a synthetic technique that uses an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enriched synthetic precursor of a desired enantiomer; v) Chemical asymmetric synthesis - a synthetic technique in which a desired enantiomer is synthesized from an achiral precursor using a chiral catalyst or chiral auxiliary to create asymmetry (i.e., chirality) in the product. vi) Diastereomeric separation - a technique in which a racemate is treated with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to more distinct diastereomeric differences, and the chiral auxiliary is then removed to yield each enantiomer. vii) Primary and secondary asymmetric transformations - techniques in which racemic diastereomers are equilibrated in solution in favor of the diastereomer of the desired enantiomer, or kinetic or thermodynamic crystallization of the diastereomer of the desired enantiomer perturbs the equilibrium, ultimately resulting in the conversion of essentially all of the material to the crystalline diastereomer of the desired enantiomer, from which the desired enantiomer is then derived. viii) Kinetic resolution - This technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) due to the different rates of reaction of enantiomers with chiral or non-racemic reagents, or catalysts, under kinetic conditions. ix) Enantiospecific synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from chiral starting materials and in which the stereochemical integrity is not or only minimally compromised during the synthesis; x) Chiral liquid chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase by their different interactions with a stationary phase. The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to create different interactions. xi) Chiral gas chromatography - a technique that uses a column containing a fixed non-racemic adsorbent phase to volatilize the racemate and separate the enantiomers by their different interactions in the gaseous mobile phase; xii) Extraction with chiral solvents - a technique for separating enantiomers by kinetic or thermodynamic dissolution of one enantiomer in a particular chiral solvent; xiii) Transport across chiral membranes - a technique in which a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids containing the racemate, and a driving force such as a concentration or pressure difference causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0161] In some embodiments, provided herein are compositions of a compound of any of Formulas (I)-(LVI) that are substantially free of the specified stereoisomer of the compound. In certain embodiments, in the methods and compounds of the present disclosure, the compound is substantially free of other stereoisomers. In some embodiments, the composition comprises at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, with the remainder comprising other species or enantiomers. In some embodiments, provided herein are compositions of a compound of any of Formulas (I)-(LVI) that are substantially free of the specified enantiomer of the compound. In certain embodiments, in the methods and compounds of the present disclosure, the compound is substantially free of other enantiomers. In some embodiments, the composition comprises at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, with the remainder comprising other species or enantiomers.

[0162] isotopically enriched compounds Also provided herein are isotopically enriched compounds, including but not limited to, isotopically enriched compounds of any of Formulas (I)-(LVI).

[0163] Isotopic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and / or toxicity profiles has previously been demonstrated for several classes of drugs. For example, Lijinsky et.al.,Food Cosmet.Toxicol.,20:393(1982);Lijinsky et.al.,J.Nat.Cancer Inst.,69: 1127(1982);Mangold et.al.,Mutation Res.308: 33(1994);Gordon et al.,Drug See Metab. Dispos., 15:589 (1987); Zello et al., Metabolism, 43:487 (1994); Gately et al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[0164] Isotopic enrichment of drugs can be used, for example, to (1) reduce or eliminate undesirable metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses required to achieve a desired effect, (4) decrease the dosage required to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrease the production of harmful metabolites in specific tissues. Isotopic enrichment of drugs may also be used to create more effective and / or safer drugs for combination therapy, whether or not the combination therapy is intended.

[0165] The substitution of an atom with one of its isotopes often results in a change in the reaction rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, if a C-H bond is broken during the rate-determining step of a chemical reaction (i.e., the step with the highest transition state energy), the substitution of its reactive hydrogen with a (heavier) isotope will cause a decrease in the reaction rate. The deuterium kinetic isotope effect ("DKIE") is the most common form of KIE. (See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[0166] The magnitude of the DKIE can be expressed as the ratio of the rate of a given reaction in which a C-H bond is broken to the rate of the same reaction in which deuterium is substituted for hydrogen and a C-D bond is broken. The DKIE can range from about 1 (no isotope effect) to very large numbers, e.g., 50 or more, meaning that the reaction can be 50 times slower or more when deuterium is substituted for hydrogen.

[0167] Substitution of tritium ("T") for hydrogen results in an even stronger bond than deuterium, giving a numerically larger isotope effect. Similarly, without limitation, with respect to carbon, 13 C, or 14 C; for sulfur 33 S, 34 S, or 36 S; for nitrogen 15 N; and oxygen 17 O, or 18 Isotopic substitution with other elements, including O, may result in similar kinetic isotope effects.

[0168] Animal bodies express a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from their circulatory systems. Examples of such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (CH) bonds to either carbon-oxygen (CO) or carbon-carbon (C=C) pi bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different PK / PD and acute and long-term toxicity profiles compared to the parent compound. For many drugs, such oxidation is rapid. Therefore, these drugs often require multiple daily or high-dose administration.

[0169] Thus, isotopic enrichment at specific positions in the compounds provided herein will produce detectable KIEs that affect the pharmacological, PK, PD, and / or toxicological profiles of the compounds provided herein compared to similar compounds with natural isotopic composition.

[0170] Compositions and Uses Pharmaceutical compositions and methods of administration The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and methods disclosed herein. Any of the compounds provided herein can be provided in a suitable pharmaceutical composition and administered by a suitable route of administration.

[0171] The methods provided herein involve administering a pharmaceutical composition comprising at least one compound provided herein and one or more compatible, pharmaceutically acceptable carriers. In this context, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and in certain embodiments, for use in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when a pharmaceutical composition is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, E.W., Remington's Pharmaceutical Sciences.

[0172] In clinical practice, the pharmaceutical compositions or compounds provided herein can be administered by any route known in the art. Exemplary administration routes include, but are not limited to, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, the pharmaceutical compositions or compounds provided herein are administered parenterally.

[0173] Compositions for parenteral administration may be emulsions or sterile solutions. Parenteral compositions may contain, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions may also contain wetting agents, isotonicity adjusting agents, emulsifying agents, dispersing agents, and stabilizing agents. Sterilization can be carried out in several ways, such as by using a bacteriological filter, by irradiation, or by heat. Parenteral compositions may also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or any other injectable sterile medium at the time of use.

[0174] In some embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic compounds.

[0175] The pharmaceutical composition may contain one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and those skilled in the art will be able to select an appropriate pharmaceutical excipient. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, the method by which the dosage form will be administered to a subject and the particular compounds in the dosage form. The composition or single unit dosage form may optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Therefore, the pharmaceutical excipients provided below are illustrative and not limiting. Additional pharmaceutical excipients include, for example, those described in Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), which is incorporated herein by reference in its entirety.

[0176] In some embodiments, the pharmaceutical composition includes an antifoaming agent. Any suitable antifoaming agent may be used. In some aspects, the antifoaming agent is selected from alcohols, ethers, oils, waxes, silicones, surfactants, and combinations thereof. In some aspects, the antifoaming agent is selected from mineral oil, vegetable oil, ethylene bisstearamide, paraffin wax, ester wax, fatty alcohol wax, long-chain fatty alcohol, fatty acid soap, fatty acid ester, silicone glycol, fluorosilicone, polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethylhexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0177] In some embodiments, the pharmaceutical composition comprises a co-solvent, specific examples of which include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0178] In some embodiments, the pharmaceutical composition comprises a buffer, specific examples of which include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0179] In some embodiments, the pharmaceutical composition comprises a carrier or filler, specific examples of which include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0180] In some embodiments, the pharmaceutical composition comprises a surfactant, specific examples of which include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene (glycol) succinate.

[0181] In some embodiments, the pharmaceutical composition comprises an anticoagulant, specific examples of which include calcium phosphate (tribasic), hydroxymethylcellulose, hydroxypropylcellulose, and magnesium oxide.

[0182] Other excipients that can be used with the pharmaceutical composition include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, release-controlling agents, diluents, dispersants, solubility enhancers, emulsifiers, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizers, solvents, stabilizers, and sugars. Specific examples of each of these agents are described, for example, in Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), which is incorporated herein by reference in its entirety.

[0183] In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is a saline solution, such as sterile isotonic saline or a dextrose solution. In some aspects, the solvent is water for injection.

[0184] In some embodiments, the pharmaceutical composition is in particulate form, such as a microparticle or nanoparticle. Microparticles and nanoparticles can be formed from any suitable material, such as a polymer or lipid. In some aspects, the microparticle or nanoparticle is a micelle, liposome, or polymersome.

[0185] Further provided herein, in some embodiments, are anhydrous pharmaceutical compositions and dosage forms comprising the compounds, as water can facilitate the degradation of some compounds.

[0186] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that contain at least one active ingredient that contains lactose and a primary or secondary amine can be anhydrous if substantial contact with steam and / or moisture is expected during manufacturing, packaging, and / or storage.

[0187] Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0188] The lactose-free compositions provided herein may contain excipients that are well known in the art and are listed, for example, in the United States Pharmacopoeia (USP) SP(XXI) / NF(XVI). Generally, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. An exemplary lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0189] Also provided are pharmaceutical compositions and dosage forms that comprise one or more excipients that reduce the rate at which the compound decomposes. Such excipients, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0190] Parenteral dosage forms In certain embodiments, parenteral dosage forms are provided. Parenteral dosage forms can be administered to a subject by various routes, including but not limited to subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration usually bypasses the subject's natural defenses against contaminants, parenteral dosage forms are usually sterile or can be sterilized before administration to a subject. Examples of parenteral dosage forms include, but are not limited to, ready-to-inject solutions, dry products that are immediately dissolved or suspended in a pharmaceutically acceptable vehicle for injection, ready-to-inject suspensions, and emulsions.

[0191] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to, USP Water for Injection; aqueous vehicles, such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles, such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0192] Excipients that increase the solubility of one or more of the antibodies disclosed herein can also be incorporated into the parenteral dosage form.

[0193] Dosage forms and unit dosage forms In human therapy, the physician will determine the pharmacology he or she considers most appropriate depending on the prophylactic or therapeutic treatment, as well as the age, weight, condition, and other factors specific to the subject being treated.

[0194] In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies, or antigen-binding fragments thereof.

[0195] The amount of a compound or composition that is effective for preventing or treating a disorder or one or more symptoms thereof varies depending on the nature and severity of the disease or condition, and the route by which the compound is administered. The frequency and dosage also vary according to factors specific to each subject, depending on the specific treatment (e.g., therapeutic or prophylactic agent) administered, the severity of the disorder, disease, or condition, the route of administration, and the subject's age, weight, response, and past medical history. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0196] In certain embodiments, exemplary doses of the compositions include milligram or microgram amounts of compound per kilogram of subject or per sample weight (e.g., from about 10 micrograms per kilogram to about 50 milligrams per kilogram, from about 100 micrograms per kilogram to about 25 milligrams per kilogram, or from about 100 micrograms per kilogram to about 10 milligrams per kilogram). In certain embodiments, dosages of the compounds provided herein are 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more per kg of subject body weight, based on the weight of the compound administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject. In another embodiment, the dosage of a composition, or a composition provided herein, administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is between 0.1 mg and 200 mg, 0.1 mg and 100 mg, 0.1 mg and 50 mg, 0.1 mg and 25 mg, 0.1 mg and 20 mg, 0.1 mg and 15 mg, 0.1 mg and 10 mg, 0.1 mg and 7.5 mg, 0.1 mg and 5 mg, 0.1 and 2.5 mg, 0.25 mg and 20 mg, 0. 25-15mg, 0.25-12mg, 0.25-10mg, 0.25mg-7.5mg, 0.25mg-5mg, 0.25mg-2.5mg, 0.5mg-20mg, 0.5-15mg, 0.5-12mg, 0.5-10mg, 0.5mg-7.5mg, 0.5mg-5mg, 0.5mg-2.5mg, 1mg-20mg, 1mg-15mg, 1mg-12mg, 1mg-10mg, 1mg-7.5mg, 1mg-5mg, or 1mg-2.5mg.

[0197] Dosage can be administered according to appropriate schedule, for example, once, twice, three times or four times a week.It is clear to those skilled in the art that in some cases, it may be necessary to use the dose of compound outside the range disclosed herein.In addition, it should be noted that clinician or treating physician will know when and how to interrupt, adjust or terminate treatment according to the response of the subject.

[0198] As will be readily apparent to those skilled in the art, different therapeutically effective amounts may be applicable to different diseases and conditions. Similarly, amounts sufficient to prevent, manage, treat, or ameliorate such disorders, but insufficient to cause or reduce side effects associated with the antibodies or antigen-binding fragments thereof provided herein, are also encompassed by the described doses, and the administration frequency schedules are described herein. Furthermore, when a subject receives multiple doses of the compositions provided herein, not all doses need to be the same. For example, the dose administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or decreased to reduce one or more side effects experienced by a particular subject.

[0199] In certain embodiments, treatment or prevention may begin with one or more loading doses, followed by one or more maintenance doses of a compound or composition provided herein.

[0200] In certain embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the compound in the blood or serum of a subject. The steady-state concentration can be determined by measurement according to techniques available to those skilled in the art, or can be based on the subject's physical characteristics, such as height, weight, and age.

[0201] In certain embodiments, repeated administrations of the same composition may be administered, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, repeated administrations of the same prophylactic or therapeutic agent may be administered, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. therapeutic application For therapeutic applications, the compounds are administered to mammals, and in particular embodiments, humans, by intravenous, intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intraarticular, intrasynovial, intrathecal, or intratumoral routes, either intravenously as a bolus or by continuous infusion over a period of time, at a pharmaceutically acceptable dose suitable for the administration form, such as those known in the art and discussed herein. The compounds are also suitably administered by peritumoral, intralesional, or perilesional routes to exert local and systemic therapeutic effects. In certain embodiments, the compounds are administered to mammals, and in particular embodiments, humans, at a pharmaceutically acceptable dose suitable for an oral administration form, such as those known in the art and discussed herein. For example, the compounds of the present disclosure may be orally administered to humans in liquid or solid form. Solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical compound may be mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato denat. The formulation may be mixed with starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, high molecular weight polyethylene glycols, and similar excipients.

[0202] The compounds provided herein may be useful for treating any disease or condition described herein (e.g., a metabolic disease or condition). In certain embodiments, the disease or condition is any disease or condition that would benefit from modulation of GLP-1 receptor activity. In certain embodiments, the disease or condition is any disease or condition that would benefit from agonizing GLP-1 receptor activity. In certain embodiments, the method reduces blood glucose levels. In certain embodiments, the method promotes insulin synthesis, stimulates insulin secretion, increases beta-cell mass, regulates gastric acid secretion, regulates gastric emptying, and / or reduces glucagon production. In certain embodiments, the disease or condition is type 2 diabetes.

[0203] In certain embodiments, the disease or condition is obesity or one or more diseases or conditions related to obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat accumulation). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0204] Examples of such obesity-related diseases and conditions include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obesity diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick syndrome), menstrual disorders (e.g., menstrual cycle abnormalities, menstrual flow and cycle abnormalities, amenorrhea, menstrual abnormalities), visceral obesity syndrome, and metabolic syndrome. In certain embodiments, the compounds described herein may be used to treat subjects who exhibit symptoms of both obesity and insulin deficiency.

[0205] In some embodiments, the disease or condition is diabetes. Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, advanced stage type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-induced diabetes, autoimmune diabetes, and pre-diabetes.

[0206] In some embodiments, the disease or condition is associated with diabetes (e.g., diabetic complications).Non-limiting examples of diabetes-related disorders include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral arterial disease, cerebrovascular disease, hypertension, and risk factors related to uncontrolled cholesterol and / or lipid levels and / or inflammation), NASH, fractures, and cognitive impairment.

[0207] Other non-limiting examples of diseases or conditions related to diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-HDL cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic syndrome X, a metabolic disorder in which activation of GLP-1R is beneficial), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0208] In some embodiments, the disease or condition is diabetes and obesity (diabetes). In certain embodiments, the compounds described herein are useful for improving the therapeutic effect of metformin.

[0209] In some embodiments, the disease or condition is a disorder of a metabolically important tissue.

[0210] In some embodiments, the disease or condition is fatty liver disease, including, but not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease due to hepatitis, fatty liver disease due to obesity, fatty liver disease due to diabetes, fatty liver disease due to insulin resistance, fatty liver disease due to hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman's disease, acute fatty liver of pregnancy, and lipodystrophy.

[0211] Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders occurring in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). NAFLD is thought to be associated with various conditions, including metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. NAFLD can cause liver disease in adults and children, ultimately leading to cirrhosis (Skelly et al., J Hepatol 2001;35:195-9; Chitturi et al., Hepatology 2002;35(2):373-9). The severity of NAFLD ranges from a relatively benign, primarily macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002;17 SuppkS 186-90). In certain embodiments, the subject is a pediatric subject (e.g., 6 to 16 years old; or 6 to 12 years old; or 6 to 10 years old). In certain embodiments, the subject is an adult subject.

[0212] Other non-limiting examples of diseases or conditions in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux disease; sleep apnea; hepatitis; fatty liver; bone disorders characterized by alterations in bone metabolism, such as postmenopausal osteoporosis, decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and alterations in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures, and malnutrition; polycystic ovary syndrome; renal diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In certain embodiments, the chemical entities described herein may be used to treat surgical trauma by improving post-operative recovery and / or by preventing the catabolic response caused by surgical trauma.

[0213] In some embodiments, the disease or condition is a cardiovascular disease. Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease or peripheral artery disease, stroke, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mmHg or higher), and a prothrombotic state (exemplified by elevated blood fibrinogen or plasminogen activator inhibitor).

[0214] In some embodiments, the disease or condition is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperactivity, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis I, brain inflammation, Friedrich ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, for example, US Patent Application Publication No. 20060275288A1.

[0215] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics, amphetamines, and attention-deficit / hyperactivity disorder (ADHD)). The chemical compounds described herein may be useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing relapse to drug abuse, and reducing anxiety caused by the absence of a given addictive substance. See, e.g., U.S. Patent Application Publication No. 20120021979A1.

[0216] In certain embodiments, the chemical entities described herein are useful for improving learning and memory by enhancing neuronal plasticity, promoting cell differentiation, and preserving dopamine neuron and motor function in Parkinson's disease.

[0217] In some embodiments, the disease or condition is an endpoint of impaired fasting glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired blood glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic states, insulin resistance syndrome, hyperinsulinemia-induced paresthesia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, impaired glucose tolerance, elevated fasting blood glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides, and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related lethargy.

[0218] In certain embodiments, the compounds described herein may reduce or slow the progression of borderline impaired fasting glucose or fasting hyperglycemia to diabetes.

[0219] In some embodiments, the disease or condition is an autoimmune disorder.Non-limiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease.See, for example, U.S. Patent Application Publication No. 20120148586A1.

[0220] In some embodiments, the disease or condition is a stomach or intestinal disorder, including, but not limited to, ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infections or other pathogens), dyspepsia, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy- and / or radiation-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal damage (e.g., aspirin-induced gastric mucosal damage), small intestinal mucosal damage, and cachexia (e.g., cancer cachexia, tuberculosis cachexia, hematological cachexia, endocrine cachexia, infectious disease cachexia, and acquired immune deficiency syndrome cachexia).

[0221] In some embodiments, the compounds described herein may be used to reduce weight (e.g., overweight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a subject (e.g., a subject in need thereof). In certain embodiments, the subject's weight gain may be due to excessive food intake or an unbalanced diet, or may be due to concomitant medication (e.g., insulin sensitizers with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, and the like). Alternatively, the weight gain may be prior to reaching obesity, or may be weight gain in an obese subject. The weight gain may also be drug-induced weight gain or weight gain after smoking cessation.

[0222] In some embodiments, the condition, disease, or disorder is an eating disorder such as hyperphagia, binge eating, bulimia, or compulsive eating.

[0223] In some embodiments, the disease or condition is an inflammatory disorder. Non-limiting examples of inflammatory disorders include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation of metabolically important tissues such as the liver, fat, pancreas, kidney, and intestine, and pro-inflammatory conditions (e.g., elevated levels of pro-inflammatory cytokines or inflammatory-like C-reactive protein markers in the blood).

[0224] In some embodiments, the disease or condition is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), and the like. ), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., For example, primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer), extragonadal germ cell tumors, ovarian germ cell tumors, low-grade ovarian tumors), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid carcinoma These include adenocarcinoma, nasal cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumors (e.g., Wilms' tumor, pediatric kidney tumor), Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0225] In certain embodiments, provided herein is a method of treatment comprising administering an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering to a subject in need thereof an amount of a compound described herein that is effective for treating a disease or condition in combination with a second agent that is effective for treating or preventing the disease or condition. In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.

[0226] In certain embodiments, the subject is a treatment-naive subject. In further embodiments, the subject has previously undergone therapy. For example, in certain embodiments, the subject has not responded to a single agent treatment regimen.

[0227] In certain embodiments, the subject is a subject who has discontinued some other therapy due to one or more adverse events associated with the other therapy. In certain embodiments, the subject is receiving some other therapy and discontinued that therapy before administering the methods provided herein. In further embodiments, the subject is receiving a therapy and continues to receive that therapy along with the administration of the compounds provided herein. The compounds described herein may be co-administered with other therapies for treating a disease or condition, according to the judgment of one skilled in the art. In certain embodiments, the methods or compositions provided herein may be co-administered with reduced doses of other therapies for treating the disease or condition.

[0228] Diagnostic Applications In some embodiments, the compounds provided herein are used in diagnostic applications, which may be useful in diagnosing and / or prognosing a disease or condition, such as, for example, a metabolic disease or condition.

[0229] In some diagnostic and prognostic applications or embodiments, the compound may be labeled with a detectable moiety. Suitable detectable moieties include, but are not limited to, radioisotopes, fluorescent labels, and enzyme substrate labels. In another embodiment, the compound need not be labeled, and the presence of the compound may be detected using a labeled antibody, or antigen-binding fragment thereof, that specifically binds to the compound.

[0230] kit In some embodiments, the compounds provided herein are provided in the form of a kit (i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure). In some embodiments, the procedure is a diagnostic assay. In certain embodiments, the procedure is a therapeutic procedure.

[0231] In some embodiments, the kit further comprises a solvent for reconstituting the compound. In some embodiments, the compound is provided in the form of a pharmaceutical composition.

[0232] In some embodiments, the kit may include a compound or composition provided herein, an optional second agent or composition, and instructions providing a healthcare provider with information on how to use the compound or composition to treat a disorder. The instructions may be provided in printed form or in the form of an electronic medium such as a floppy disk, CD, or DVD, or a website address where such instructions can be obtained. A unit dose of a compound or composition provided herein, or a second agent or composition, may comprise a dose that, when administered to a subject, can maintain a therapeutically or prophylactically effective plasma level of the compound or composition in the subject for at least one day. In some embodiments, the compound or composition may be included as a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0233] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes solid matrices or materials conventionally used in systems that can hold within certain limits the compounds provided herein and / or second agents suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil-laminated envelopes, etc. When using electron beam sterilization technology, the packaging must be of sufficiently low density to allow sterilization of the contents.

[0234] Preparation and synthesis procedures In certain embodiments, the compounds described herein are according to the compounds of Formula IIj-IIn shown in Scheme G1. Scheme G1 [ka]

[0235] In some embodiments, the compounds described herein are prepared as outlined in Schemes 1-3. The synthesis of the compounds in this application is not limited to these general reaction schemes shown here. Please see the Examples section for detailed syntheses of each individual compound.

[0236] [ka] Scheme 1. Compounds having formula S1 can be synthesized as shown in Scheme 1. S1b can be prepared from S1a by Mitsunobu reaction with S1a or alkylation of a phenol with the mesylate of S1a. TFA-catalyzed cleavage of the Boc protecting group in S1b gives the azetidine S1c. Alkylation of S1c followed by hydrolysis gives S1.

[0237] [ka] Scheme 2. Compounds having formula S2 and S2' can be prepared as shown in Scheme 2. Compound S2c can be prepared from halide S2a and pinacolborane S2b by Suzuki reaction. S2d can be obtained by Mitsunobu reaction using S2c or alkylation of a phenol using the mesylate of S2c. TFA-catalyzed cleavage of the Boc protecting group in S2d gives pyrroline S2e. Alkylation of S2e followed by hydrolysis gives S2. Similarly, compound S2' can be prepared by alkylation of pyrrolidine S2f (which can be obtained by selective hydrogenation of the endocyclic double bond in S2e) followed by hydrolysis.

[0238] [ka] Scheme 3. Compounds having formula S3 can be prepared as shown in Scheme 3. S3c is obtained by SNAr reaction or metal-catalyzed coupling reaction of S3a with S3b. 4 Hydrolysis of the group affords acid S3d, which undergoes amidation to afford ester S3e. Acetic acid-mediated imidazole formation affords S3f, which is then hydrolyzed to afford S3. [Example]

[0239] Preparation of compounds

[0240] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from Acros Organics (Pittsburgh, PA), Advanced ChemBlocks, Inc. (Burlingame, CA), Aldrich Chemical (Milwaukee, WI, e.g., Sigma Chemical and Fluka), AK Scientific (Union City, CA), AstaTech, Inc. (Bristol, PA), Aurum Pharmatech LLC (Franklin Park, NJ), Combi-Blocks, Inc. (San Diego, CA), Enamine (Monmouth Jct., NJ), Fisher Scientific Co. (Pittsburgh, PA), Frontier Scientific (Logan, UT), TCI America (Portland, OR), and VWR (Radnor, PA). Specific reactants and similar reactants are optionally identified through indexes of known chemical substances produced by the Chemical Abstract Service of the American Chemical Society; these indexes are available in most public and university libraries and online databases.

[0241] Suitable reference books detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing their preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992; R.C. Larock, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes. Some compounds require the application of protecting groups. The need for such protection is within the skill of the art. For a general description of protecting groups and their use, see T.W. Greene, P.G.M. Nuts, and Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1999.

[0242] Analytical methods and instruments

[0243] Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 or 600 MHz using a Bruker or Varian spectrometer. NMR spectra are reported as chemical shift δ (ppm), multiplicity, coupling constant J (Hz), and integral relative to the residual solvent signal. Tetramethylsilane (TMS) was used as an internal standard in some cases. Mass spectral data were measured using one of two systems: System A: A Waters Acquity i-class ultra-performance liquid chromatography (UPLC) system equipped with an Acquity photodiode array detector, an Acquity evaporative light scattering detector (ELSD), and a Waters ZQ mass spectrometer. Data were acquired using Waters MassLynx 4.1 software, and purity was characterized by UV at 220 nm, evaporative light scattering detection (ELSD), and electrospray ionization (ESI) (column: Acquity UPLC BEH C18 1.7μ ι 2.1 × 50 mm). System B: Agilent LC / MS consisting of a 1200 Series LC and a 6140 quadrupole MS detector (column: Agilent USGYL01131, HPH-C18 2.7 μM, 2.1 × 50 mm). Solvent: acetonitrile / water with 0.1% formic acid. Flow rate: 0.7 mL / min. Preparative HPLC purification was performed at a flow rate of 15 mL / min with UV detection at 214 nm and 254 nm (column: Jupiter® 10 μM Proteo 90 Å, 250 × 21.2 mm A). Solvent: acetonitrile / water (with modifiers such as 0.1% trifluoroacetic acid, formic acid, or acetic acid)). Compound purity was checked by analytical HPLC (Waters Acquity UPLC H-Class instrument) at a flow rate of 0.5 mL / min (Acquity BEH C18, 50 × 2.1 mm column).

[0244] Abbreviations used in the examples include: [Table 2-1] [Table 2-2]

[0245] Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Reaction times and yields were not optimized. Example numbers and compound numbers are the same.

[0246] Preparation of common intermediates: Intermediate Ih. Methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Ih) Step A. (S)-2-((benzyloxy)methyl)oxetane (Ia) [ka] To a solution of KOtBu (2.97 g, 30.4 mmol) in tBuOH (50 mL) was added trimethylsulfoxonium (6.68 g, 30.4 mmol). The reaction mixture was stirred at 60 °C for 30 minutes, and then (2S)-2-[(benzyloxy)methyl]oxirane (5 g, 30.4 mmol) was added. The mixture was heated at 80 °C for 2 hours. Upon completion, the mixture was cooled to 25 °C and filtered through Celite. The filter cake was washed with petroleum ether (10 mL). Water (20 mL) was added to the filtrate and extracted with petroleum ether (2 × 10 mL). The combined organic layers were washed with saturated NH4Cl (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography (petroleum ether: EtOAc = 1:1) to give the title compound (Ia) (2.5 g, 47%) as a yellow oil. m / z(ESI, +ve ion)=201.1[M+Na] + .

[0247] Step B. (S)-Oxetan-2-ylmethanol (Ib) [ka] To a solution of Ia (7 g, 39.3 mmol) in THF (90 mL) was added Pd(OH) (700 mg, 3.93 mmol). The reaction mixture was stirred at 45 °C under 0.4 MPa H for 48 h. After completion, the crude mixture was filtered through Celite and the resulting crude mixture (Ib) in THF was carried on to the next step without any further purification. m / z (ESI, +ve ion) = 111.1 [M+Na] + .

[0248] Step C. (S)-Oxetan-2-ylmethyl methanesulfonate (Ic) [ka] To a solution of Ib (6 g, 68 mmol) in THF (100 mL) was added methanesulfonic anhydride (17.1 g, 102 mmol) and TEA (13.6 g, 136.5 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum: EtOAc = 1:1) to give the title product (Ic) (6 g, 53.1%) as a yellow oil. m / z (ESI, +ve ion) = 167.1 [M+H] + .

[0249] Step D. (S)-2-(azidomethyl)oxetane (Id) [ka] To a solution of Ic (6 g, 36.1 mmol) in DMF (100 mL) was added NaN3 (7.02 g, 108 mmol). The reaction mixture was stirred at 80 °C for 16 h. Water (20 mL) was added to the reaction, extracted with EtOAc (3 × 20 mL), and washed with HO (10 mL). The organic layer (Id) was concentrated and used in the next step without any further purification. m / z (ESI, +ve ion) = 114.1 [M+H] + .

[0250] Step E. (S)-Oxetan-2-ylmethanamine (Ie) [ka] To a solution of Id (900 mg, 7.96 mmol) in THF (30 mL) was added Pd / C (10 mg). The reaction mixture was stirred under hydrogen at 20° C. for 2 h. After completion, the crude reaction mixture was filtered through Celite. The filtrate (Ie) was used in the next step without any further purification. m / z (ESI, +ve ion) = 88.2 [M+H] + .

[0251] Step F. Methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (If) [ka] To a solution of Ie (700 mg, 10.5 mmol) in THF (3 mL) was added methyl 3-fluoro-4-nitrobenzoate (2.09 g, 10.5 mmol) and TEA (3.18 g, 31.5 mmol). The reaction mixture was stirred at 25 °C for 16 h, and then water (15 mL) was added. The solution was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum: EtOAc = 1:1) to give the title product (If) (1.2 g, 43.9%) as a yellow solid. m / z (ESI, +ve ion) = 267.1 [M+H] + .

[0252] Step G. Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (Ig) [ka] To a solution of If (800 mg, 7.9 mmol) in THF (8 mL) was added Pd / C (100 mg). The reaction mixture was stirred under 50 psi H2 at 20 °C for 3 h. After completion, the crude mixture was filtered through Celite and the filtrate was concentrated to give the title compound (Ig) (0.6 g, 43.9%) as a yellow solid. m / z (ESI, +ve ion) = 237.2 [M+H] + .

[0253] Step H. Methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Ih) [ka] To a solution of Ig (700 mg, 2.96 mmol) in MeCN (10 mL) were added 2-chloro-1,1,1-trimethoxyethane (456 mg, 2.96 mmol) and 4-methyl-benzenesulfonic acid (25 mg, 0.14 mmol). The reaction mixture was stirred at 60° C. for 2 h. The residue was purified by silica gel column chromatography (petroleum: EtOAc = 1:1) to give the title product (Ih) (0.6 g, 68.9%) as a yellow solid. m / z (ESI, +ve ion) = 295.1 [M+H] + .

[0254] Intermediate IIf. Methyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (IIf) Step A. Ethyl 1-ethyl-1H-imidazole-5-carboxylate (IIa) [ka] To a solution of ethyl lH-imidazole-5-carboxylate (2.8 g, 20.0 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 1.2 g, 30.0 mmol) at 0 °C. After stirring at the same temperature for 0.5 h, iodoethane (3.12 g, 20.0 mmol) was added, and the resulting mixture was stirred at 0 °C for an additional 0.5 h. Upon completion, the mixture was quenched with HO (30 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with HO (30 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 5:1) to give the title product (IIa) (850 mg, 25%) as a white solid. m / z(ESI, +ve ion)=169.1[M+H] + .

[0255] Step B. 1-Ethyl-1H-imidazole-5-carboxamide (IIb) [ka] A solution of IIa (3.6 g, 21.4 mmol) in 7N NH solution in MeOH (50 mL) was stirred at 80 °C in a sealed reactor for 36 h. After completion, the mixture was concentrated in vacuo to give a crude residue. The crude residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (IIb) (1.9 g, 64%) as a white solid. m / z (ESI, +ve ion) = 140.1 [M+H] + .

[0256] Step C. (1-Ethyl-1H-imidazol-5-yl)methanamine (IIc) [ka] To a solution of IIb (1.9 g, 13.6 mmol) in THF (20 mL) was added LiAlH (1.1 g, 27.2 mmol) at 0 °C. The mixture was stirred at 60 °C under N for 16 h. After completion, the mixture was quenched with NaSO 10H O and filtered. The filtrate was extracted with DCM (100 mL). The organic layer was concentrated in vacuo to give the crude title product (IIc) (1.4 g) as a colorless oil, which was used in the next step without further purification. m / z (ESI, +ve ion) = 126.2 [M+H] + .

[0257] Step D. Methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (IId) [ka] A mixture of IIc (1.4 g, 11.1 mmol), methyl 3-fluoro-4-nitrobenzoate (2.4 g, 12.2 mmol), and TEA (3.3 g, 33.3 mmol) in THF (20 mL) was stirred at 25 °C for 16 h. After completion, the mixture was diluted with HO (50 mL) and extracted with DCM (50 mL × 3). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (IId) (1.6 g, 47%) as a white solid. m / z (ESI, +ve ion) = 305.2 [M+H] + .

[0258] Step E. Methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (IIe) [ka] A mixture of IId (1.6 g, 5.26 mmol) and 10% Pd / C (200 mg) in MeOH (10 mL) was stirred under H at 25 °C for 2 h. After completion, the mixture was filtered through a pad of Celite and rinsed with additional MeOH (100 mL). The combined organic layers were concentrated in vacuo to give a crude residue. This residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (IIe) (1.3 g, 90%) as a brown solid. m / z (ESI, +ve ion) = 275.2 [M+H] + .

[0259] Step F. Methyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (IIf) [ka] To a solution of 57e (100 mg, 0.36 mmol) in CHCN (3 mL) was added 2-chloro-1,1,1-trimethoxyethane (67.7 mg, 0.44 mmol) and p-toluenesulfonic acid monohydrate (3.4 mg, 0.018 mmol) at room temperature. The mixture was heated to 60 °C and stirred overnight. The crude reaction mixture was purified by reverse-phase HPLC (CHCN and water containing 0.1% HOAc as a modifier) ​​to give the title product (IIf) (46.6 mg, 39.0%) as a white solid. m / z (ESI, +ve ion) = 333.1 [M+H] + .

[0260] Intermediate IIIf. tert-Butyl 2-(2,5-difluoro-4-hydroxyphenyl)acetate (IIIf) [ka] Step A. 1-Allyl-2,5-difluoro-4-methoxybenzene (IIIa) [ka] A solution of 1-bromo-2,5-difluoro-4-methoxybenzene (5 g, 22.4 mmol), allyltributyltin (8.9 g, 26.8 mmol), and Pd(PPh) (2.59 g, 2.2 mmol) in DMF (100 mL) was stirred at 110 °C for 18 h under a N atmosphere. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were concentrated and purified by silica gel column chromatography (EtOAc:petroleum ether = 1:15) to give the title product (IIIa) (2.63 g, 57.6%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 6.89 (dd, J = 11.56, 7.04 Hz, 1H), 6.67 (dd, J = 10.10, 7.14 Hz, 1H), 5.83 - 5.95 (m, 1H), 5.03 - 5.12 (m, 2H), 3.85 (s, 3H), 3.31 (dd, J = 6.50, 1.05 Hz, 2H).

[0261] Step B. 2-(2,5-Difluoro-4-methoxyphenyl)acetic acid (IIIb) [ka] To a mixture of IIIa (2.5 g, 13.6 mmol), NaIO (11.64 g, 54.4 mmol) in a mixture of CCl / CHCN / HO (40 mL / 40 mL / 70 mL), ruthenium(III) chloride (560 mg, 2.7 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 2 h, poured into water (50 mL), and extracted with DCM (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the impure crude title product (IIIb) (2.2 g) as a dark green solid, which was used in the next step without further purification. m / z (ESI, +ve ion) = 203.1 [M+H] + .

[0262] Step C. 2-(2,5-Difluoro-4-hydroxyphenyl)acetic acid (IIIc) [ka] To a stirred solution of crude IIIb (650 mg, 3.2 mmol) in DCM (6 mL) was added BBr3 (1.5 mL) at 0 °C. The reaction was stirred at 25 °C for 2 h, poured into ice water, and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated and purified by reverse-phase HPLC (32% CH3OH in HO) to give the title product (IIIc) (441 mg, 65%) as a gray solid. m / z (ESI, +ve ion) = 189.1 [M+H] + .

[0263] Step D. 2-(4-Acetoxy-2,5-difluorophenyl)acetic acid (IIId) [ka] To a mixture of IIIc (50 mg, 0.26 mmol) and AcO (54 mg, 0.53 mmol) in DCM (3.0 mL) was added one drop of concentrated HSO. The resulting clear solution was stirred at 25 °C for 1.5 h, poured into water (5 mL), and extracted with EtOAc (15 mL × 2). The combined organic layers were concentrated under reduced pressure and purified by reverse-phase HPLC (37% CHOH in HO) to give the title product (IIId) (37 mg, 54%) as a white solid. m / z (ESI, +ve ion) = 253.0 [M+Na] + .

[0264] Step E. tert-Butyl 2-(4-acetoxy-2,5-difluorophenyl)acetate (IIIe) [ka] A solution of IIId (100 mg, 0.43 mmol), BocO (190 mg, 0.87 mmol), and DMAP (11 mg, 0.09 mmol) in t-BuOH (5 mL) was stirred at 50 °C for 1 h. The reaction was concentrated and purified by silica gel column chromatography (EtOAc / petroleum ether = 1:10) to give the title product (IIIe) (69 mg, 50%) as a colorless oil. m / z (ESI, +ve ion) = 309.0 [M+Na] + .

[0265] Step F. tert-Butyl 2-(2,5-difluoro-4-hydroxyphenyl)acetate (IIIf) [ka] A mixture of IIIe (380 mg, 1.33 mmol) and KCO (275 mg, 2 mmol, 1.5 equiv) in CHOH (5 mL) was stirred at 25 °C for 0.5 h. The reaction was poured into water (25 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were concentrated and purified by reverse-phase HPLC (37% CHCN in H0 (containing 0.5% TFA as a modifier)) to give the title product (IIIf) (320 mg, 88%) as a white solid. m / z (ESI, +ve ion) = 267.0 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 7.12 (dd, J = 11.50, 7.19 Hz, 1H), 6.74 (dd, J = 10.80, 7.44 Hz, 1H), 3.47 (s, 2H), 1.39 (s, 9H).

[0266] Example 119. 1-(((S)-Oxetan-2-yl)methyl)-2-((3-(3-phenoxyphenyl)pyrrolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (119) [ka] Step A. Methyl 1-(((S)-oxetan-2-yl)methyl)-2-((3-(3-phenoxyphenyl)pyrrolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (119a) [ka] A solution of 3-(3-phenoxyphenyl)pyrrolidine (20 mg, 0.084 mmol), Ih (19.7 mg, 0.084 mmol), and DIPEA (0.029 mL, 0.17 mmol) in DCM (0.84 mL) was heated to 40° C. overnight. The crude material was directly purified by silica gel column chromatography (gradient elution from 0 to 100% EtOAc in hexanes) to give the title product (119a) (32 mg, 77%). m / z (ESI, +ve ion) = 498.1 [M+H] + .

[0267] Step B. 1-(((S)-Oxetan-2-yl)methyl)-2-((3-(3-phenoxyphenyl)pyrrolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (119) [ka] To a solution of 119a (30 mg, 0.06 mmol) in THF / HO (0.6 mL, 2:1), LiOH (2.5 mg, 0.06 mmol) was added and stirred for 2 h. The reaction was neutralized with 1 N HCl and extracted with EtOAc. The organic layer was dried, filtered, concentrated, and purified by silica gel column chromatography (gradient elution from 0 to 10% MeOH in DCM) to give the title product (119) (17 mg, 58%) as a white solid. m / z (ESI, +ve ion) = 484.3 [M+H] + .

[0268] Example 127. (S)-2-((4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (127) [ka] Step A. tert-Butyl 4-((3-(methoxycarbonyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (127a) [ka] A solution of methyl 1H-pyrazole-3-carboxylate (1.26 g, 10.0 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (2.77 g, 10.0 mmol), and CsCO (9.78 g, 30.0 mmol) in CHCN (50 mL) was stirred at 60 °C for 5 h. Upon completion, the reaction was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with HO (30 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude residue, which was purified by reverse-phase HPLC (HO with CHCN (containing 0.1% formic acid as a modifier)) to give the title product (127a) (1.60 g, 49%) as a white solid. m / z (ESI, +ve ion) = 346.1 [M+Na] + .

[0269] Step B. tert-Butyl 4-((3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (127b) [ka] To a solution of 127a (1.60 g, 4.9 mmol) in 20 mL of anhydrous THF was added DIBAL-H solution (1 N in hexane, 14.7 mL, 14.7 mmol) at 0 °C. The reaction was stirred at 15 °C under N atmosphere for 2 h. Upon completion, the reaction was quenched with NaSO.10H0. The mixture was filtered and the filter cake was rinsed with DCM (100 mL). The organic layer was concentrated to give the title product (127b) (970 mg, 67%) as a colorless oil. m / z (ESI, +ve ion) = 296.2 [M+H] + .

[0270] Step C. tert-Butyl 4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (127c) [ka] To a solution of 127b (310 mg, 1.1 mmol), 2,4-dichlorophenol (187 mg, 1.2 mmol), and PPh3 (303 mg, 1.2 mmol) in THF (10 mL) was added DEAD (201 mg, 1.2 mmol) at 0 °C. The reaction was stirred at 15 °C under a N2 atmosphere for 5 h. Upon completion, the reaction was diluted with HO (20 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with HO (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by silica gel column chromatography (petroleum: EtOAc = 10:1) to give the title product (127c) (81 mg, 17%) as a colorless oil. m / z (ESI, +ve ion) = 462.0 [M+Na] + .

[0271] Step D. 4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidine (127d) [ka] To a solution of 127c (81 mg, 0.18 mmol) in DCM (10 mL) was added 2,6-lutidine (432 mg, 3.7 mmol) and TMSOTf (400 mg, 1.8 mmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction was quenched with NH4Cl (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with HO (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title product (127d) as a yellow oil, which was used in the next step without further purification. m / z (ESI, +ve ion) = 340.1 [M+H] + .

[0272] Step E. Methyl (S)-2-((4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (127e) [ka] To a mixture of 127d (crude material from Step D, 0.18 mmol) and K2CO3 (75 mg, 0.54 mmol) in DMF (5 mL) was added Ih (53 mg, 0.18 mmol) at 10 °C. After stirring at the same temperature for 16 h, the reaction was diluted with HO (5 mL) and extracted with DCM (20 mL × 3). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. It was purified by silica gel column chromatography (DCM / MeOH = 50:1) to give the title product (127e) (61 mg, 57%) as a white solid. m / z (ESI, +ve ion) = 598.1 [M+H] + .

[0273] Step F. (S)-2-((4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (127) [ka] To a mixture of 127e (61 mg, 0.1 mmol) in THF (3 mL) and HO (1 mL) was added lithium hydroxide (24 mg, 1.0 mmol), and the mixture was stirred at 30 °C for 5 h. Upon completion, 1 N HCl was added to the reaction to adjust the pH to 7. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase HPLC (CHCN in HO (containing 0.1% TFA as a modifier)) to give the title product (127) (23.2 mg, 39%) as a white solid. m / z (ESI, +ve ion) = 584.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.28 - 8.41 (m, 1H), 7.97 - 8.11 (m, 1H), 7.79 (d, J = 8.56 Hz, 1H), 7.63 (d, J = 2.20 Hz, 1H), 7.38 (dd, J = 2.32, 1.10 Hz, 1H), 7.13 - 7.28 (m, 2H), 6.42 (d, J = 1.96 Hz, 1H), 5.16 - 5.26 (m, 1 H), 5.14 (s, 2 H), 4.79 (d, J = 3.42 Hz, 2H), 4.70 - 4.76 (m, 1H), 4.58 - 4.70 (m, 2H), 4.39 (dt, J = 9.11, 5.96 Hz, 1H), 4.14 (d, J = 6.85 Hz, 2H), 3.78 (br d, J = 10.03 Hz, 2H), 3.14 - 3.29 (m, 2H), 2.68 - 2.87 (m, 1H), 2.41 - 2.56 (m, 1H), 2.15 - 2.32 (m, 1H), 1.74 - 1.93 (m, 2H), 1.49 - 1.68 (m, 2H).

[0274] Example 134. 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((3-phenoxypyrrolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (134) [ka] Step A. Methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((3-(3-phenoxyphenyl)pyrrolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (134a) [ka] A solution of 3-(3-phenoxyphenyl)pyrrolidine (4 mg, 0.017 mmol), IIf (4.6 mg, 0.014 mmol), and EtN (14 mg, 0.14 mmol) in DMF (1 mL) was stirred at room temperature for 20 h. Upon completion, the reaction was purified by reverse-phase HPLC (gradient elution from 0 to 90% CHCN in water (containing 0.1% TFA as a modifier)) to afford the title compound (134a) (8.2 mg) as a white solid containing some impurities, which was used in the next step without further purification. m / z (ESI, +ve ion) = 536.4 [M+H] + .

[0275] Step B. 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((3-(3-phenoxyphenyl)pyrrolidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (134) [ka] A solution of 134a (8.2 mg, crude) in THF (0.5 mL) was treated with 2 N NaOH (0.5 mL) and MeOH (4 drops). The resulting mixture was stirred at room temperature for 20 h. Upon completion, the reaction was purified by reverse-phase HPLC (gradient elution from 0 to 60% CHCN in water (containing 0.1% TFA as a modifier)) to afford the title product (134) (3.7 mg, 41% over two steps, racemic) as a white solid. 1 H NMR (600 MHz, CD3OD ) δ ppm 8.99 (s, 1H), 8.24 (br d, J = 0.73 Hz, 1H), 8.04 - 8.07 (m, 1H), 7.83 (d, J = 8.44 Hz, 1H), 7.33 - 7.39 (m, 3H), 7.08 - 7.15 (m, 3H), 7.03 (br t, J = 2.02 Hz, 1H), 6.96 - 7.00 (m, 2H), 6.88 - 6.92 (m, 1H), 5.81 (s, 2H), 4.31 (q, J = 7.34 Hz, 2H), 3.92 - 4.01 (m, 2H), 3.65 - 3.75 (m, 3H), 2.53 - 2.60 (m, 2H), 2.21 - 2.29 (m, 2H), 1.53 (t, J = 7.34 Hz, 3H) m / z (ESI, +ve ion) = 522.3 [M+H] + .

[0276] Example 147. 2-((3-((2-((2,4-dichlorophenoxy)methyl)oxazol-5-yl)methyl)azetidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (147) [ka] Step A. Methyl 5-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)oxazole-2-carboxylate (147a) [ka] To a solution of methyl 5-((bromotriphenyl-λ5-phosphanyl)methyl)oxazole-2-carboxylate (211 mg, 0.44 mmol, prepared by heating methyl 5-(bromomethyl)-1,3-oxazole-2-carboxylate with triphenylphosphine in toluene at 90° C. for 24 hours, decanting the solvent, and drying the solid residue on a high vacuum pump) in anhydrous DMF (2.2 mL) was added NaH (19 mg, 0.47 mmol, 60% in mineral oil) at 0° C. After stirring for 10 minutes, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (50 mg, 0.29 mmol) in DMF (1.5 mL) was added dropwise, and the reaction was allowed to warm to room temperature. After 16 hours, the reaction was quenched with saturated NH4Cl and extracted with EtOAc (5 mL × 2). The organic layer was washed with HO (5 mL), brine (5 mL), dried over NaSO, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (gradient elution from 0 to 90% EtOAc in hexanes) to give the title product (147a) (48 mg, 56%). m / z (ESI, +ve ion) = 239.3 [M-tBu+H] + .

[0277] Step B. Methyl 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)oxazole-2-carboxylate (147b) [ka] To 147a (45 mg, 0.15 mmol) in EtOH (1.5 mL) was added 10% Pd / C (8 mg, 0.008 mmol) at room temperature. The mixture was degassed with hydrogen for 10 min and then stirred under a H balloon for 4 h. The reaction was filtered through a pad of Celite, rinsed with EtOAc, and concentrated to give the title product (147b) (42 mg), which was used in the next step without further purification. m / z (ESI, +ve ion) = 241.1 [M - tBu + H] +.

[0278] Step C. tert-Butyl 3-((2-(hydroxymethyl)oxazol-5-yl)methyl)azetidine-1-carboxylate (147c) [ka] To a solution of crude 147b (42 mg) in absolute EtOH (1.4 mL) at 0 °C, NaBH (16 mg, 0.43 mmol) and CaCl (47 mg, 0.43 mmol) were added. The reaction was then stirred at room temperature for 4 h, quenched by the dropwise addition of 1 N HCl (1 mL), and extracted with EtOAc (5 mL × 3). The organic layer was washed with HO (5 mL), brine (5 mL), dried over NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution from 0 to 15% MeOH in DCM) to give the title product (147c) (32 mg, 84% over two steps). m / z (ESI, +ve ion) = 291.1 [M+Na] + .

[0279] Step D. tert-Butyl 3-((2-((2,4-dichlorophenoxy)methyl)oxazol-5-yl)methyl)azetidine-1-carboxylate (147d) [ka] To 147c (30 mg, 0.11 mmol) in anhydrous THF (1.1 mL) was added DIAD (41 mg, 0.20 mmol), PPh3 (53 mg, 0.20 mmol), and 2,4-dichlorophenol (22 mg, 0.14 mmol) at 0 °C. The reaction was allowed to warm to room temperature. After 3 h, HO (3 mL) was added, and the reaction was extracted with EtOAc (3 mL × 3). The organic layer was washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated to give the crude residue. This was purified by silica gel column chromatography (gradient elution from 0 to 90% EtOAc in hexane) to give the title product (147d) (12 mg, 21%). m / z (ESI, +ve ion) = 436.0 [M+Na] + .

[0280] Step E. 5-(Azetidin-3-ylmethyl)-2-((2,4-dichlorophenoxy)methyl)oxazole (147e) [ka] To a solution of 147d (11 mg, 0.027 mmol) in DCM (0.6 mL) was added TFA (0.051 mL). After stirring at room temperature for 5 h, the reaction was concentrated, redissolved in EtOAc, and washed with saturated NaHCO. The aqueous layer was extracted with EtOAc (×2), and the combined organic layers were dried, filtered, and concentrated to give the crude title product (147e) (8.3 mg), which was used in the next step without further purification.

[0281] Step E. 2-((3-((2-((2,4-dichlorophenoxy)methyl)oxazol-5-yl)methyl)azetidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (147) [ka] The title product (147) was synthesized from crude 147e using a procedure similar to that described in Steps A and B of Example 119. m / z (ESI, +ve ion) = 595.1 [M+H] + . 1 H NMR (600 MHz, MeOD) δ ppm 9.07 (d, J = 1.10 Hz, 1H), 8.24 (d, J = 0.73 Hz, 1H), 8.05 (dd, J = 8.44, 1.47 Hz, 1H), 7.82 (d, J = 8.44 Hz, 1H), 7.40 (d, J = 2.20 Hz, 1H), 7.28 (dd, J = 8.80, 2.57 Hz, 1H), 7.20 (d, J = 8.80 Hz, 1H), 7.13 (d, J=1.47 Hz, 1H), 6.98 (s, 1H), 5.78 (s, 2H), 5.22 (s, 2H), 4.91 (s, 2H), 4.47 - 4.57 (m, 2H), 4.21 - 4.36 (m, 4H), 3.33 - 3.37 (m, 1H), 3.17 - 3.24 (m, 2H), 1.53 (t, J = 7.34 Hz, 3H).

[0282] Examples 167 and 191 were synthesized using procedures similar to those described in Example 147.

[0283] Example 225 was synthesized from 147a using Step B of Example 127 (toluene as solvent) followed by Steps D and E of Example 147 in a similar manner as described therein.

[0284] Example 173. 2-((4-((2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (173) [ka] Step A. 2-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine (173a) [ka] A mixture of 5-chloro-2-ethynylpyridine (0.18 g, 1.31 mmol), 3-bromobenzene-1,2-diol (0.25 g, 1.31 mmol), and triruthenium dodecacarbonyl (0.017 g, 0.026 mmol) in toluene (2.6 mL) was degassed with argon for 1 minute. The resulting mixture was stirred at 100 °C overnight. Upon completion, the reaction mixture was diluted with EtOAc (5 mL) and filtered through a pad of Celite. The filtrate was concentrated and purified by silica gel column chromatography (gradient elution from 0 to 10% EtOAc in hexanes) to give the title product (173a) (0.25 g, 59%) as a pale yellow oil. m / z (ESI, +ve ion) = 326.1 [M+H] + .

[0285] Step B. tert-Butyl 4-((2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidine-1-carboxylate (173b) [ka] Next, 1-N-Boc-4-methylenepiperidine (0.17 mL, 0.85 mmol) was degassed with argon for 1 min, followed by the addition of a solution of 9-BBN in THF (1.7 mL, 0.85 mmol). The reaction was stirred at 70 °C for 1 h. It was then cooled to room temperature and transferred to a solution of 173a (0.25 g, 0.76 mmol), Pd(dppf)Cl (0.017 g, 0.023 mmol), and KCO (0.14 g, 1.01 mmol) in DMF (1.76 mL) and water (0.18 mL). The resulting mixture was degassed with argon for an additional 1 min and then stirred at 60 °C overnight. Upon completion, the reaction mixture was poured into water (5 mL) and the pH was adjusted to 11 with 1 N NaOH. It was then diluted with EtOAc (10 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried over NaSO, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (gradient elution from 0 to 30% EtOAc in hexanes) to give the title product (173b) (0.19 g, 56%) as a colorless oil. m / z (ESI, +ve ion) = 445.4 [M+H] + .

[0286] Step C. 5-Chloro-2-(2-methyl-4-(piperidin-4-ylmethyl)benzo[d][1,3]dioxol-2-yl)pyridine (173c) [ka] A solution of 173b (192 mg, 0.43 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at room temperature for 10 min. The reaction was concentrated to remove volatiles and diluted with EtOAc (10 mL). The organic layer was washed with saturated NaHCO3 (5 mL), brine (3 mL), dried over Na2SO4, filtered, and concentrated to give the crude title product (173c) (159 mg) as a yellow oil, which was used in the next step without further purification. m / z (ESI, +ve ion) = 345.3 [M+H] + .

[0287] Step D. Methyl 2-((4-((2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (173d) [ka] A solution of 173c (9.8 mg, 0.028 mmol), Ih (8.8 mg, 0.030 mmol), and DIPEA (0.099 mL, 0.57 mmol) in DMF (0.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL × 2), brine (3 mL), dried over NaSO, filtered, and concentrated to give a crude residue. This was purified by silica gel column chromatography (gradient elution from 80 to 100% EtOAc in hexanes followed by 0 to 20% MeOH in DCM) to give the title product (173d) (6 mg, 35%) as a colorless oil. m / z (ESI, +ve ion) = 603.3 [M+H] + .

[0288] Step E. 2-((4-((2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (173) [ka] A solution of 173d (6 mg, 0.010 mmol) and LiOH (2.1 mg, 0.05 mmol) in 0.4 mL of THF:MeOH:HO (2:1:1) was stirred overnight at 30 °C. Upon completion, the reaction mixture was diluted to 1 mL with water and purified by reverse-phase HPLC (gradient elution from 30 to 70% CHCN in HO with 0.1% TFA as a modifier) ​​to give the title product (173) (6.9 mg, 99%) as a white solid. m / z (ESI, +ve ion) = 589.3 [M+H] + . 1 H NMR (600 MHz, CD3OD) δ ppm 8.60 (br t, J = 2.4 Hz, 1H), 8.33 (br d, J = 1.10 Hz, 1H), 8.04 (dd, J = 8.4, 1.5 Hz, 1H), 7.88 (dd, J = 8.44 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.65 - 7.68 (m, 1H), 6.81 (t, J = 1.0 Hz, 1H), 6.76 (d, J = 1.0 Hz, 1H), 6.69 (br d, J = 7.7 Hz, 1H), 5.17 - 5.23 (m, 1H), 4.55 - 4.80 (m, 5H), 4.34 - 4.41 (m, 1H), 3.67 - 3.78 (m, 2H), 3.10 - 3.25 (m, 2H), 2.75 - 2.84 (m, 1H), 2.65 (br d, J = 6.6 Hz, 2H), 2.48 (ddd, J = 16.9, 11.4, 7.3 Hz, 1H), 2.02 (s, 3H), 1.80 - 2.01 (m, 3H), 1.46 - 1.64 (m, 2H). Examples 172, 184, and 185 were synthesized using procedures similar to those described in Example 173.

[0289] Example 177. (S)-2-((3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)methyl)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (177) [ka] Step A. 4-Bromo-2-((2,4-dichlorophenoxy)methyl)pyridine (177a) [ka] DIAD (5.00 g, 24.7 mmol), PPh3 (6.49 g, 24.7 mmol), and 2,4-dichlorophenol (2.69 g, 16.5 mmol) were added to a solution of (4-bromopyridin-2-yl)methanol (3.10 g, 16.5 mmol) in anhydrous THF (33 mL) at 0 °C. After 1 h, HO (30 mL) was added, and the reaction was extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give a crude residue. This was purified by silica gel column chromatography (gradient elution from 0 to 50% EtOAc in hexane) and further purified by recrystallization with EtOAc and hexane to give the title product (177a) (4.65 g, 85%). m / z (ESI, +ve ion) = 334.0 [M + H] + .

[0290] Step B. tert-Butyl 3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)methylene)azetidine-1-carboxylate (177b) [ka] To a solution of 177a (1.2 g, 3.60 mmol) in anhydrous CHCN (36 mL) was added Pd(OAc) (162 mg, 0.72 mmol), tri-o-tolylphosphane (439 mg, 1.44 mmol), tert-butyl 3-methyleneazetidine-1-carboxylate (732 mg, 4.32 mmol), and iPrNEt (1.88 mL, 1.40 g, 10.80 mmol) at room temperature. Argon was bubbled through the mixture for 15 minutes, and the mixture was heated to 110 °C. After 16 hours, the reaction was cooled to room temperature, saturated NaHCO (30 mL) was added, and the reaction was extracted with EtOAc (20 mL × 3). The organic layer was washed with brine, dried over NaSO, filtered, and concentrated to give the crude residue. This was purified by silica gel column chromatography (gradient elution from 0% to 40% EtOAc in hexane) to give the title product (177b) (450 mg, 30%) as a yellow solid. m / z (ESI, +ve ion) = 421.4 [M + H] + .

[0291] Step C. tert-Butyl 3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)methyl)azetidine-1-carboxylate (177c) [ka] To a solution of 177b (50 mg, 0.12 mmol) in EtOAc (0.6 mL) was added PtO2 (1.4 mg, 0.006 mmol) at room temperature. The mixture was degassed with hydrogen for 10 minutes and then stirred under a H2 balloon for 16 hours. The reaction was filtered through a pad of Celite, rinsed with EtOAc, and concentrated to give the crude title product (177c) (55 mg), which was used in the next step without further purification. m / z (ESI, +ve ion) = 423.3 [M + H] + .

[0292] Step D. (S)-2-((3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)methyl)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (177) [ka] The title product (177) was synthesized from 177c using a procedure similar to that described in Steps C-E of Example 173. 1 H NMR (600 MHz, MeOD) δ ppm 8.53 (d, J = 5.14 Hz, 1H), 8.30 (d, J = 1.10 Hz, 1H), 8.00 - 8.04 (m, 1H), 7.75 (d, J = 8.07 Hz, 1H), 7.58 (s, 1H), 7.42 (d, J = 2.57 Hz, 1H), 7.34 (dd, J = 5.14, 1.47 Hz, 1H), 7.27 (dd, J = 8.80, 2.57 Hz, 1H), 7.13 (d, J = 8.80 Hz, 1H), 5.27 (s, 2H), 5.17 (qd, J = 7.09, 2.57 Hz, 1H), 4.91 - 5.01 (m, 2H), 4.61 - 4.68 (m, 2H), 4.52 - 4.59 (m, 1H), 4.41 - 4.50 (m, 2H), 4.37 (dt, J = 9.26, 6.01 Hz, 1H), 4.17 - 4.27 (m, 2H), 3.37 (dt, J = 16.41, 8.12 Hz, 1H), 3.14 - 3.23 (m, 2H), 2.79 (dtd, J=11.51, 8.09, 8.09, 6.05 Hz, 1H), 2.38 - 2.51 (m, 1H). m / z (ESI, +ve ion) = 567.3 [M+H] +

[0293] Compound examples 175, 176, 180, 181, and 190 were synthesized using procedures similar to those described in Example 177.

[0294] Example 226 was synthesized using a procedure similar to that described in Example 177 without the hydrogenation step.

[0295] Example 192. (S)-2-((3-(3-((2,4-dichlorophenoxy)methyl)phenoxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (192) [ka] Step A. tert-Butyl 3-(tosyloxy)azetidine-1-carboxylate (192a) [ka] A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.99 g, 11.5 mmol) in DMF (5 mL) was stirred at 0 °C for 10 min. 4-Methylbenzenesulfonyl chloride (2.41 g, 12.6 mmol) and EtN (11.2 g, 34.5 mmol) were added at 0 °C. The resulting mixture was warmed to room temperature and stirred for 16 h. Upon completion, the reaction was concentrated to remove the solvent. HO (10 mL) was added and the reaction was extracted with EtOAc (20 mL × 3). The organic layer was dried, filtered, and concentrated to give the title product (192a) (2.5 g, 63%) as a yellow oil, which was used in the next step without further purification. m / z (ESI, +ve ion) = 330.2 [M+H] + .

[0296] Step B. tert-Butyl 3-(3-(methoxycarbonyl)phenoxy)azetidine-1-carboxylate (192b) [ka] A solution of 192a (2.5 g, 7.6 mmol), methyl 3-hydroxybenzoate (1.16 g, 7.6 mmol), and CsCO (7.43 g, 22.8 mmol) in DMF (5 mL) was stirred at 80 °C for 3 h. Upon completion, the reaction was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried, filtered, and concentrated to give the crude residue, which was purified by silica gel column chromatography (petroleum ether: EtOAc = 10:1) to give the title product (192b) (1.20 g, 49.9%) as a yellow oil. m / z (ESI, +ve ion) = 330.1 [M+Na] + .

[0297] Step C. tert-Butyl 3-(3-(hydroxymethyl)phenoxy)azetidine-1-carboxylate (192c) [ka] To a solution of 192b (600 mg, 1.9 mmol) in THF (5 mL) was added LiAlH (36.92 mg, 0.97 mmol). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction was quenched with HO (2 mL) and extracted with EtOAc (5 mL × 3). The organic layer was dried, filtered, and concentrated to give the crude residue, which was purified by silica gel column chromatography (petroleum ether: EtOAc = 5:1) to give the title product (192c) (460 mg, 84.3%) as a white solid. m / z (ESI, +ve ion) = 302.2 [M+Na] + .

[0298] Step D. tert-Butyl 3-(3-((2,4-dichlorophenoxy)methyl)phenoxy)azetidine-1-carboxylate (192d) [ka] A solution of 2,4-dichlorophenol (122 mg, 0.75 mmol), 192c (210 mg, 0.75 mmol), PPh3 (294 mg, 1.12 mmol), and DEAD (195 mg, 1.12 mmol) in anhydrous THF (5 mL) was stirred at 20 °C for 16 h under a N2 atmosphere. Upon completion, the reaction was diluted with HO (2 mL) and extracted with EtOAc (5 mL × 3). The organic layer was dried, filtered, and concentrated to give the crude residue, which was purified by silica gel column chromatography (petroleum ether: EtOAc = 5:1) to give the title product (192d) (148 mg, 45.5%) as a white solid. m / z (ESI, +ve ion) = 446.0 [M+Na] + .

[0299] Step E. (S)-2-((3-(3-((2,4-dichlorophenoxy)methyl)phenoxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (192) [ka] The title product (192) was synthesized from 192d using a procedure similar to that described in Step D of Example 177. m / z (ESI, +ve ion) = 568.3 [M+H] + .

[0300] Example 194 was synthesized using a procedure similar to that described in Example 192.

[0301] Examples 210 and 212 were synthesized using procedures similar to those described in Example 192.

[0302] Example 193. (S)-2-((3-((2-((4-chloro-2-cyanophenoxy)methyl)pyridin-4-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step A. tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (193a) [ka] To a mixture of tert-butyl (3-hydroxyazetidin-1-yl)formate (2.0 g, 11.5 mmol) and DIPEA (3.8 mL, 23 mmol) in DCM (10 mL) was added a solution of methanesulfonic anhydride (3.0 g, 17.2 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1.5 h and concentrated under reduced pressure to give the crude residue, which was purified by silica gel column chromatography (petroleum ether: EtOAc = 10:1) to give the title product (193a) (2.9 g, 89%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.20 (s, 1H), 4.27 (ddd, J = 10.3, 6.7, 1.1 Hz, 2H), 4.10 (ddd, J = 10.3, 4.2, 1.2 Hz, 2H), 3.06 (s, 3H), 1.44 (d, J = 2.4 Hz, 9H).

[0303] Step B. 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid (193b) [ka] A mixture of 193a (1.38 g, 5.48 mmol), methyl 4-hydroxypyridine-2-carboxylate (0.7 g, 4.57 mmol), CsCO (2.23 g, 6.86 mmol), and potassium iodide (151 mg, 0.91 mmol) in DMF (10 mL) was heated at 80 °C for 12 h. The mixture was cooled to 18 °C, poured into water (10 mL), and adjusted to pH = 7 with concentrated hydrochloric acid. The resulting mixture was purified by reverse-phase HPLC (41% CHCN in H2O (containing 0.5% TFA as a modifier)) to give impure title product (193b) (480 mg) as a white solid. m / z (ESI, +ve ion) = 295.1 [M+H] + .

[0304] Step C. tert-Butyl 3-((2-(hydroxymethyl)pyridin-4-yl)oxy)azetidine-1-carboxylate (193c) [ka] To a mixture of 193b (430 mg, 1.45 mmol) in THF (10 mL) was added BH3-Me2S (4.7 mL, 9.5 mmol, 2N in THF) at 0 °C. The reaction was heated at 40 °C for 2 h and quenched with CH3OH (15 mL). The resulting mixture was stirred at 70 °C for an additional 30 min. LCMS revealed that some of the product was still complexed with BH3. The mixture was concentrated under reduced pressure to give the crude title product (193c), which was used in the next step without further purification. m / z (ESI, +ve ion) = 281.3 [M+H] + .

[0305] Step D. tert-Butyl 3-((2-((4-chloro-2-cyanophenoxy)methyl)pyridin-4-yl)oxy)azetidine-1-carboxylate (193d) [ka] To a mixture of crude 193c (430 mg, 1.63 mmol), 5-chloro-2-hydroxybenzonitrile (251 mg, 1.63 mmol), and PPh3 (557 mg, 2.12 mmol) in THF (15 mL) was added DEAD (370 mg, 1.12 mmol) at 0 °C under a N2 atmosphere. The reaction was warmed to room temperature, stirred for 18 h, poured into water (20 mL), and extracted with EtOAc (15 mL × 3). The organic layer was washed with HO (10 mL), brine (10 mL), dried, and concentrated under reduced pressure to give the crude residue, which was purified by reverse-phase HPLC (69% CH3CN in HO (containing 0.05% TFA as a modifier)) to give the title product (193d) (35 mg) as a white solid. MS (ESI, positive ion) m / z: 416.2 (M+1).

[0306] Step E. (S)-2-((3-((2-((4-chloro-2-cyanophenoxy)methyl)pyridin-4-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (193) [ka] The title product (193) was synthesized from 193d using a procedure similar to that described in Step D of Example 177. m / z (ESI, +ve ion) = 560.3 [M+H] + .

[0307] Examples 211 and 218 were synthesized using procedures similar to those described in Example 193.

[0308] Example 197. 2-((3-(3-((2,4-dichlorophenoxy)methyl)benzyl)azetidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (197) [ka] Step A. 1-((3-bromobenzyl)oxy)-2,4-dichlorobenzene (197a) [ka] A mixture of 2,4-dichlorophenol (410 mg, 2.5 mmol), 1-bromo-3-(bromomethyl)benzene (629 mg, 2.5 mmol), and K2CO3 (695 mg, 5.0 mmol) in DMF (8 mL) was stirred at room temperature for 0.5 h. Upon completion, the reaction was quenched with water (25 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. This was purified by silica gel column chromatography (EtOAc in hexane) to give the title product (197a) (692 mg, 41%). m / z (ESI, +ve ion) = 334.2 [M+H] + .

[0309] Step B. tert-Butyl 3-(3-((2,4-dichlorophenoxy)methyl)benzylidene)azetidine-1-carboxylate. 197b [ka] A solution of Pd(dba) (169 mg, 0.2 mmol) and BINAP (260 mg, 0.4 mmol) in CHCN (3 mL) was heated at 85 °C for 5 min and then transferred to a mixture of 197a (692 mg, 2.1 mmol), tert-butyl 3-methylideneazetidine-1-carboxylate (388 mg, 2.3 mmol), and CsCO (1.36 g, 4.2 mmol) in CHCN (18 mL). The mixture was degassed with argon and stirred at 85 °C under an argon atmosphere for 16 h. Upon completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc in hexane) to give the title product (197b) (265 mg, 30%) as a dark brown oil. m / z (ESI, +ve ion) = 442.2 [M+Na] + .

[0310] Step C. tert-Butyl 3-(3-((2,4-dichlorophenoxy)methyl)benzyl)azetidine-1-carboxylate (197c) [ka] PtO2 (7.6 mg, 0.3 mmol) was suspended in a solution of 197b (20 mg, 0.05 mmol) in ethyl acetate (2 mL). The mixture was degassed with hydrogen and stirred under a hydrogen balloon at room temperature for 1 h. Upon completion, the reaction was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (hexane with EtOAc) to give the title product (197c) (11 mg, 56%) as a colorless oil. m / z (ESI, +ve ion) = 444.2 [M+Na] + .

[0311] Step D. 3-(3-((2,4-dichlorophenoxy)methyl)benzyl)azetidine (197d) [ka] A solution of 197c (11 mg, 0.03 mmol) in DCM (2 mL) was treated with TFA (1 mL) at room temperature for 10 min. Upon completion, the solvent was removed under reduced pressure and the resulting crude material was purified by reverse-phase HPLC (gradient elution from 0% to 90% CHCN in water with 0.1% TFA as a modifier) ​​to give the title product (197d) (9.1 mg, 80%) as a white solid. m / z (ESI, +ve ion) = 322.2 [M+H] + .

[0312] Step E. Methyl 2-((3-(3-((2,4-dichlorophenoxy)methyl)benzyl)azetidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (197e) [ka] A solution of 197d (9.1 mg, 0.02 mmol), 57f (7.6 mg, 0.023 mmol), and triethylamine (42 mg, 0.42 mmol) in DMF (1 mL) was stirred at room temperature for 22 h. Upon completion, the reaction was purified by reverse-phase HPLC (gradient elution from 20% to 100% CHCN in water (containing 0.1% TFA as a modifier)) to give the title product (197e) (8.2 mg, 54%). m / z (ESI, +ve ion) = 618.3 [M+H] + .

[0313] Step F. 2-((3-(3-((2,4-dichlorophenoxy)methyl)benzyl)azetidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (197) [ka] A solution of 197e (8.2 mg, 0.011 mmol) in CHCN (0.5 mL) was treated with 2 N NaOH (0.5 mL). The resulting mixture was stirred at room temperature for 26 h. Upon completion, the reaction was purified by reverse-phase HPLC (gradient elution from 0% to 75% CHCN in water (containing 0.1% formic acid as a modifier)) to afford the title product (197) (5.3 mg, 66%) as a white solid. 1H NMR (600 MHz, CD3OD) δ ppm 8.16 (br d, J = 0.73 Hz, 1H), 7.98 (dd, J = 8.44, 1.47 Hz, 1H), 7.79 - 7.83 (m, 1H), 7.71 (d, J = 8.44 Hz, 1H), 7.34 (d, J = 2.57 Hz, 1H), 7.25 - 7.33 (m, 3H), 7.20 (dd, J = 8.80, 2.57 Hz, 1H), 7.12 - 7.15 (m, 1H), 7.07 (d, J = 8.80 Hz, 1H), 6.69 - 6.72 (m, 1H), 5.68 (s, 2H), 5.15 (s, 2H), 4.12 (s, 2H), 4.05 (q, J = 7.34 Hz, 2H), 3.65 (br t, J = 7.34 Hz, 2H), 3.32 - 3.38 (m, 2H), 2.89 - 2.93 (m, 2H), 2.83 - 2.89 (m, 1H), 1.24 (t, J = 7.34 Hz, 3H). m / z (ESI, +ve ion) = 604.3 [M+H] + .

[0314] Compound examples 195 and 196 were synthesized using procedures similar to those described in Example 197.

[0315] Example 201. 2-((4-((2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (201) [ka] Step A. 4-Chloro-1-(1,1-dimethoxyethyl)-2-fluorobenzene (201a) [ka] To a solution of 1-(4-chloro-2-fluorophenyl)ethanone (25 g, 0.145 mol) and trimethoxymethane (46 g, 0.435 mol) in MeOH (150 mL) was added TsOH (249 mg, 1.45 mmol). The mixture was stirred at 45 °C for 2 h. The mixture was then diluted with EtOAc (500 mL) and washed with brine (500 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated to give the crude title product (201a) (30 g) as a colorless oil.

[0316] Step B. 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (201b) [ka] To a solution of 201a (28 g, 0.128 mol) and 3-bromobenzene-1,2-diol (24.2 g, 0.128 mol) in toluene (200 mL) was added TsOH (44 mg, 0.256 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was then evaporated to dryness, and the crude residue was purified by silica gel column chromatography (petroleum ether) to give the title product (201b, racemic mixture) (12.2 g, 27.7%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.54 (t, J = 8.4 Hz, 1H), 7.11 - 7.17 (m, 2H), 6.95 (dd, J = 8.0, 1.4 Hz, 1H), 6.67 - 6.77 (m, 2H), 2.11 (d, J = 1.0Hz, 3H).

[0317] Step C. tert-Butyl 4-((2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidine-1-carboxylate (201c) [ka] The title product (201c) was synthesized from 201b using a procedure similar to that described in Step B of Example 173. m / z (ESI, +ve ion) = 484.1 [M+Na] + .

[0318] Step D. 4-((2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidine (201d) [ka] To a solution of 201c (350 mg, 0.76 mmol) and 2,6-lutidine (821 mg, 7.60 mmol) in DCM (10 mL) was added TMSOTf (843 mg, 3.8 mmol). The reaction was stirred at 0 °C for 2 h and washed with brine (10 mL × 3). The DCM layer was dried, filtered, and concentrated to give the crude title product (201d) (275 mg) as a colorless oil. m / z (ESI, +ve ion) = 362.1 [M+H] + .

[0319] Step E. Methyl 2-((4-((2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (201e) [ka] To a solution of 201d (55 mg, 0.15 mmol) and Ih (45 mg, 0.15 mmol) in DMF (3 mL) was added K2CO3 (41 mg, 0.30 mmol). After stirring at 20 °C for 16 h, the mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated, and the crude residue was purified by silica gel column chromatography (5% MeOH in DCM) to give the title product (201e) (85 mg, 91.4%) as a white solid. m / z (ESI, +ve ion) = 620.2 [M+H] + .

[0320] Step F. 2-((4-((2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)methyl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (201) [ka] To a solution of 201e (85 mg, 0.14 mmol) in THF / HO (1:1, 3 mL) was added LiOH (6.6 mg, 0.27 mmol). After stirring at 20 °C for 2 h, the reaction was adjusted to pH = 6 with TFA and purified by reverse-phase HPLC (40% CHCN / HO (containing 0.05% TFA as a modifier)) to give the title product (201) (97 mg, 98.2%) as a white solid. m / z (ESI, +ve ion) = 606.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.25 (dt, J = 10.9, 2.4 Hz, 1H), 7.18 - 7.22 (m, 1H), 6.72 - 6.82 (m, 2H), 6.68 (dd, J = 7.4, 1.3 Hz, 1H), 5.15 - 5.24 (m, 1H), 4.58 - 4.82 (m, 5H), 4.35 - 4.43 (m, 1H), 3.56 - 3.68 (m, 2H), 3.00 - 3.15 (m, 2H), 2.73 - 2.84 (m, 1H), 2.57 - 2.70 (m, 2H), 2.43 - 2.54 (m, 1H), 2.03 (s, 3H), 1.76 - 2.02 (m, 3H), 1.45 - 1.60 (m, 2H).

[0321] Example 209 was synthesized using a procedure similar to that described for Example 201.

[0322] Examples 222 and 223 (stereochemistry arbitrarily assigned) were synthesized as in Example 209, but with an additional SFC chiral separation step (Daicel CHIRALCEL AD column, mobile phase: CO / IPA 60 / 40 containing 0.2% NH (7 M solution in MeOH)) before the final hydrolysis. Example 222 was obtained from the early eluting peak in the chiral separation.

[0323] Example 213. (S)-2-((3-((2-((2,4-dichlorophenoxy)methyl)oxazol-5-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (213) [ka] Step A. tert-Butyl 3-((2-((2,4-dichlorophenoxy)methyl)oxazol-5-yl)oxy)azetidine-1-carboxylate (213a) [ka] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (25 mg, 0.144 mmol) in anhydrous DMF (0.2 M) was added NaH (8.66 mg, 0.22 mmol, 60% dispersion in mineral oil) under an Ar atmosphere at 0 °C. The mixture was stirred at room temperature for 10 min and then heated to 50 °C for 25 min, after which 474e (51.3 mg, 0.16 mmol) was added at the same temperature. After 30 min, the reaction was quenched with HO and extracted with EtOAc (×2). The combined organic layers were washed with HO, brine, dried over NaSO, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution from 0 to 60% EtOAc in hexane) to give impure title product (213a) (26 mg). m / z (ESI, +ve ion) = 415.2 [M+H] + .

[0324] Step B. (S)-2-((3-((2-((2,4-dichlorophenoxy)methyl)oxazol-5-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (213) [ka] The title product (213) was synthesized from 213a using a procedure similar to that described in Step D of Example 177. m / z (ESI, +ve ion) = 559.2 [M+H] + .

[0325] Example 219. 2-((3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)oxy)azetidin-1-yl)methyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (219) [ka] Step A. tert-Butyl 2-((3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)oxy)azetidin-1-yl)methyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (219a) [ka] A solution of 219a (prepared in a similar manner to 193d, 6.4 mg, 0.020 mmol), tert-butyl 2-(chloromethyl)-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (6.8 mg, 0.020 mmol), and DIPEA (68.6 μL, 0.39 mmol) in DMF (0.2 mL) was stirred at room temperature for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL × 2), brine (3 mL), dried over NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution from 80 to 100% EtOAc in hexanes followed by 0 to 20% MeOH in DCM) to give the title product (219b) (9.6 mg, 77%) as a pale yellow oil. m / z (ESI, +ve ion) = 636.3 [M+H] + .

[0326] Step B. 2-((3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)oxy)azetidin-1-yl)methyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (219) [ka] A solution of 219b (10.0 mg, 0.016 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature overnight. Upon completion, the reaction solvent was removed under reduced pressure. The resulting residue was diluted to 1 mL with water and purified by reverse-phase HPLC (gradient elution from 35 to 65% CHCN in HO with 0.1% TFA as a modifier) ​​to afford the title product 219 (10.9 mg, 100%) as a white solid. 1 H NMR (600 MHz, CD3OD) δ ppm 8.58 (d, J = 8.2 Hz, 1H), 8.40 (d, J = 1.1 Hz, 1H), 8.16 (s, 1H), 8.01 - 8.03 (m, 1H), 7.74 - 7.76 (m, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.35 (s, 1H), 7.31 (dd, J = 8.8, 2.6 Hz, 1H), 7.16 - 7.19 (m, 2H), 5.72 (s, 2H), 5.46 (tt, J = 6.2, 4.4 Hz, 1H), 5.33 (s, 2H), 4.98 (s, 2H), 4.78 - 4.88 (m, 2H), 4.48 (br dd, J = 12.1, 3.7 Hz, 2H). m / z (ESI, +ve ion) = 580.2 [M+H] + .

[0327] Examples 228 (derived from 192d), 236, 237 (derived from 192d), and 238 (derived from 192d) were synthesized using a procedure similar to that described for Example 219. Example 229 was synthesized using a procedure similar to that described for Example 228.

[0328] Example 233. 2-(((2S,3S)-3-(3-((2,4-dichlorophenoxy)methyl)phenoxy)-2-methylazetidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step A. tert-Butyl (2S,3S)-3-(3-((2,4-dichlorophenoxy)methyl)phenoxy)-2-methylazetidine-1-carboxylate (233) [ka] To a solution of 197a (80 mg, 0.24 mmol) and tert-butyl (2S,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (45 mg, 0.24 mmol) in anhydrous toluene (2.4 mL) was added Pd(dba) (9.6 mg, 0.012 mmol), t-BuXphos (5.1 mg, 0.012 mmol), and CsCO (157 mg, 0.48 mmol) at room temperature. Argon was bubbled through the mixture for 15 minutes and heated to 90 °C. After stirring for 3 hours, the reaction was cooled to room temperature and 1 N HCl (2 mL) was added. The reaction mixture was extracted with EtOAc (3 mL × 3), dried over NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution from 0 to 20% EtOAc in hexane) to give the title product (233a) (41 mg, 43%) as a colorless oil. m / z (ESI, +ve ion) = 462.3 [M + Na] + .

[0329] Step B. 2-(((2S,3S)-3-(3-((2,4-dichlorophenoxy)methyl)phenoxy)-2-methylazetidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (233) [ka] The title product (233) was synthesized using a procedure similar to that described in Step D of Example 177. m / z (ESI, +ve ion) = 620.3 [M+H] + . 1H NMR (600 MHz, CD3OD) δ ppm 9.05 (s, 1H), 8.23 ​​(s, 1H), 8.05 (d, J = 8.80 Hz, 1H), 7.82 (d, J = 8.80 Hz, 1H), 7.41 (d, J = 2.57 Hz, 1H), 7.37 (t, J = 8.07 Hz, 1H), 7.24 (dd, J = 8.80, 2.20 Hz, 1H), 7.14 (br d, J = 7.70 Hz, 1H), 7.09 - 7.12 (m, 2H), 7.05 (s, 1H), 6.90 (br d, J = 8.44 Hz, 1H), 5.82 (br d, J = 2.57 Hz, 2H), 5.24 - 5.29 (m, 1H), 5.18 (s, 2H), 4.58 (br d, J = 2.93 Hz, 1H), 4.39 - 4.45 (m, 1H), 4.33 (q, J=7.34 Hz, 2H), 1.60 (br d, J = 6.97 Hz, 3H), 1.54 (t, J = 7.34 Hz, 3H).

[0330] Examples 234 and 235 were synthesized using procedures similar to those described in Example 233.

[0331] Example 244. (S)-2-((3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (244) [ka] Step A. Methyl (S)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)picolinate (244a) [ka] To a stirred suspension of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (128 mg, 0.69 mmol), methyl 4-hydroxypyridine-2-carboxylate (0.1 g, 0.65 mmol), and PPh3 (214 mg, 0.82 mmol) in THF was added dropwise DIAD (165 mg, 0.82 mmol) at room temperature. After 15 min, the reaction was heated at 55 °C overnight. After cooling, the reaction was filtered through a pad of Celite and rinsed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography (gradient elution from 10 to 60% acetone in hexanes) to give the impure product containing triphenylphosphine oxide (244a) as a white solid. m / z (ESI, +ve ion) = 323.3 [M+H] + .

[0332] Step B. tert-Butyl (S)-3-((2-(hydroxymethyl)pyridin-4-yl)oxy)pyrrolidine-1-carboxylate (244b) [ka] To a stirring solution of 244a (211 mg, impure, 0.653 mmol) in EtOH (3.3 mL) at 0 °C was added CaCl (217 mg, 1.96 mmol), followed by NaBH (70.2 mg, 1.96 mmol). After stirring at room temperature for 1 h, the reaction was cooled in an ice bath, quenched with 1 N HCl, diluted with saturated NH Cl, and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution from 0 to 15% MeOH in DCM) to give the title product (244b) (87 mg, 45% over two steps). m / z (ESI, +ve ion) = 295.4 [M+H] + .

[0333] Step C. (S)-2-((3-((2-((2,4-dichlorophenoxy)methyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (244) [ka] The title product (244) was synthesized using a procedure similar to that described in Steps D and E of Example 193. m / z (ESI, +ve ion) = 621.3 [M+H] + . Examples 245, 289, and 298 were synthesized using procedures similar to those described in Example 244.

[0334] Example 273 was prepared from 177a using Step A of Example 213, Step E of Example 147, followed by Steps E and F of Example 201 in a similar manner as described therein.

[0335] Example 293 was synthesized using a procedure similar to that described for Example 273.

[0336] Example 281. 2-((4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (281) [ka] Step A. tert-Butyl 4-((3-(((methylsulfonyl)oxy)methyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (281a) [ka] A solution of 127b (105 mg, 0.36 mmol), MsCl (61 mg, 0.53 mmol), and DIPEA (184 mg, 1.42 mmol) in anhydrous DCM (2 mL) was stirred at 20 °C for 1 h. Upon completion, the organic layer was dried and concentrated to give the crude title product (281a) (105 mg, 83%) as a yellow oil. m / z (ESI, +ve ion) = 310.1 [M-OMs+OMe] + .

[0337] Step B. tert-Butyl 4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (281b) [ka] To a solution of 2,4-dichlorophenol (46 mg, 0.28 mmol) and 281a (105 mg, 0.28 mmol) in DMF (2 mL) was added KCO (117 mg, 0.84 mmol) and KI (47 mg, 0.28 mmol). The reaction mixture was stirred at 80 °C under N atmosphere for 3 h. Upon completion, the mixture was quenched with HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with HO (5 mL), brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue, which was purified by preparative TLC (DCM:MeOH = 10:1) to give the title product (281b) (65 mg, 51%) as a yellow oil. m / z (ESI, +ve ion) = 462.1 [M+Na] + .

[0338] Step C. 4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidine (281c) [ka] A solution of 281b (65 mg, 0.15 mmol) in DCM / TFA (2 mL, 4:1) was stirred at 20 °C for 1 h. Upon completion, saturated aqueous sodium bicarbonate was added to the mixture in an ice bath to adjust the pH to 7. The reaction was then diluted with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried, filtered, and concentrated to give the crude title product (281c) (51 mg, 96%) as a yellow oil. m / z (ESI, +ve ion) = 340.0 [M+H] + .

[0339] Step D. Methyl 2-((4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (281d) [ka] To a solution of 281c (43 mg, 0.13 mmol) and methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-(((methylsulfonyl)oxy)methyl)-1H-benzo[d]imidazole-6-carboxylate (51 mg, 0.13 mmol) in DMF (2 mL) was added KCO (53 mg, 0.38 mmol) and KI (21 mg, 0.13 mmol) at 20 °C. The reaction was stirred under a N atmosphere at 20 °C for 3 h. Upon completion, the reaction was quenched with HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with HO (5 mL), brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title product (281d) (42 mg, 49.6%) as a yellow oil. m / z (ESI, +ve ion) = 636.2 [M+H] + .

[0340] Step E. 2-((4-((3-((2,4-dichlorophenoxy)methyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (281) [ka] A solution of 281d (42 mg, 0.066 mmol) and LiOH (8 mg, 0.33 mmol) in THF / HO (2 mL, 1:1) was stirred at 20 °C for 12 h. Upon completion, 1 N HCl was added to the mixture in an ice bath to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were dried, filtered, concentrated, and purified by reverse-phase HPLC (30% CHCN in HO (containing 0.05% TFA as a modifier)) to give the title product (281) (17.5 mg, 42%) as a white solid. m / z (ESI, +ve ion) = 622.1 [M+H] + .

[0341] Example 282 was synthesized using a procedure similar to that described for Example 281.

[0342] Example 350 was synthesized from tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate and Ih using steps A (using MsO) and B of Example 192, followed by step B of Example 127 and steps A-E of Example 281 in a similar manner as described therein.

[0343] Example 351 was synthesized using a procedure similar to that described in Example 350.

[0344] Example 360. 2-(((S)-3-((2-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (360) [ka] Step A. 4-Chloro-2-((4-chloro-2-fluorophenoxy)methyl)pyrimidine (360a) [ka] To a solution of 4-chloro-2-(chloromethyl)pyrimidine (230 mg, 1.41 mmol) and KCO (388 mg, 2.81 mmol) in DMF (5 mL) was added 4-chloro-2-fluorophenol (206 mg, 1.41 mmol). The reaction was stirred at 25 °C for 16 h, diluted with EtOAc (30 mL), and washed with brine (30 mL × 2). The organic layer was dried, filtered, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: EtOAc = 2:1) to give the title product (360a) (230 mg, 47.8%). m / z (ESI, +ve ion) = 269.1 [M+H] + .

[0345] Step B. tert-Butyl (S)-3-((2-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (360b) [ka] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (16 mg, 0.88 mmol) in THF (10 mL) was added NaH (35 mg, 0.88 mmol) at 0 °C and stirred at the same temperature for 0.5 h. 360a (200 mg, 0.73 mmol) was added to the reaction, and the resulting mixture was stirred at 25 °C for 16 h. The reaction was diluted with EtOAc (30 mL) and washed with brine (30 mL × 2). The organic layer was dried, filtered, and evaporated to dryness, and the crude residue was purified by silica gel column chromatography (35% EtOAc in petroleum ether) to give the title product (360b) (210 mg, 67.7%) as a colorless oil. m / z (ESI, +ve ion) = 424.1 [M+H]+ .

[0346] Step C. (S)-2-((4-chloro-2-fluorophenoxy)methyl)-4-(pyrrolidin-3-yloxy)pyrimidine (360c) [ka] A solution of 360b (200 mg, 0.47 mmol) in 4 N HCl in dioxane (5 mL) was stirred at 25 °C for 2 h. The mixture was then concentrated under reduced pressure to give the crude title product (360c) (170 mg) as a white solid, which was used in the next step without further purification. m / z (ESI, +ve ion) = 324.1 [M+H] + .

[0347] Step D. Methyl 2-(((S)-3-((2-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (360d) [ka] To a mixture of 360c (35 mg, 0.11 mmol) and K2CO3 (30 mg, 0.22 mmol) in DMF (1 mL) was added Ih (32 mg, 0.11 mmol). The reaction was stirred at 25 °C for 16 h and then filtered. The filtrate was purified by reverse-phase HPLC (45% CH3CN / H2O (containing 0.05% TFA as a modifier)) to give the title product (360d) (35 mg) as a yellow solid containing some impurities. m / z (ESI, +ve ion) = 582.1 [M+H] + .

[0348] Step E. 2-(((S)-3-((2-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (360) [ka] To a solution of 360d (35 mg, 0.06 mmol) in THF / HO (1 mL, 1:1) was added LiOH (3 mg, 0.125 mmol). The reaction was stirred at 25 °C for 2 h. Upon completion, the reaction was adjusted to pH = 7 with 1 N HCl. The resulting residue was purified by reverse-phase HPLC (40% CHCN in HO) to afford the title product (360) (20 mg, 55.8%) as a white solid. m / z (ESI, +ve ion) = 568.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.41 (d, J = 5.92 Hz, 1H), 8.29 (s, 1H), 7.95 (dd, J = 8.52, 1.4 Hz, 1H), 7.63 (d, J = 8.52 Hz, 1H), 7.13 (dd, J = 10.36, 1.72 Hz, 1H), 6.94 - 7.06 (m, 2H), 6.77 (d, J = 5.92 Hz, 1H), 5.42 (d, J = 6.12 Hz, 1H), 5.16 - 5.28 (m, 3H), 4.80 (dd, J = 9.84, 5.52 Hz, 1H), 4.56 - 4.71 (m, 2H), 4.43 (dt, J = 9.16, 5.92 Hz, 1H), 4.11 (d, J = 13.72 Hz, 1H), 3.99 (d, J = 13.72 Hz, 1H), 2.83 - 2.96 (m, 2H), 2.76 (dt, J = 14.92, 8.4 Hz, 2H), 2.43 - 2.62 (m, 2H), 2.28 (td, J = 13.8, 7.60 Hz, 1H), 1.92 (dd, J = 8.90, 6.24 Hz, 1H).

[0349] Example 361 was synthesized using a procedure similar to that described in Example 360.

[0350] Example 383. 2-((3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (383) [ka] Step A. tert-Butyl 3-(3-(hydroxymethyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (383a) [ka] A mixture of (3-bromophenyl)methanol (450 mg, 2.4 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.5 g, 1.6 mmol), Pd(dppf)Cl (0.24 g, 0.32 mmol), and KCO (0.67 g, 4.8 mmol) in dioxane / HO (10 / 2.5 mL) was stirred at 95° C. for 2 h. After completion, water (30 mL) was added. The reaction was extracted with EtOAc (10 mL × 3), and the combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: EtOAc = 1:1) to give the title product (383a) (0.42 g, 79%, white oil). m / z (ESI, +ve ion) = 220.1 [M- t Bu+H] + .

[0351] Step B. tert-Butyl 3-(3-(((methylsulfonyl)oxy)methyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (383b) [ka] To a solution of 383a (0.5 g, 1.8 mmol) in THF (10 mL) was added EtN (0.367 g, 3.6 mmol) and methanesulfonic anhydride (0.47 g, 2.7 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h, quenched with water (10 mL), and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude title product (383b) (0.62 g) as a white solid. m / z (ESI, +ve ion) = 376.1 [M+Na] + .

[0352] Step C. tert-Butyl 3-(3-((2,4-dichlorophenoxy)methyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (383c) [ka] To a solution of 383b (0.41 g, 1.16 mmol) and 2,4-dichlorophenol (0.19 g, 1.16 mmol) in DMF (10 mL) was added CsCO (0.76 g, 2.23 mmol) at 20 °C. After stirring at 55 °C for 1 h, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with HO (10 mL), brine (10 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by reverse-phase HPLC (70% CHCN in HO (containing 0.05% formic acid as a modifier)) to give the title product (383c) (0.42 g, 84%) as a white solid. m / z (ESI, +ve ion) = 364.0 [M- t Bu+H] + .

[0353] Step D. tert-Butyl 3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidine-1-carboxylate (383d) [ka] To a solution of 383c (0.2 g, 0.48 mmol) in THF (5 mL) was added PtO2 (5.4 mg, 0.024 mmol) at 20 °C. The reaction mixture was stirred under 50 psi H2 atmosphere at 20 °C for 10 h. Upon completion, the reaction was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC (70% CH3CN in H2O (containing 0.05% formic acid as a modifier)) to give the title product (383d, racemic) (120 mg, 60%) as a white oil. m / z (ESI, +ve ion) = 444.0 [M+Na] + .

[0354] Step E. 3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidine (383e) [ka] To a solution of 383d (200 mg, 0.4 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 0 °C. The mixture was stirred at 20 °C under N2 atmosphere for 1 h. After completion, the mixture was concentrated under reduced pressure to give the crude title product (383e) (102 mg) as a white solid, which was used in the next step without any further purification. m / z (ESI, +ve ion) = 322.0 [M+H] + .

[0355] Step F. Methyl 2-((3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (383f) [ka] To a solution of Ih (76 mg, 0.26 mmol) in CHCN (2 mL) were added 383e (84 mg, 0.26 mmol) and KCO (216 mg, 1.56 mmol). The reaction mixture was stirred at 20 °C for 5 h. Upon completion, the mixture was quenched with water (10 mL), extracted with EtOAc (10 mL × 3), and washed with water and brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (gradient elution from 0 to 50% EtOAc in petroleum ether) to give the title product (383f) (50 mg, 34.4%) as a white solid. m / z (ESI, +ve ion) = 580.2 [M+H] + .

[0356] Step G. 2-((3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (383) [ka] To a solution of 383f (40 mg, 0.07 mmol) in a mixed solvent of MeOH / THF / HO (1:1:1, 3 mL) was added LiOH (8.25 mg, 0.7 mmol). The reaction mixture was stirred at 20 °C for 5 h. Upon completion, the reaction was adjusted to pH = 6 with 10% citric acid and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase HPLC (60% CHCN in HO (containing 0.05% NHHCO as a modifier)) to give the title product (383) (15 mg, 38%, diastereomeric mixture) as a white solid. m / z (ESI, +ve ion) = 566.1 [M+H] + . 1H NMR (400 MHz, CD3OD) δ ppm 8.29 (d, J = 0.88 Hz, 1H), 7.97 (dd, J = 8.33, 0.88 Hz, 1H), 7.67 (d, J = 8.33 Hz, 1H), 7.38 - 7.45 (m, 2H), 7.18 - 7.34 (m, 4H), 7.09 (dd, J = 8.99, 2.85 Hz, 1H), 5.18 - 5.27 (m, 1H), 5.15 (s, 2H), 4.83 (d, J = 7.0 Hz, 1H), 4.65 - 4.72 (m, 1H), 4.61 (td, J = 7.78, 5.92, 1H), 4.38 - 4.44 (m, 1H), 4.26 - 4.35 (m, 1H), 4.18 (dd, J = 13.59, 6.58 Hz, 1H), 3.43 - 3.56 (m, 1H), 3.14 - 3.25 (m, 1H), 2.91 - 3.09 (m, 2H), 2.70 - 2.88 (m, 2H), 2.33 - 2.54 (m, 2H), 1.91 - 2.06 (m, 1H).

[0357] Examples 400 and 401 were synthesized using a procedure similar to that described in Example 383, except that Step D (the hydrogenation step) was omitted.

[0358] Example 384. (S)-2-((3-(6-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (384) [ka] Step A. tert-Butyl 3-(6-(hydroxymethyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (384a) [ka] A solution of (6-bromopyridin-2-yl)methanol (191.0 mg, 1.02 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (200 mg, 0.68 mmol), Pd(dppf)Cl (99.2 mg, 0.14 mmol), and KCO (187.0 mg, 1.36 mmol) in 1,4-dioxane (5.0 mL) and water (1.25 mL) was purged with argon for 5 minutes. The reaction was heated at 90 °C for 1 hour. Upon completion, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated, and the crude residue was purified by silica gel column chromatography (gradient elution from 30 to 80% EtOAc in hexanes) to give the title product (384a) (152.0 mg, 81%) as a yellow oil. m / z (ESI, +ve ion) = 277.4 [M+H] + .

[0359] Step B. tert-Butyl 3-(6-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (384b) [ka] To a solution of 384a (50.0 mg, 0.18 mmol), 2,4-dichlorophenol (31.0 mg, 0.19 mmol), and PPh3 (71.2 mg, 0.27 mmol) in THF (0.9 mL) was added DIAD (53.4 μL, 0.27 mmol). After stirring at room temperature for 1 h, the reaction solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution from 10% to 50% EtOAc in hexane) to give the title product (384b) (61.0 mg, 80%) as a white solid. m / z (ESI, +ve ion) = 421.3 [M+H] + .

[0360] Step C. 2-((2,4-dichlorophenoxy)methyl)-6-(2,5-dihydro-1H-pyrrol-3-yl)pyridine 2,2,2-trifluoroacetate (384c) [ka] A solution of 384b (19.0 mg, 0.045 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 5 minutes. Upon completion, the reaction solvent was removed under reduced pressure to give the crude title product (384c) (19.6 mg) as a yellow oil, which was used in the next step reaction without further purification. m / z (ESI, +ve ion) = 321.3 [M+H] + .

[0361] Step D. Methyl (S)-2-((3-(6-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (384d) [ka] A solution of 384c (8.8 mg, 0.020 mmol), Ih (7.1 mg, 0.024 mmol), and DIPEA (70.4 μL, 0.40 mmol) in DMF (0.2 mL) was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL × 2), brine (3 mL), dried over NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution from 80 to 100% EtOAc in hexanes followed by 0 to 20% MeOH in DCM) to afford the title product (384d) (6.7 mg, 57%) as a white solid. m / z (ESI, +ve ion) = 579.3 [M+H] + .

[0362] Step E. (S)-2-((3-(6-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (384) [ka] A solution of 384d (6.7 mg, 0.012 mmol) and LiOH (1.4 mg, 0.058 mmol) in 0.4 mL of 2:1:1 THF:MeOH:HO was stirred overnight at 30° C. Upon completion, the reaction mixture was diluted to 1 mL with water and purified by reverse-phase HPLC (gradient elution from 35 to 65% CHCN in HO with 0.05% NHOH as a modifier) ​​to give the title product (384) (6.0 mg, 89%) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ ppm 12.7 (s, 1H), 8.27 (s, 1H), 7.80 - 7.85 (m, 2H), 7.68 (br d, J = 8.4 Hz, 1H), 7.59 (br d, J = 7.3, 1H), 7.57 (br d, J = 2.6 Hz, 1H), 7.39 (br d, J = 7.7 Hz, 1H), 7.32 (br dd, J = 8.8, 2.6 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H), 5.24 (s, 2H), 5.08 (ddd, J = 14.4, 7.3, 2.9 Hz, 1H), 4.81 (br dd, J = 15.2, 7.2 Hz, 1H), 4.66 (br dd, J = 15.4, 2.9 Hz, 1H), 4.48 (br dd, J = 13.4, 7.9 Hz, 1H), 4.36 (dt, J = 9.1, 5.9 Hz, 1H), 4.12 - 4.35 (m, 2H), 3.70 - 4.00 (m, 4H), 2.65 - 2.74 (m, 1H), 2.36 - 2.44 (m, 1H). m / z (ESI, +ve ion) = 565.2 [M+H]+ .

[0363] Examples 385, 388, 393, 402, 403, 417, 418, 426, 436, 437, and 438 were synthesized using a procedure similar to that described in Example 384.

[0364] Example 386. 2-((3-(6-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (386) [ka] Step A. tert-Butyl 3-(6-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)pyrrolidine-1-carboxylate (386a) [ka] To a solution of 384b (45 mg, 0.11 mmol) in THF (2 mL) was added PtO2 (1.22 mg, 0.005 mmol) at 20 °C. The reaction mixture was purged with H2 for 5 min, and the reaction mixture was stirred under a balloon of H2 overnight. The reaction was filtered and concentrated to give the crude title product (386a, racemic) (7.9 mg, 18%), which was used in the next step without further purification. m / z (ESI, +ve ion) = 423.3 [M+H] + .

[0365] Step B. 2-((3-(6-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (386) [ka] The title product (386, diastereomeric mixture) was synthesized using a procedure similar to that described in Steps C-E of Example 384. m / z (ESI, +ve ion) = 567.3 [M+H] + .

[0366] Examples 389, 391, 399, 419, and 420 were synthesized using procedures similar to those described in Example 386.

[0367] Example 390. 2-((3-(4-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (390) [ka] Step A. 2-((3-(4-((2,4-dichlorophenoxy)methyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (390) [ka] A solution of 390a (prepared in a similar manner to 384d, 27.6 mg, 0.044 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature overnight. Upon completion, the reaction solvent was removed under reduced pressure, and the resulting residue was diluted to 1 mL with water and purified by reverse-phase HPLC (20% to 60% CHCN in HO gradient elution with 0.1% TFA as a modifier) ​​to afford the title product (390) (15.0 mg, 50%) as a white solid. m / z (ESI, +ve ion) = 576.3 [M+H] + . 1H NMR (600 MHz, CD3OD) δ ppm 8.57 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 1.1 Hz, 1H), 8.15 (s, 1H), 8.04 (dd, J = 8.6, 1.7 Hz, 1H), 7.87 (s, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.49 (br d, J = 5.1 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.34 (s, 1H), 7.28 (dd, J = 8.8, 2.6 Hz, 1H), 7.13 (d, J = 9.2Hz, 1H), 6.72 - 6.74 (m, 1H), 5.75 (s, 2H), 5.28 (s, 2H), 5.12 (s, 2H), 4.77 - 4.89 (m, 2H), 4.64 (br s, 2H).

[0368] Examples 387, 392, 394, and 404 were synthesized using procedures similar to those described in Example 390.

[0369] Example 398 was synthesized using a procedure similar to that described in Example 397, except that the final step was performed after Step A of Example 390.

[0370] Example 395. (S)-2-((3-(2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (395) [ka] Step A. 4-((4-chloropyrimidin-2-yl)methoxy)-3-fluorobenzonitrile (395a) [ka] A mixture of 3-fluoro-4-hydroxybenzonitrile (81.8 mg, 0.6 mmol) and 4-chloro-2-(chloromethyl)pyrimidine (81 mg, 0.5 mmol) in DMF (4 mL) was treated with CsCO (324 mg, 1 mmol) at room temperature. The reaction mixture was stirred for 2 h, quenched with water (50 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc in hexane) to afford the title product (395a) (93 mg, 71%) as a white solid. m / z (ESI, +ve ion) = 264.1 [M+H] + .

[0371] Step B. tert-Butyl 3-(2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (395b) [ka] A suspension of 395a (26 mg, 0.1 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (29 mg, 0.1 mmol), and KPO (42 mg, 0.2 mmol) in 1,4-dioxane / water (8 mL / 4 mL) was purged with argon and placed under an argon balloon. After adding Pd(dppf)Cl (7.2 mg, 0.01 mmol), the mixture was subjected to the same degassing and argon protection procedures. The mixture was heated to 100 °C overnight. Upon completion, the reaction was poured into EtOAc (20 mL), and the aqueous phase was extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (hexane with EtOAc) to give the title product (395b) (10 mg, 23%). m / z (ESI, +ve ion) = 397.4 [M+H] + .

[0372] Step C. 4-((4-(2,5-dihydro-1H-pyrrol-3-yl)pyrimidin-2-yl)methoxy)-3-fluorobenzonitrile (395c) [ka] 395b (10 mg, 0.025 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL) at room temperature. After 10 min, the resulting solution was concentrated under reduced pressure, redissolved in DMSO (1 mL), and purified by reverse-phase HPLC (gradient elution from 0% to 90% CHCN in water with 0.1% TFA as a modifier) ​​to give the title product (395c) (7 mg, 68%) as a white solid. m / z (ESI, +ve ion) = 297.3 [M+H] + .

[0373] Step D. Methyl (S)-2-((3-(2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (395d) [ka] To a solution of 395c (7 mg, 0.024 mmol) and Ih (7 mg, 0.024 mmol) in DMF (1 mL) was added EtN (47.8 mg, 0.47 mmol). The reaction mixture was stirred overnight at room temperature and then purified by reverse-phase HPLC (gradient elution from 0% to 60% CHCN in water with 0.1% TFA as a modifier) ​​to give the title product (395d) (11 mg, 72%) as a white solid. m / z (ESI, +ve ion) = 555.3 [M+H] + .

[0374] Step E. (S)-2-((3-(2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (395) [ka] 395d (10 mg, 0.018 mmol) was dissolved in CHCN (1 mL) and treated with 2 N NaOH (0.5 mL). The mixture was stirred vigorously at room temperature for 24 h and then purified by reverse-phase HPLC (gradient elution from 0 to 50% CHCN in water (containing 0.05% NHOH as a modifier)) to give the title product (395) (6.3 mg, 63%) as a white solid. m / z (ESI, +ve ion) = 541.3 [M+H] + . 1H NMR (600 MHz, CD3OD) δ ppm 8.67 (d, J = 5.50 Hz, 1H), 8.25 (d, J = 0.73 Hz, 1H), 7.98 (dd, J = 8.62, 1.65 Hz, 1H), 7.66 (d, J = 8.07 Hz, 1H), 7.50 (d, J = 5.50 Hz, 1H), 7.40 - 7.46 (m, 2H), 7.20 - 7.24 (m, 1H), 6.91 - 6.94 (m, 1H), 5.42 (s, 2H), 5.25 (qd, J = 7.07, 2.89 Hz, 1H), 4.87 (m, 1H), 4.69 (br dd, J = 15.41, 2.93 Hz, 1H), 4.60 - 4.65 (m, 1H), 4.45 (dt, J = 9.17, 5.87 Hz, 1H), 4.35 (d, J = 13.57 Hz, 1H), 4.27 (d, J = 13.57 Hz, 1H), 3.89 - 3.94 (m, 2H), 3.82 - 3.87 (m, 2H), 2.78 (dtd, J = 11.23, 8.14, 8.14, 6.24 Hz, 1H), 2.51 (ddt, J = 11.28, 8.99, 7.11, 7.11 Hz, 1H).

[0375] Example 396. (S)-2-((3-(6-((4-chloro-2-fluorophenoxy)methyl)pyrazin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (396) [ka] Step A. Methyl 6-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)pyrazine-2-carboxylate (396a) [ka] To a solution of methyl 6-chloropyrazine-2-carboxylate (200 mg, 1.16 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (342 mg, 1.16 mmol) in 1,4-dioxane / HO (9:1, 3.1 mL) was added Pd(dppf)Cl (42 mg, 0.058 mmol) and CsCO (755 mg, 2.32 mmol) at room temperature. Argon was bubbled through the mixture for 15 minutes, and then the mixture was heated to 90 °C. After 2 hours, the mixture was cooled to room temperature, and HO (2 mL) was added. The reaction mixture was extracted with EtOAc (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (gradient elution from 0 to 40% EtOAc in hexanes) to give the title product (396a) (263 mg, 74%) as a yellow solid. m / z (ESI, +ve ion) = 328.3 [M+Na] + .

[0376] Step B. tert-Butyl 3-(6-(hydroxymethyl)pyrazin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (396b) [ka] To a solution of 396a (100 mg, 0.33 mmol) in absolute EtOH (3.3 mL) at 0 °C, NaBH (35 mg, 0.99 mmol) and CaCl (109 mg, 0.99 mmol) were added. After stirring at room temperature for 1.5 h, 1 N HCl (1 mL) was added dropwise at 0 °C, and the reaction was extracted with EtOAc (5 mL × 3). The combined organic layers were dried over NaSO, filtered, concentrated, and purified by silica gel column chromatography (gradient elution from 0 to 15% MeOH in CHCl) to give the title product (396b) (35 mg, 39%). m / z (ESI, +ve ion) = 278.3 [M+H] + .

[0377] Step C. tert-Butyl 3-(6-((4-chloro-2-fluorophenoxy)methyl)pyrazin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (396c) [ka] To a solution of 396b (35 mg, 0.13 mmol) in anhydrous CHCl (0.7 mL) at 0 °C, PPh (49.7 mg, 0.19 mmol), 4-chloro-2-fluorophenol (18.5 mg, 0.13 mmol), and a solution of DCAD (69.5 mg, 0.19 mmol) in anhydrous CHCl (0.7 mL) were added dropwise. The resulting mixture was stirred at room temperature for 1 h, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution from 0 to 40% EtOAc in hexane) to give the title product (396c) (42 mg, 82%). m / z (ESI, +ve ion) = 428.3 [M+Na] + .

[0378] Step D. (S)-2-((3-(6-((4-chloro-2-fluorophenoxy)methyl)pyrazin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (16) [ka] The title product (396) was synthesized from 396c using a procedure similar to that described in Steps C-E of Example 384. Formic acid was used as a modifier in the final purification step. m / z (ESI, +ve ion) = 550.2 [M+H] + . 1H NMR (600 MHz, CD3OD) ppm δ 8.78 (s, 1H), 8.59 (s, 1 H), 8.33 (d, J = 0.73 Hz, 1H), 7.99 (dd, J = 8.44, 1.47 Hz, 1H), 7.71 (d, J = 8.44 Hz, 1H), 7.17 - 7.21 (m, 2H), 7.07 - 7.10 (m, 1H), 6.83 (t, J = 2.02 Hz, 1H), 5.23 - 5.28 (m, 3H), 4.87 - 4.91 (m, 1H), 4.72 (dd, J = 15.41, 2.57 Hz, 1H), 4.61 - 4.66 (m, 1H), 4.46 (dt, J = 9.26, 6.01 Hz, 1H), 4.29 - 4.42 (m, 2H), 4.01 - 4.09 (m, 2H) 3.84 - 3.94 (m, 2H), 2.76 - 2.83 (m, 1H), 2.49 - 2.55 (m, 1H).

[0379] Example 397. 2-((3-(4-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (397) [ka] Step A. tert-Butyl 3-(4-(hydroxymethyl)pyridin-2-yl)pyrrolidine-1-carboxylate (397b) [ka] To a solution of 397a (synthesized similarly to 384a, 56.5 mg, 0.20 mmol) in THF (5 mL) was added PtO2 (2.3 mg, 0.01 mmol) at 20 °C. H2 was bubbled through the reaction mixture for 5 min, and the reaction mixture was stirred under a balloon of H2 overnight. The reaction was filtered and concentrated to give the crude title product (397b, racemic), containing some unreacted starting material 397a, which was used in the next step without further purification. m / z (ESI, +ve ion) = 279.4 [M+H] + .

[0380] Step B. tert-Butyl 3-(4-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)pyrrolidine-1-carboxylate (397c) [ka] The title product (397c) was synthesized from 397b using a procedure similar to that described in Step B of Example 384. m / z (ESI, +ve ion) = 407.3 [M+H] + .

[0381] Step C. 2-((3-(4-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (397) [ka] The title product (397, diastereomeric mixture) was synthesized from 397c using a procedure similar to that described in Steps C-E of Example 384. m / z (ESI, +ve ion) = 551.3 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ ppm 8.50 (d, J = 5.1 Hz, 1H), 8.08 (s, 1H), 7.77 (dd, J = 8.3, 1.3 Hz, 1H), 7.42 - 7.49 (m, 2H), 7.35 (s, 1H), 7.18 - 7.26 (m, 3H), 5.22 (s, 2H), 5.05 (qd, J = 7.0, 3.1 Hz, 1H), 4.71 (ddd, J = 15.2, 7.0, 4.2 Hz, 1H), 4.57 (ddd, J = 15.2, 8.6, 3.3 Hz, 1H), 4.43 - 4.48 (m, 1H), 4.33 (dq, J = 9.1, 5.9 Hz, 1H), 4.07 (dd, J = 13.4, 5.7 Hz, 1H), 3.90 (dd, J = 13.2, 7.7 Hz, 1H), 3.48 - 3.56 (m, 1H), 2.98 - 3.08 (m, 1H), 2.60 - 2.85 (m, 4H), 2.34 - 2.44 (m, 1H), 2.17 - 2.26 (m, 1H), 2.03 (td, J = 13.3, 7.15 Hz, 1H). m / z (ESI, +ve ion) = 551.30 [M+H] + .

[0382] Examples 456 and 457 were synthesized from (6-bromo-5-fluoropyridin-2-yl)methanol as described in Example 397.

[0383] Examples 405 and 406. 2-(((S)-3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (405) and 2-(((R)-3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (406). [ka] Step A. tert-Butyl (S)-3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidine-1-carboxylate (383d-P1) and tert-butyl (R)-3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidine-1-carboxylate (383d-P2) [ka] 800 mg of 383d was subjected to SFC chiral separation (Acquity UPC 2 column; Daicel CHIRALPAK OX-3 3 mm * The mixture was separated using a 150 mm, 3 μm column (flow rate 2.0 mL / min, mobile phase: CO / MeOH = 85:15 containing 0.1% DEA). 383d-P1 (300 mg) and 383d-P2 (305 mg) (stereochemistry arbitrarily assigned) were obtained. 383d-P1 was the early eluting peak.

[0384] Step B. 2-(((S)-3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (405) and 2-(((R)-3-(3-((2,4-dichlorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (406) [ka] The title product (405) was synthesized from 383d-P1 using a procedure similar to that described in Steps E-G of Example 383. m / z (ESI, +ve ion) = 566.1 [M+H] + . 1H NMR (400 MHz, MeOD) δ ppm 8.27 (d, J = 0.9 Hz, 1H), 7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.42 (br s, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.24 - 7.34 (m, 3H), 7.21 (dd, J = 8.8, 2.5 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 5.16 - 5.25 (m, 1H), 5.15 (d, J = 7.4 Hz, 2H), 4.81 - 4.83 (m, 1H), 4.69 (dd, J = 15.4, 2.7 Hz, 1H), 4.60 (td, J = 7.9, 6.0 Hz, 1H), 4.41 (dt, J = 9.1, 6.0 Hz, 1H), 4.28 (d, J = 13.8 Hz, 1H), 4.14 (d, J = 13.8 Hz, 1H), 3.41 - 3.53 (m, 1H), 3.14 (dd, J = 10.8, 6.4 Hz, 1H), 2.88 - 3.03 (m, 2H), 2.81 (dd, J = 9.5, 7.2 Hz, 1H), 2.69 - 2.77 (m, 1H), 2.32 - 2.53 (m, 2H), 1.96 (dt, J = 15.6, 7.4 Hz, 1H).

[0385] The title product (406) was synthesized from 383d-P2 using a procedure similar to that described in Steps E-G of Example 383. m / z (ESI, +ve ion) = 566.2 [M+H] + . 1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.93 (dd, J = 8.4, 1.3 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.5 Hz, 2H), 7.19 - 7.32 (m, 4H), 7.09 (d, J = 8.9 Hz, 1H), 5.21 - 5.25 (m, 1H), 5.14 (s, 2H), 4.88 - 4.91 (m, 1H), 4.69 (dd, J = 15.3, 2.9 Hz, 1H), 4.56 - 4.63 (m, 1H), 4.43 (dd, J = 6.0, 3.1 Hz, 1H), 4.17 (d, J = 13.5 Hz, 1H), 4.04 (d, J = 13.5 Hz, 1H), 3.38 - 3.45 (m, 1H), 3.07 (t, J = 8.5 Hz, 1H), 2.83 - 2.92 (m, 1H), 2.84 - 2.70 (m, 2H), 2.65 (dd, J = 9.1, 7.0 Hz, 1H), 2.45 - 2.55 (m, 1H), 2.31 - 2.40 (m, 1H), 1.88 - 1.96 (m, 1H).

[0386] Example 407. (S)-2-((3-(6-((4-chloro-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (407) [ka] Step A. tert-Butyl 3-(5-fluoro-6-(hydroxymethyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (407a) [ka] A solution of (6-chloro-3-fluoropyridin-2-yl)methanol (185.0 mg, 1.15 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (260 mg, 0.88 mmol), Pd(dppf)Cl (129.0 mg, 0.18 mmol), and KCO (243.0 mg, 1.76 mmol) in 1,4-dioxane (5.0 mL) and water (1.25 mL) was purged with argon for 5 minutes. This was stirred at 90 °C for 2 hours. Upon completion, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution from 20% to 70% EtOAc in hexane) to give the title product (407a) (183.0 mg, 71%) as a colorless oil. m / z (ESI, +ve ion) = 317.3 [M+Na] + .

[0387] Step B. tert-Butyl 3-(6-((4-chloro-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (407b) [ka] To a solution of 407a (90.0 mg, 0.31 mmol), 4-chloro-2-fluorophenol (47.1 mg, 0.32 mmol), and PPh3 (120.0 mg, 0.46 mmol) in THF (1.5 mL) was added DIAD (90.3 μL, 0.46 mmol). After stirring at room temperature for 1 h, the reaction solvent was removed under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution: 0 to 40% EtOAc in hexanes) to afford the title product (407b) (115.0 mg, 89%) as a white solid. m / z (ESI, +ve ion) = 445.3 [M+Na] + .

[0388] Step C. (S)-2-((3-(6-((4-chloro-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (407) [ka] The title product (407) was synthesized using a procedure similar to that described in Steps C-E of Example 384. m / z (ESI, +ve ion) = 567.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.00 (s, 1H), 7.72 - 7.79 (m, 3H), 7.34 - 7.42 (m, 3H), 7.17 - 7.20 (m, 1H), 6.60 - 6.63 (m, 1H), 5.27 (s, 2H), 5.07 (ddd, J=14.31, 6.97, 3.30 Hz, 1H), 4.70 (br dd, J=15.22, 7.15 Hz, 1H), 4.53 - 4.58 (m, 1H), 4.44 - 4.50 (m, 1H), 4.36 (dt, J=8.89, 6.01 Hz, 1H), 4.23 (d, J=13.57 Hz, 1H), 4.11 (br d, J=13.57 Hz, 1H), 3.83 - 3.92 (m, 2H), 3.68 - 3.80 (m, 2H), 2.64 - 2.71 (m, 1H), 2.40 - 2.46 (m, 1H).

[0389] Examples 408, 413, 416, 421, 422, 424, 429, 430, 440, 451, 452, and 458 were synthesized using procedures similar to those described in Example 407.

[0390] Example 423 was a by-product isolated in the final step synthesis of Example 422.

[0391] Example 425 was a by-product isolated in the final step synthesis of Example 424.

[0392] Example 409 was synthesized from 407b using Step A of Example 386 followed by Steps C-E of Example 384 in a similar manner as described therein.

[0393] Example 410 was synthesized using a procedure similar to that described for Example 409.

[0394] Examples 411 and 412. 2-(((S)-3-(3-((4-chloro-2-fluorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (411) and 2-(((R)-3-(3-((4-chloro-2-fluorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (412). [ka] Step A. Methyl 2-(((S)-3-(3-(hydroxymethyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (411a-P1) and methyl 2-(((R)-3-(3-(hydroxymethyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (411a-P2) [ka] The title products (411a-P1 and 411a-P2) were synthesized from 383a using a procedure similar to that described in Steps D-F of Example 383, followed by chiral separation (Daicel CHIRALPAK AZ-3, mobile phase: CO2 / MeOH = 60 / 40 containing 0.2% NH3 (7 M solution in MeOH). 411a-P1 is the early eluting peak. Stereochemistry has been arbitrarily assigned. m / z (ESI, +ve ion) = 436.2 [M+H] + .

[0395] Step B. Methyl 2-(((S)-3-(3-(((methylsulfonyl)oxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (411b) [ka] To a stirred solution of 411a-P1 (40 mg, 0.09 mmol), methanesulfonic anhydride (40 mg, 0.23 mmol) in DCM (2 mL) at 25 °C was added DIPEA (36 mg, 0.28 mmol). After stirring for 2 h, the reaction was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried and concentrated to give the crude title product (411b) (50 mg, 95%) as a white solid. m / z (ESI, +ve ion) = 514.2 [M+H] + .

[0396] Step C. Methyl 2-(((S)-3-(3-((4-chloro-2-fluorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (411c) [ka] To a stirred solution of 411b (50 mg, 0.10 mmol) and 4-chloro-2-fluorophenol (14 mg, 0.10 mmol) in DMF (2 mL) at 80 °C was added K2CO3 (40 mg, 0.29 mmol). After heating for 6 h, the reaction was diluted with HO (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: EtOAc = 2:1) to give the title product (411c) (40 mg, 67% yield) as a white solid. m / z (ESI, +ve ion) = 564.2 [M+H] + .

[0397] Step D. 2-(((S)-3-(3-((4-chloro-2-fluorophenoxy)methyl)phenyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (411) [ka] To a stirred solution of 411c (30 mg, 0.05 mmol) in MeOH (1.0 mL) at 25 °C was added a solution of lithium hydroxide (13 mg, 0.53 mmol) in HO (0.5 mL). After stirring for 3 h, the mixture was adjusted to pH = 5 by adding 1 N HCl in an ice bath. The reaction mixture was then extracted with EtOAc (5 mL × 3). The combined organic layers were dried, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (411) (24 mg, 78%) as a white solid. m / z (ESI, +ve ion) = 550.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ ppm 8.28 (d, J = 0.88 Hz, 1H), 7.96 (dd, J = 8.55, 1.53 Hz, 1H), 7.66 (d, J = 8.33 Hz, 1H), 7.39 (s, 1H), 7.23 - 7.35 (m, 3 H), 7.17 (dd, J = 10.96, 2.19 Hz, 1H), 7.03 - 7.14 (m, 2H), 5.17 - 5.26 (m, 1H), 5.12 (s, 2H), 4.81 - 4.86 (m, 1H), 4.70 (dd, J = 15.35, 2.63 Hz, 1H), 4.56 - 4.65 (m, 1H), 4.41 (dt, J = 8.99, 6.03 Hz, 1H), 4.10 - 4.31 (m, 2H), 3.41 - 3.52 (m, 1H), 3.14 (t, J = 8.77 Hz, 1H), 2.69 - 3.03 (m, 4H), 2.33 - 2.52 (m, 2H), 1.90 - 2.02 (m, 1H).

[0398] Example 412 was synthesized from 411a-P2 using a procedure similar to that described in Example 411. m / z (ESI, +ve ion) = 550.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ ppm 8.28 (s, 1 H), 7.97 (dd, J = 8.56, 1.47 Hz, 1H), 7.66 (d, J = 8.31 Hz, 1H), 7.39 (s, 1H), 7.23 - 7.35 (m, 3H), 7.17 (dd, J = 10.88, 2.32 Hz, 1H), 7.02 - 7.14 (m, 2H), 5.22 (qd, J = 7.17, 2.69 Hz, 1H), 5.12 (s, 2H), 4.88 - 4.91 (m, 1H), 4.69 (dd, J = 15.41, 2.69 Hz, 1H), 4.61 (td, J = 7.83, 5.87 Hz, 1H), 4.43 (dt, J = 9.11, 5.96 Hz, 1H), 4.28 (d, J = 13.69 Hz, 1H), 4.11 - 4.19 (m, 1H), 3.47 (dt, J = 16.20, 7.92 Hz, 1H), 3.17 (t, J = 8.80 Hz, 1H), 2.85 - 3.05 (m, 2H), 2.70 -2.82 (m, 2H), 2.33 - 2.56 (m, 2H), 1.90 - 2.03 (m, 1H).

[0399] Examples 414 and 415; 439 and 443 were synthesized using procedures similar to those described in Examples 411 and 412.

[0400] Example 427. 2-(((R)-3-(2-((4-chloro-2-fluorophenoxy)methyl)pyridin-4-yl)pyrrolidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (427) [ka] Step A. tert-Butyl 3-(2-(hydroxymethyl)pyridin-4-yl)pyrrolidine-1-carboxylate (427b) [ka] To a stirred solution of 427a (synthesized as described for 383a, 4.5 g, 16.2 mmol) in THF (50 mL) under an H atmosphere at 25 °C was added PtO (0.37 g, 1.6 mmol). After stirring for 5 h, the reaction was diluted with H O (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: EtOAc = 2:1) to give the title product (427b) (2.5 g, 53%) as a colorless oil. m / z (ESI, +ve ion) = 279.2 [M+H] + .

[0401] Step B. tert-Butyl (S)-3-(2-((4-chloro-2-fluorophenoxy)methyl)pyridin-4-yl)pyrrolidine-1-carboxylate (427c-P1) and tert-butyl (R)-3-(2-((4-chloro-2-fluorophenoxy)methyl)pyridin-4-yl)pyrrolidine-1-carboxylate (427c-P2) [ka] The title products (427c-P1 and 427c-P2) were synthesized using a procedure similar to that described in Steps B and C of Example 383, followed by chiral separation (chiralpak-OJ column, mobile phase: CO2-MeOH containing 0.1% DEA). 427c-P1 is the early eluting peak, and 427c-P2 is the late eluting peak.

[0402] Step C. (R)-2-((4-chloro-2-fluorophenoxy)methyl)-4-(pyrrolidin-3-yl)pyridine (427d) [ka] A solution of 427c-P2 (20 mg, 0.05 mmol) in HCl (4 M in 1,4 dioxane, 1 mL) was stirred at 25 °C for 2 h. After completion, 1 N NaOH was added to the reaction in an ice bath to adjust the pH to 8. The reaction mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were dried, filtered, and concentrated to give the crude title product (427d) (15 mg) as a white solid. m / z (ESI, +ve ion) = 307.1 [M+H] + .

[0403] Step D. 2-(((R)-3-(2-((4-chloro-2-fluorophenoxy)methyl)pyridin-4-yl)pyrrolidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (427) [ka] The title product (427) was prepared by a procedure similar to that described in Steps F and G of Example 383. m / z (ESI, +ve ion) = 569.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ ppm 8.42 (d, J = 5.26 Hz, 1H), 8.11 (s, 1H), 7.62 (br d, J = 10.96 Hz, 1H), 7.56 (s, 1H), 7.32 (dd, J = 5.26, 1.32 Hz, 1H), 7.19 (dd, J = 10.96, 2.63 Hz, 1H), 7.04 - 7.15 (m, 2H), 5.14 - 5.25 (m, 3H), 4.84 (br d, J = 7.02 Hz, 1H), 4.67 (dd, J = 15.57, 2.41Hz, 1H), 4.55 - 4.63 (m, 1H), 4.41 (dt, J = 9.21, 5.92 Hz, 1H), 4.06 - 4.29 (m, 2H), 3.45 - 3.56 (m, 1H), 3.10 (t, J=8.55 Hz, 1H), 3.02 (td, J = 8.77, 4.39 Hz, 1H), 2.68 - 2.88 (m, 3H), 2.36 - 2.52 (m, 2H), 1.87 - 1.99 (m, 1H).

[0404] Example 428 was synthesized from 427c-P1 using a procedure similar to that described in Example 427. Examples 433 and 434 were synthesized using a procedure similar to that described in Example 427.

[0405] Examples 431 and 432 were synthesized using a procedure similar to that described in Example 428.

[0406] Example 435. (S)-2-((3-(4-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (435) [ka] Step A. (2-Chloropyrimidin-4-yl)methanol (435a) [ka] 2-Chloropyrimidine-4-carboxylic acid (793 mg, 5 mmol) was dissolved in THF (16.7 mL) and cooled to 0 °C. Triethylamine (704 μL, 5.05 mmol) was added slowly and stirred for 5 min. Isobutyl chloroformate (655 μL, 5.05 mmol) was added dropwise, and the reaction mixture was warmed to 21 °C and stirred for 1 h. The reaction was then filtered and rinsed with THF (5 mL). The filtrate was cooled to 0 °C, and a solution of NaBH (378 mg, 2 equiv., 10 mmol) in water (3 mL) was added dropwise. After stirring at 21 °C for 2 h, the mixture was poured into HO (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (gradient elution from 15 to 100% EtOAc in DCM) to give the title product (435a) (347 mg, 48%). m / z (ESI, +ve ion) = 145.2 [M+H] + .

[0407] Step B. tert-Butyl 3-(4-(hydroxymethyl)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (435b) [ka] A mixture of 435a (347 mg, 2.4 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (709 mg, 2.4 mmol), KCO (2.4 mL, 4.8 mmol, 2 M in water), and 1,4-dioxane (9.6 mL) was thoroughly purged with N for 5 minutes. Pd(dppf)Cl (87.8 mg, 120 μmol) was added, and the reaction mixture was heated to 90 °C for 3 hours. After cooling, the reaction mixture was diluted with EtOAc (20 mL) and washed with NH Cl (5 mL), HO (5 mL), and brine (5 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (gradient elution from 15 to 100% EtOAc in DCM) to give the title product (435b) (461 mg, 69%). m / z (ESI, +ve ion) = 300.3 [M+Na] + .

[0408] Step C. tert-Butyl 3-(4-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (435c) [ka] 435b (139 mg, 0.5 mmol), 4-chloro-2-fluorophenol (55.8 μL, 525 μmol), PPh3 (197 mg, 750 μmol), and DCM (1.97 mL) were cooled to 0 °C. N-({[(4-chlorophenyl)methoxy]carbonyl}imino)[(4-chlorophenyl)methoxy]formamide (DCAD) (275 mg, 750 μmol) was added slowly. After stirring at room temperature for 1 h, the reaction was filtered and directly purified by silica gel column chromatography (gradient elution from 0 to 50% EtOAc in DCM) to give the title product (435c) (178 mg, 87%) as a colorless solid. m / z (ESI, +ve ion) = 428.3 [M+Na] + .

[0409] Step D. (S)-2-((3-(4-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (435) [ka] The title product (435) was synthesized from 435c using a procedure similar to that described in Steps C-E of Example 384. m / z (ESI, +ve ion) = 550.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.72 (d, J = 5.27 Hz, 1H), 8.17 (d, J = 0.75 Hz, 1H), 7.96 (dd, J = 8.28, 1.51 Hz, 1H), 7.61 (d, J = 8.53 Hz, 1H), 7.44 (d, J = 5.02 Hz, 1H), 7.20 - 7.24 (m, 1H), 7.08 - 7.15 (m, 2H), 6.97 (t, J = 1.88 Hz, 1H), 5.26 (qd, J = 7.07, 2.89 Hz, 1H), 5.21 (s, 2H), 4.72 - 4.80 (m, 1 H), 4.66 - 4.74 (m, 1H), 4.59 - 4.66 (m, 1H), 4.46 (dt, J = 9.03, 6.02 Hz, 1H), 4.35 - 4.41 (m, 1H), 4.25 - 4.31 (m, 1H), 3.96 - 4.06 (m, 2H), 3.80 - 3.91 (m, 2H), 2.74 - 2.82 (m, 1H), 2.48 - 2.57 (m, 1H).

[0410] Examples 441 and 442 were prepared by steps A-C of Example 427, except that chiral separation (SFC separation, Daicel CHIRALCEL AD, 250 mm) was performed after removal of Boc. *30 mm ID, 10 μm; mobile phase: CO / MeOH=85 / 15 containing 0.2% NH (7 M in MeOH)), followed by steps D and E of Example 384 as described therein.

[0411] Examples 444 and 445 were prepared using Step A of Example 427 followed by Steps B, C, E, F, and G of Example 383 in a similar manner as described therein, followed by chiral separation (SFC, Daicel CHIRALCEL AZ, 250 mm * The synthesis was carried out using a 30 mm ID, 10 μm mobile phase: CO2 / MeOH = 60 / 40 containing 0.2% NH3 (7 M in MeOH).

[0412] Example 446 was synthesized using Step A of Example 411 followed by Steps G, B, and C of Example 383 in a manner similar to that described therein.

[0413] Example 447 was synthesized using Step A of Example 411 followed by Steps B, C, and G of Example 383 in a similar manner as described therein. Example 448 was synthesized in a similar manner as described in Example 447.

[0414] Example 449. 2-(((R)-3-(3-((4-cyano-2-fluorophenoxy)methyl)-4-fluorophenyl)pyrrolidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (449) [ka] Step A. tert-Butyl 3-(4-fluoro-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (449a) [ka] The title product (449a) was synthesized using a procedure similar to that described in Step A of Example 383. m / z (ESI, +ve ion) = 344.0 [M+Na] + .

[0415] Step B. tert-Butyl 3-(4-fluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (449b) [ka] The title product (449b) was synthesized using a procedure similar to that described in Step A of Example 427. m / z (ESI, +ve ion) = 346.1 [M+Na] + .

[0416] Step C. tert-Butyl 3-(4-fluoro-3-(hydroxymethyl)phenyl)pyrrolidine-1-carboxylate (449c) [ka] To a mixture of 449b (1.6 g, 4.95 mmol) in THF was added LiAlH4 (188 mg, 4.95 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 h. Upon completion, the reaction was quenched with Na2SO4.10H2O and filtered. The filter cake was rinsed with THF (100 mL). The combined organic layers were concentrated to give the crude title product (449c) (1.5 g) as a yellow solid, which was used in the next step without further purification. m / z (ESI, +ve ion) = 318.1 [M+Na] + .

[0417] Step D. (R)-3-Fluoro-4-((2-fluoro-5-(pyrrolidin-3-yl)benzyl)oxy)benzonitrile (449d-P1) and (S)-3-Fluoro-4-((2-fluoro-5-(pyrrolidin-3-yl)benzyl)oxy)benzonitrile (449d-P2) [ka] The title products (449d-P1 and 449d-P2) were obtained using steps B and C of Example 383 in a similar manner as described therein, followed by chiral SFC separation (Daicel CHIRALCEL 0Z, 250 mm * 30 mm ID, 10 μm; mobile phase: CO₂ / MeOH = 85 / 15 containing 0.2% NH₃ (7 M solution in MeOH). m / z (ESI, +ve ion) = 437.1 [M+Na]. + 449d-P1 is the early eluting peak. Stereochemistry has been arbitrarily assigned.

[0418] Step E. 2-(((R)-3-(3-((4-cyano-2-fluorophenoxy)methyl)-4-fluorophenyl)pyrrolidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (449) [ka] The title product (449) was synthesized from 449d-P1 using a procedure similar to that described in Steps C-E of Example 384. 1H NMR (400 MHz, DMSO-d6 ) δ ppm 7.78 - 7.83 (m, 1 H), 7.75 (s, 1 H), 7.61 - 7.69 (m, 1 H), 7.41 - 7.48 (m, 2 H), 7.32 - 7.38 (m, 1 H), 7.25 - 7.32 (m, 1 H), 7.12 (dd, J = 9.91, 8.66 Hz, 1 H), 5.20 (s, 2 H), 4.94 - 5.04 (m, 1 H), 4.63 (dd, J = 15.31, 7.28 Hz, 1 H), 4.48 - 4.56 (m, 1 H), 4.33 - 4.43 (m, 1 H), 4.24 (dt, J =8.91, 5.96 Hz, 1 H), 3.99 (d, J = 13.55 Hz, 1 H), 3.83 (d, J =13.30 Hz, 1 H), 3.13 - 3.19 (m, 1 H), 2.88 (t, J = 8.41 Hz, 1 H), 2.62 - 2.75 (m, 2 H), 2.28 - 2.35 (m, 2 H), 2.16 - 2.24 (m, 2 H), 1.63 - 1.75 (m, 1 H).

[0419] Example 450 was synthesized from 449d-P2 (late eluting peak) using a procedure similar to that described in Example 449.

[0420] Example 453 was synthesized from methyl 6-chloro-3-fluoropicolinate using Steps A-C of Example 449, followed by Steps B, C, E, and F of Example 383 in a similar manner as described therein, followed by chiral UPCC separation of the enantiomers (Daicel CHIRALCEL AZ, 250 mm × 30 mm ID, 10 μm; CO / MeOH = 70 / 30 containing 0.2% NH (7 M in MeOH)), followed by Step G of Example 383 in a similar manner as described therein. 453 was formed from the early eluting peak.

[0421] Examples 454 (from the early eluting peak) and 455 (from the late eluting peak) were synthesized using a procedure similar to that described in Example 453. Chiral separation conditions: UPCC (Daicel CHIRALPAK AZ_3,3 * 150 mm, 3 μm; mobile phase: CO2 / MeOH = 60 / 40 containing 0.1% DEA).

[0422] Example 459. (S)-2-(4-((2-((4-chloro-2-fluorophenoxy)methyl)pyridin-4-yl)oxy)-2-fluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (459) [ka] Step A. (4-Bromopyridin-2-yl)methyl methanesulfonate (459a) [ka] To a solution of (4-bromopyridin-2-yl)methanol (3 g, 0.016 mol) in DCM (50 mL) was added DIPEA (6.2 g, 0.05 mol). After stirring for 3 min, methanesulfonic anhydride (4.18 mg, 0.02 mol) was added at 0 °C. After stirring at 20 °C for 1 h, the reaction was quenched with HO (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude title product (459a) (3 g), which was used in the next step without further purification. m / z (ESI, +ve ion) = 267.9 [M+H] + .

[0423] Step B. 4-Bromo-2-((4-chloro-2-fluorophenoxy)methyl)pyridine (459b) [ka] To a solution of 459a (3 g, 0.01 mol) in DMF (20 mL) was added 4-chloro-2-fluorophenol (1.82 g, 0.01 mol) and K2CO3 (15.62 g, 0.113 mol). The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with HO (8 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title product (459b) (3.0 g, 79%) as a colorless oil. m / z (ESI, +ve ion) = 317.9 [M+H] + .

[0424] Step C. Methyl 2-(4-((2-((4-chloro-2-fluorophenoxy)methyl)pyridin-4-yl)oxy)-2-fluorophenyl)acetate (459c) [ka] 459b (1.0 g, 3.2 mmol), methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (0.59 g, 3.2 mmol), CuI (0.06 g, 0.0003 mol), pyridine-2-carboxylic acid (0.08 g, 0.6 mmol), and KPO (1.36 g, 0.0064 mol) were placed in a vial and argon was bubbled through it. DMSO (20 mL) was added. The reaction was heated at 100 °C for 12 h, cooled, quenched with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated and purified by preparative HPLC (MeCN in HO (containing 0.05% TFA as a modifier)) to give the title product (459c) (300 mg, 22%) as a brown solid. m / z (ESI, +ve ion) = 420.3 [M+H] + .

[0425] Step D. 2-(4-((2-((4-chloro-2-fluorophenoxy)methyl)pyridin-4-yl)oxy)-2-fluorophenyl)acetic acid (459d) [ka] To a stirring solution of 459c (300 mg, 0.71 mmol) in MeOH / THF / HO (1:1:2, 20 mL) was added LiOH ...

Claims

1. A compound of formula I, or a pharma- ceutically acceptable salt, or stereoisomer thereof: 【Chemical 341】 wherein A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted bicyclic; Ring C is a substituted or unsubstituted C ４ -C ６ Heterocycloalkyl, substituted or unsubstituted C ５ heterocycloalkenyl, or substituted or unsubstituted phenyl, where heterocycloalkyl and heterocycloalkenyl are each L, as shown. ３ at least one N bonded to D １ , D ２ , and D ３ 0, 1, or 2 of the groups are N, and the rest are CH or CR ６ and W is CR １４ or C; W is CR １４ when W is C, the adjacent dashed line represents a double bond, or when L ２ is -C(H)=; L １ is a bond, —O—, —CH ２ - and -OCH ２ - selected from the group consisting of; L ２ is a bond, -CH ２ selected from the group consisting of -, -C(H)=, and -O-; L ３ is -CH ２ - and L ４ does not exist or L ４ L １ and together with rings A and B form a fused tricyclic ring, and L ５ does not exist; L ５ does not exist or L ５ L ２ and together with rings B and C form a fused tricyclic ring; L ４ does not exist; R ４ is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R ５ は、-COOH、-COCF ３ 、-C(OH)CF ３ 、-CONHCN、-CONHOH、CONHOMe、-CONHSO ２ N(Me) ２ 、-PO ３ H ２ 、-PO(Me)(OH)、-SO ３ 2019-02-20 ２ NH ２ 、-SO ２ NHMe、-B(OH) ２ 、 【Chemical 342】 and tetrazolyl; Each R ６ is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R １１ R １２ NCO- and R １１ R １２ N-; R １１ is hydrogen or alkyl; R １２ is hydrogen or alkyl; R １３ is hydrogen or alkyl; R １４ is hydrogen, cyano, halo, hydroxyl, alkyl, haloalkyl, or methyl; wherein the ring C is C ６ When ring B is heterocycloalkyl, it is pyrazole or 【Chemical 343】 or a pharma- ceutically acceptable salt, or stereoisomer thereof.

2. 2. A compound according to claim 1, according to formula Ia, Ib, or Ic, or a pharma- ceutically acceptable salt or stereoisomer thereof, 【Chemical 344】 wherein A is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; Ring B is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring C is further unsubstituted or further substituted and / or bridged and / or fused; C １ , C ２ , C ３ , and C ４ 0, 1, or 2 of the formula are N, and the rest are CH or CR ６ and D １ , D ２ , and D ３ 0, 1, or 2 of the groups are N, and the rest are CH or CR ６ and W is CH or C; when W is CH, the adjacent dashed lines represent a single bond; when W is C, the adjacent dashed lines represent a double bond; or L ２ is -C(H)=; L １ is -O-, -CH ２ - and OCH ２ - selected from the group consisting of; L ２ is a bond, -CH ２ -, -C(H)=, -CF ２ -, -O-, and -O-; L ３ is -CH ２ - and L ４ does not exist or L ４ L １ and together with rings A and B form a fused tricyclic ring, and L ５ does not exist; L ５ does not exist or L ５ L ２ and together with rings B and C form a fused tricyclic ring; L ４ does not exist; R ４ is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R ５ は、-COOH、-COCF ３ 、-C(OH)CF ３ 、-CONHCN、-CONHOH、CONHOMe、-CONHSO ２ N(Me) ２ 、-PO ３ H ２ 、-PO(Me)(OH)、-SO ３ 2019-02-20 ２ NH ２ 、-SO ２ NHMe、-B(OH) ２ 、 【Chemical 345】 and tetrazolyl; Each R ６ is alkyl, substituted alkyl, halo, hydroxyl, alkoxyl, R １１ R １２ NCO- and R １１ R １２ N-; R １１ is hydrogen or alkyl; R １２ is hydrogen, or alkyl; and R １３ is hydrogen, or alkyl, or a pharma- ceutically acceptable salt or stereoisomer thereof.

3. 2. The compound of claim 1 according to formula IIe, IIf, or IIi-IIn, or a pharma- ceutically acceptable salt, or stereoisomer thereof: 【Chemical 346】 In the formula, A １ , A ２ , A ３ , A ４ , and A ５ 0, 1, or 2 of the formula are N, and the rest are CH or CR １ and B １ , B ２ , B ３ , and B ４ 0, 1, or 2 of the formula are N, and the rest are CH or CR ２ and in formula IIb, B ４ does not exist; C １ , C ２ , C ３ , and C ４ 0, 1, or 2 of the groups are N, and the rest are CH or CR ６ and D １ , D ２ , and D ３ 0, 1, or 2 of the groups are N, and the rest are CH or CR ６ and Each R １ is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R １１ R １２ NCO-; Each R ２ is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R １１ R １２ NCO-; Each R ３ is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R １１ R １２ NCO-; R ４ is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R ５ は、-COOH、-COCF ３ 、-C(OH)CF ３ 、-CONHCN、-CONHOH、CONHOMe、-CONHSO ２ N(Me) ２ 、-PO ３ H ２ 、-PO(Me)(OH)、-SO ３ 2019-02-20 ２ NH ２ 、-SO ２ NHMe、-B(OH) ２ 、 【Chemical 347】 and tetrazolyl; Each R ６ is independently selected from the group consisting of F and methyl; R １１ is hydrogen or alkyl; R １２ is hydrogen or alkyl; R １３ is hydrogen or alkyl; o is 1, 2, 3, or 4; p is 0 or 1; and The compound, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein q is 0 or 1.

4. 2. The compound of claim 1 according to any of the following formulas, or a pharma- ceutically acceptable salt, or stereoisomer thereof: 【Hua 348-1】 【Hua 348-2】 【Hua 348-3】 【Hua 348-4】 In the formula, each R １ is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy, and R １１ R １２ NCO-; Each R ３ is alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy, and R １１ R １２ NCO-; R ４ is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; R ５ は、-COOH、-COCF ３ 、-C(OH)CF ３ 、-CONHCN、-CONHOH、CONHOMe、-CONHSO ２ N(Me) ２ 、-PO ３ H ２ 、-PO(Me)(OH)、-SO ３ 2019-02-20 ２ NH ２ 、-SO ２ NHMe、-B(OH) ２ 、 【Chemical 349】 and tetrazolyl; Each R １１ is hydrogen or alkyl; Each R １２ is hydrogen or alkyl; Each R １３ is hydrogen or alkyl; R １４ is hydrogen, cyano, halo, hydroxyl, or methyl; and The compound, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein n is an integer from 0 to 5; o is an integer from 0 to 4; p is 0 or 1; and q is 0 or 1.

5. Each R ２ and R ３ The compound of claim 1 , wherein is H or F.

6. The compound of claim 1 , wherein m is 0 and o is 0.

7. The compound of claim 1 , wherein W is N or CH.

8. The compound of claim 1 , wherein W is C.

9. The compound of claim 1 , wherein W is CH.

10. The compound of claim 1 , wherein W is N.

11. R ４ is selected from the group consisting of 1-(cyanomethyl)-cycloprop-1-yl-methyl, (1-ethyl-1H-imidazol-5-yl)-methyl, 1-(fluoromethyl)-cycloprop-1-yl-methyl, isoxazol-5-yl-methyl, oxetan-2-yl-methyl, (2S)-oxetan-2-yl-methyl, oxelan-3-yl-methyl, (3R)-oxelan-3-yl-methyl, 1,3-oxazol-2-yl-methyl, and tetrahydrofur-2-yl-methyl.

12. R ４ is selected from the group consisting of (1-ethyl-1H-imidazol-5-yl)-methyl, oxetan-2-yl-methyl, (2S)-oxetan-2-yl-methyl, oxelan-3-yl-methyl, (3R)-oxelan-3-yl-methyl, and 1,3-oxazol-2-yl-methyl.

13. R ４ is selected from the group consisting of 1-(cyanomethyl)-cycloprop-1-yl-methyl, 1-(fluoromethyl)-cycloprop-1-yl-methyl, isoxazol-5-yl-methyl, and tetrahydrofur-2-yl-methyl.

14. R ４ The compound of claim 1, wherein is selected from the group consisting of oxetan-2-yl-methyl and (1-ethyl-1H-imidazol-5-yl)-methyl.

15. R ４ The compound of claim 1, wherein is oxetan-2-yl-methyl.

16. R ４ The compound of claim 1, wherein is (2S)-oxetan-2-yl-methyl.

17. R ４ The compound of claim 1, wherein is (1-ethyl-1H-imidazol-5-yl)-methyl.

18. R ４ The compound of claim 1, wherein is selected from the group consisting of oxelan-3-yl-methyl and 1,3-oxazol-2-yl-methyl.

19. R ４ The compound of claim 1, wherein is (3R)-oxelan-3-yl-methyl.

20. R ４ The compound of claim 1, wherein is 1,3-oxazol-2-yl-methyl.

21. R ５ The compound according to claim 1, wherein is -COOH or -COOMe.

22. R ５ The compound of claim 1, wherein is -COOH.

23. R ５ The compound of claim 1 , wherein is tetrazolyl.

24. R ５ The compound of claim 1, wherein is 1H-1,2,3,4-tetrazol-5-yl.

25. L ２ But -CH ２ The compound according to claim 1, wherein

26. L ２ The compound of claim 1, wherein is -CH= or -O-.

27. L ２ The compound of claim 1, wherein is -CH=-.

28. L ２ The compound according to claim 1, wherein is -O-.

29. L ３ But -CH ２ The compound according to claim 1, wherein

30. L １ But, -OCH ２ - and L ２ But -CH ２ The compound of claim 1, wherein:

31. L １ The compound according to claim 1, wherein is -O-.

32. 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, selected from: 【Table 4-1】 【Table 4-2】 【Table 4-3】 【Table 4-4】 【Table 4-5】 【Table 4-6】 【Table 4-7】 【Table 4-8】 【Table 4-9】 【Table 4-10】 【Table 4-11】 【Table 4-12】 【Table 4-13】 【Table 4-14】 【Table 4-15】 【Table 4-16】 【Table 4-17】 【Table 4-18】 【Table 4-19】 【Table 4-20】 【Table 4-21】 【Table 4-22】 【Table 4-23】 【Table 4-24】 【Table 4-25】 【Table 4-26】 【Table 4-27】 【Table 4-28】 【Table 4-29】 【Table 4-30】 【Table 4-31】 【Table 4-32】 【Table 4-33】 【Table 4-34】 【Table 4-35】 【Table 4-36】 【Table 4-37】 【Table 4-38】 【Table 4-39】 【Table 4-40】 【Table 4-41】

33. A compound selected from compounds 529, 530, 533, 534, 535, and 551, or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 350】 34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, excipients or diluents.

35. A pharmaceutical composition for treating a metabolic disease or disorder, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharma- ceutical acceptable salt thereof.

36. A compound according to any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, for use in therapy.

37. 34. A compound according to any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a metabolic disease or disorder.

38. 34. Use of a compound according to any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a metabolic disease or disorder.

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