CN117043154A - GPCR receptor agonists, pharmaceutical compositions comprising same, and methods of use thereof - Google Patents

GPCR receptor agonists, pharmaceutical compositions comprising same, and methods of use thereof Download PDF

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CN117043154A
CN117043154A CN202280024605.7A CN202280024605A CN117043154A CN 117043154 A CN117043154 A CN 117043154A CN 202280024605 A CN202280024605 A CN 202280024605A CN 117043154 A CN117043154 A CN 117043154A
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alkyl
methyl
certain embodiments
substituted
group
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Inventor
X·杜
R·富奇尼
X·冉
C-H·叶
X·周
R·高
J·W·郑
L·刘
S·M·萨基亚
X·王
H·卡瓦依
C·李
D·劳埃德
S·汉森
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Camote Medical Co ltd
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Camote Medical Co ltd
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Priority claimed from PCT/US2022/014156 external-priority patent/WO2022165076A1/en
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Abstract

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

Description

GPCR receptor agonists, pharmaceutical compositions comprising same, and methods of use thereof
Cross Reference to Related Applications
The present application is of interest in PCT International application, U.S. provisional application Ser. No. 63/274,893, issued on month 11 and 2 of 2021, U.S. provisional application Ser. No. 63/183,612, issued on month 5 and 3 of 2021, U.S. provisional application Ser. No. 63/143,025, issued on month 1 and 28 of 2021, each of which is incorporated herein by reference in its entirety.
Technical Field
Provided herein are GLP-1 receptor modulator compounds; pharmaceutical compositions comprising said compounds; a method of producing the compound; and methods of treatment using the compounds and compositions. The compounds and compositions are useful, for example, in methods of treating and preventing metabolic diseases or disorders, methods of detecting metabolic diseases or disorders, and methods of diagnosing metabolic diseases or disorders.
Background
Diabetes is a severe chronic disease that occurs when the pancreas does not produce enough insulin or when the body is unable to use the insulin it produces effectively. Complications of diabetes include damage to the heart, blood vessels, eyes, kidneys and nerves. Diabetes can increase the risk of heart disease and stroke. The consequences include severe impact on quality of life, health and death. WHO Global Report on Diabetes,2016,World Health Organization. By 2017, about 4.62 million people worldwide (about 6.28% of the population) are affected by type 2 diabetes, and this prevalence is increasing dramatically. Khan et al 2020,J.Epidemiol.Glob.Health 10 (1): 107-111. The global economic burden of diabetes in 2015 is estimated to be $ 1.3 trillion, and it is estimated that by 2030 it will increase to $ 2.1 trillion. Bommer et al 2018,Diabetes Care 41 (5): 963-970. About 90-95% of all diabetes cases are type 2 diabetes. Tripathi and Srivastava,2016, med. Sci. Monit.12 (7): RA130-147.
Glucagon-like peptide-1 receptor (GLP-1 receptor or GLP 1R) has become a potential target for the treatment of type 2 diabetes. Its ligand glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion, and increases insulin synthesis and has many other effects. Doyle and Egan,2007, pharmacol. Ther.113 (3): 546-593. GLP-1 is known to delay gastric emptying, inhibit food intake, increase satiety, and reduce body weight in humans. Shah and Vella,2014Rev Endocr Metab Disord.15 (3): 181-187. Activation of the GLP-1 receptor has been shown to have beneficial effects on insulin secretion, glucose sensing in beta cells, transcription, synthesis, proliferation and maintenance of survival. Doyle and Egan,2007 (above). Although the GLP-1 receptor is a promising therapeutic target, only a few GLP-1 receptor drugs have been approved so far, and most or all of these drugs are peptide or polypeptide drugs.
Additional therapies for the treatment of metabolic diseases and disorders such as type 2 diabetes are needed. Small molecules targeting the GLP-1 receptor should provide a safe, stable and easy to administer therapeutic approach for metabolic diseases and disorders such as type 2 diabetes.
Disclosure of Invention
Provided herein are GLP-1 receptor modulator compounds of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii) and their subformulae; a composition comprising the compound: a method of producing the compound; and methods of using the compounds and compositions in therapy and diagnosis. Compounds of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII) and their subformulae and embodiments are useful for modulating GLP-1 receptor activity. In certain embodiments, the compounds are useful for agonizing the activity of the GLP-1 receptor. In certain embodiments, the compounds are useful for treating diseases or conditions modulated by GLP-1 receptors.
In one aspect, there is provided a compound of formula (I):
wherein A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, -NMe 2 or-CF 3 ；
Ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted bicyclic ring;
ring C is a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkenyl, each containing at least one N, attached to L as depicted 3 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =;
L 1 selected from the group consisting of: bond, -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -, -NH-, -N (Me) -and process for preparing the same
L 3 is-CH 2 -or-C (O) -;
L 4 is absent, or L 4 And L is equal to 1 And rings A and B together form a fused tricyclic ring, and L 5 Is absent;
L 5 is absent, or L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring, and L 4 Is absent;
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 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkylOxy, 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, hydroxy, alkyl, haloalkyl, methyl, CH 2 F or CH 2 OH；
Wherein when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -orOr L 3 is-C (O) -, or both.
In one aspect, there is provided a compound of formula (Ia):
wherein A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, -NMe 2 or-CF 3 ；
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 One, or both of zero are N, and the remainder are CH or CR 6 ；
W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond;
when W is C, an adjacent dashed line indicates a double bond, e.g. L 2 is-C (H) =;
L 1 selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -, -O-, -NH-; -N (Me) -and methods of use
L 3 is-CH 2 -or-C (O) -;
L 4 is absent, or L 4 And L is equal to 1 And rings A and B together form a fused tricyclic ring, and L 5 Is absent;
L 5 is absent, or L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring, and L 4 Is absent;
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 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 Independently selected from the group consisting of: alkyl, quiltSubstituted alkyl, halo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-；
R 11 Is hydrogen or alkyl;
R 12 is hydrogen or alkyl; and is also provided with
R 13 Is hydrogen or alkyl;
wherein, when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -orOr L 3 is-C (O) -, or both.
In one aspect, there is provided a compound of formula (XXX) or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; when W is C, an adjacent dashed line indicates a double bond, e.g. L 2 is-C (H) =;
A 1 、A 2 、A 3 、A 4 and A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；
B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
L 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -, -NH-, -N (Me) -and process for preparing the same
L 3 is-CH 2 -or-C (O) -;
each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
R 4 Is unsubstituted alkyl, substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heterocycloalkyl alkylene, or substituted heterocycloalkyl alkylene;
R 5 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy,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; and is also provided with
o is an integer from 0 to 4.
In one aspect, provided herein is a compound of formula XXXI, or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; a is that 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
L 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -, -NH-, -N (Me) -and process for preparing the same
L 3 is-CH 2 -or-C (O) -;
each R 3 Independently selected from the group consisting of: alkyl (C)Group, substituted alkyl, halo, cyano, azido, alkoxy, 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 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、
And tetrazolyl;
each R 6 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; and is also provided with
o is 1, 2, 3 or 4.
In certain aspects, the compounds are useful in methods of treating and preventing metabolic diseases and disorders, methods of detecting metabolic diseases and disorders, and methods of diagnosing metabolic diseases and disorders.
In another aspect, compositions comprising compounds of formula (I), (Ia), (XXX) or (XXXI) are provided. In some embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition may be used. In another aspect, provided herein is a kit comprising a compound of formula (I), (Ia), (XXX) or (XXXI) or an embodiment thereof or a pharmaceutical composition thereof.
In another aspect, provided herein are methods of using the compounds or compositions described herein. In some embodiments, the method is for treatment. In some embodiments, the method is a diagnostic method. In some embodiments, the method is an analytical method. In some embodiments, the compounds or compositions described herein are used to treat a disease or disorder. In some aspects, the disease or condition is selected from metabolic diseases or conditions. In certain embodiments, the disease is type 2 diabetes.
Also provided herein is the use of the compounds described herein and compositions thereof for the treatment of metabolic diseases or disorders. Also provided herein are uses of the compounds and compositions thereof described herein for the treatment of type 2 diabetes.
Drawings
Figure 1 provides an intravenous glucose tolerance test (IVGTT) performed in cynomolgus monkeys.
Detailed Description
GLP-1 receptor compounds useful in the treatment of metabolic diseases or disorders such as type 2 diabetes are described herein.
Definition of the definition
Unless defined otherwise, all technical terms, notations and other scientific terms used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or ease of reference. The techniques and procedures described or referenced herein are generally well understood and commonly employed by those skilled in the art using conventional methods. Unless otherwise indicated, procedures involving the use of commercially available kits and reagents are generally performed according to manufacturer-determined protocols and conditions, where appropriate.
As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
The term "about" indicates and encompasses the indicated values as well as ranges above and below the stated values. In certain embodiments, the term "about" indicates the specified value ± 10%, ± 5% or ± 1%. In certain embodiments, the term "about" indicates a specified value ± one standard deviation of the value. In certain embodiments, for example, on a logarithmic scale (e.g., pH), the term "about" indicates a specified value of ±0.3, ±0.2, or ±0.1.
Unless otherwise indicated, the following terms have the following meanings when referring to the compounds provided herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. If there are multiple definitions of terms herein, those in this section control unless stated otherwise.
"Alkoxy (Alkoxy/Alkoxyl)" refers to the group-OR "wherein R" is alkyl OR cycloalkyl. In certain embodiments, alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1, 2-dimethylbutoxy, and the like.
The term "alkoxyamine" as used herein refers to the group-alkylene-O-NH 2 Wherein alkylene is as defined herein. In some embodiments, the alkoxyamine group can react with an aldehyde to form an oxime residue. Examples of alkoxyamine groups include-CH 2 CH 2 -O-NH 2 and-CH 2 -O-NH 2 。
The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon unless specified otherwise. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group comprises one to ten carbon atoms (i.e., C 1 To C 10 Alkyl). In certain embodiments, the alkyl is lower alkyl, e.g., C 1-6 Alkyl groups, and the like. In certain embodiments, the alkyl group is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2-dimethylbutyl and 2, 3-dimethylbutyl. In certain embodiments, "substituted alkyl" means substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br)) Or iodo (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino, alkoxy, aryl, heteroaryl, cycloalkyl, cyano, oxo, alkyne and heterocycloalkylalkylene. In some embodiments, the alkyl group is unsubstituted.
The term "alkylene" as used herein refers to a divalent alkyl group as defined herein, unless specified otherwise. "substituted alkylene" refers to an alkylene group substituted as described herein for alkyl. In some embodiments, the alkylene is unsubstituted.
"alkenyl" refers to an ethylenically unsaturated hydrocarbon group, in certain embodiments, having up to about eleven carbon atoms, or two to six carbon atoms (e.g., "lower alkenyl"), which may be linear or branched, and having at least one or one to two sites of ethylenic unsaturation. "substituted alkenyl" refers to an alkenyl group substituted as described herein for alkyl.
"alkenylene" refers to a divalent alkenyl group as defined herein. Lower alkenylene is, for example, C 2 -C 6 -alkenylene.
"alkynyl" refers to an acetylenically unsaturated hydrocarbon group, in certain embodiments, having up to about eleven carbon atoms, or two to six carbon atoms (e.g., "lower alkynyl"), which may be linear or branched, and having at least one or one to two sites of acetylenically unsaturation. Non-limiting examples of alkynyl groups include acetylene (-C≡CH), propargyl (-CH) 2 C≡ch), and the like. "substituted alkynyl" refers to an alkynyl group substituted as described herein for alkyl.
"alkynylene" refers to a divalent alkynyl group as defined herein. Lower alkynylene radicals are, for example, C 2 -C 6 -alkynylene groups.
"amino" means-NH 2 。
As used herein, and unless otherwise specified, the term "alkylamino" refers to the group-NHR ", where R" is, for example, C as defined herein 1-10 An alkyl group. In certain embodiments, the alkylamino group is C 1-6 An alkylamino group.
As used herein, and unless otherwise specified, the term "dialkylamino" refers to the groups-NR "R", wherein each R "is independently C as defined herein 1-10 An alkyl group. In certain embodiments, the dialkylamino group is a di-C 1-6 An alkylamino group.
As used herein, and unless otherwise specified, the term "aryl" refers to phenyl, biphenyl, or naphthyl. The term includes both substituted and unsubstituted moieties. Aryl groups may be substituted with any of the described moieties, including but not limited to one or more moieties (e.g., one, two, or three moieties in some embodiments) selected from the group consisting of: halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, each of which is independently unprotected, or protected as desired, as will be appreciated by those skilled in the art (e.g., greene, et al, protective Groups in Organic Synthesis, john Wiley and Sons, second edition, 1991); and wherein the aryl groups in the arylamino and aryloxy substituents are not further substituted.
As used herein, and unless otherwise specified, the term "arylamino" refers to a-NR 'R "group where R' is hydrogen or C 1 -C 6 -an alkyl group; and R "is aryl as defined herein.
As used herein, and unless otherwise specified, the term "arylene" refers to a divalent aryl group as defined herein.
As used herein, and unless otherwise specified, the term "aryloxy" refers to an-OR group, wherein R is aryl as defined herein.
"Alkylene aryl" refers to an arylene group, as defined herein, wherein the aryl ring is substituted with one or two alkyl groups. "substituted alkarylene" refers to an alkarylene group as defined herein, wherein the arylene group is further substituted as defined herein for the aryl group.
"aralkylene" means-alkyl-aryleneRadicals or arylene-alkyl radicals, e.g. -C 1 -C 2 Alkyl-arylene-, -arylene-C 1 -C 2 alkyl-or-C 1 -C 2 alkyl-arylene-C 1 -C 2 Alkyl-groups, wherein arylene is as defined herein. "substituted aralkylene" refers to an aralkylene group as defined herein, wherein the aralkylene group is substituted as defined herein for an aryl group. "substituted C 1 -C 2 Alkyl "means C substituted as defined herein for alkyl 1 -C 2 An alkyl group.
"arylalkylene" means-alkyl-arylene or arylene-alkyl, e.g., -C 1 -C 2 Alkyl-arylene-, -arylene-C 1 -C 2 alkyl-or-C 1 -C 2 alkyl-arylene-C 1 -C 2 Alkyl-groups, wherein arylene is as defined herein. "substituted arylalkylene" refers to arylalkylene as defined herein wherein the arylalkylene is substituted as defined herein for aryl. "substituted C 1 -C 2 Alkyl "means C substituted as defined herein for alkyl 1 -C 2 An alkyl group.
"Carboxyl (Carboxyl) refers to-C (O) OH or-COOH.
The term "cycloalkyl" as used herein refers to saturated cyclic hydrocarbons unless specified otherwise. In certain embodiments, cycloalkyl groups may be saturated, and/or bridged, and/or unbridged, and/or fused bicyclic groups. In certain embodiments, cycloalkyl groups include three to ten carbon atoms (i.e., C 3 To C 10 Cycloalkyl). In some embodiments, cycloalkyl has three to fifteen carbons (C 3-15 ) Three to ten carbons (C 3-10 ) Three to seven carbons (C) 3-7 ) Or three to six carbons (C 3 -C 6 ) (i.e., "lower cycloalkyl"). In certain embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo [2.1.1 ]Hexyl, bicyclo [2.2.1]Heptyl, decalin or adamantyl.
As used hereinThe term "cycloalkylene" refers to a divalent cycloalkyl group as defined herein. In certain embodiments, the cycloalkylene is cyclopropyleneCyclobutylidene->Cyclopentylene->Cyclohexylene groupCycloheptylene->Etc. Lower cycloalkylene means C 3 -C 6 -cycloalkylene.
The term "cycloalkylalkyl" as used herein refers to an alkyl group as defined herein substituted with one or two cycloalkyl groups as defined herein, unless otherwise specified.
The term "ester" as used herein refers to-C (O) OR-COOR, wherein R is alkyl as defined herein.
The term "haloalkyl" refers to an alkyl group as defined herein substituted with one or more independently selected halogen atoms (e.g., one, two, three, four, or five in some embodiments).
The term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more carbon atoms are replaced with a heteroatom. As used herein, "heteroalkenyl" refers to an alkenyl group, as defined herein, wherein one or more carbon atoms are replaced with a heteroatom. As used herein, "heteroalkynyl" refers to an alkynyl group, as defined herein, in which one or more carbon atoms are replaced with 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 halo (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino, and alkoxy. In some embodiments, the heteroalkyl group may comprise one, two, three, or four heteroatoms. Those skilled in the art will recognize that a 4-membered heteroalkyl may typically contain one or two heteroatoms, a 5-or 6-membered heteroalkyl may typically contain one, two or three heteroatoms, and a 7-to 10-membered heteroalkyl may typically contain one, two, three or four heteroatoms.
The term "heteroalkylene" as used herein refers to a divalent heteroalkyl group as defined herein. "substituted heteroalkylene" refers to a divalent heteroalkyl as defined herein substituted as described for heteroalkyl.
The term "heterocycloalkyl" refers to a monovalent monocyclic or polycyclic non-aromatic ring system in which one or more ring atoms are heteroatoms independently selected from oxygen (O), sulfur (S), and nitrogen (N) (e.g., in which the nitrogen or sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized), and the remaining ring atoms of the non-aromatic ring are carbon atoms. In certain embodiments, the heterocycloalkyl group is a monovalent monocyclic or multicyclic fully saturated ring system. In certain embodiments, the heterocycloalkyl group has three to twenty, three to fifteen, three to ten, three to eight, four to seven, four to eleven, or five to six ring atoms. The heterocycloalkyl group may 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, which may include fused or bridged ring systems, and wherein a nitrogen or sulfur atom may optionally be oxidized, and/or a nitrogen atom may optionally be quaternized. In some embodiments, heterocycloalkyl includes, but is not limited to, 2, 5-diazabicyclo [2.2.2] octanyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazolyl, dioxolanyl, 1, 4-dithiohexyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3, 5-trithiohexenyl. In certain embodiments, heterocycloalkyl groups may also be optionally substituted as described herein. In certain embodiments, heterocycloalkyl is substituted with one, two, or three groups independently selected from halo (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino, oxo, cyano, and alkoxy. In some embodiments, the heterocycloalkyl group can include one, two, three, or four heteroatoms. Those skilled in the art will recognize that a 4-membered heterocycloalkyl group may typically contain one or two heteroatoms, a 5-or 6-membered heterocycloalkyl group may typically contain one, two or three heteroatoms, and a 7-to 10-membered heterocycloalkyl group may typically contain one, two, three or four heteroatoms.
"heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined herein.
The term "heteroaryl" refers to monovalent monocyclic aromatic groups and/or polycyclic aromatic groups wherein at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen in the ring. Each ring of the 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, heteroaryl groups have five to twenty, five to fifteen, or five to ten ring atoms. Heteroaryl groups 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, furyl, 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, benzotriazole, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienopyridinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perizolyl, phenanthroline, phenanthridine, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl groups may also be optionally substituted as described herein. "substituted heteroaryl" is a substituted heteroaryl as defined for aryl.
The term "heteroarylene" refers to a divalent heteroaryl group as defined herein. "substituted heteroarylene" is a substituted heteroarylene as defined for aryl.
The term "heteroarylalkylene" refers to-alkyl-heteroarylene-or-heteroarylene-alkyl, e.g., -C 1 -C 2 Alkyl-heteroarylene-, -heteroarylene-C 1 -C 2 alkyl-or-C 1 -C 2 alkyl-heteroarylene-C 1 -C 2 Alkyl-groups, wherein heteroarylene is as defined herein. "substituted heteroarylalkylene" refers to a heteroarylalkylene as defined herein, wherein the heteroarylalkylene is substituted as defined herein for aryl. "substituted C 1 -C 2 Alkyl "means C substituted as defined herein for alkyl 1 -C 2 An alkyl group.
As used herein, "oxo" refers to = O.
As used herein, and unless otherwise specified, the term "protecting group" refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent it from further reaction or to achieve other objectives. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. (see, e.g., greene, et al, protective Groups in Organic Synthesis, john Wiley and Sons, fourth edition, 2006, incorporated herein by reference).
By "pharmaceutically acceptable salt" is meant any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art. Such salts include, but are not limited to, (1) acid addition salts formed with 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, caproic 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, ethanesulfonic acid, 1, 2-ethane-disulfonic 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, t-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, mucic acid, and the like; or (2) when the acidic protons (a) present in the parent compound are replaced with metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions) or alkali or alkaline earth metal hydroxides (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide) or ammonia; or (b) salts formed upon complexation with organic bases such as aliphatic, alicyclic, or aromatic organic amines including, but not limited to, ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine (chloroprocaine), procaine (procaine), N-benzylphenethylamine, N-methyl-reduced glucamine piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, and the like.
Pharmaceutically acceptable salts also include, for example, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and when the compound contains basic functionality, salts with non-toxic organic or inorganic acids, such as hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3- (4-hydroxybenzoyl) benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (methanesulfonate), ethanesulfonate, 1, 2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate/besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, t-butyl, lauryl sulfate, gluconate, glutamate, hydroxynaphthalene hydrochloride, stearin, cyclohexyl, quinic acid, mucic acid, and the like.
The term "substantially free" or "substantially free" with respect to a composition means that the composition comprises at least 85 wt.% or 90 wt.%, in certain embodiments, 95 wt.%, 98 wt.%, 99 wt.%, or 100 wt.%; or in certain embodiments, 95%, 98%, 99% or 100% of the designated enantiomer or diastereomer of the compound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of one of the two enantiomers. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of one of the two diastereomers. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of enantiomers (i.e., racemic or 50:50 mixtures of the compounds).
Similarly, the term "isolated" with respect to a composition means that the composition includes at least 85%, 90%, 95%, 98% or 99% to 100% by weight of the compound, the remainder comprising other chemicals, enantiomers or diastereomers.
"solvate" refers to a compound provided herein or a salt thereof that also includes a stoichiometric or non-stoichiometric combination of solvents through non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.
"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 of a given atom. Atoms comprising their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, an atom of a compound recited herein is intended to represent any stable isotope of that atom. For example, when a position is specifically designated as hydrogen (H) unless otherwise stated, that position is understood to have hydrogen at its natural isotopic composition.
"isotopically enriched" refers to the percentage of incorporation of a certain amount of a particular isotope at a given atom in a molecule that replaces the natural isotopic abundance of that atom. For example, deuterium (D) enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at a given position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. 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.
The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of said atom. "isotopically enriched" may also mean that the compound contains at least one atom having an isotopic composition different from the natural isotopic composition of said atom.
As used herein, "alkyl", "alkylene", "alkylamino", "dialkylamino", "cycloalkyl", "aryl", "arylene", "alkoxy", "amino", "carboxy", "heterocycloalkyl", "heteroaryl", "heteroarylene", "carboxy" and "amino acid" groups optionally contain deuterium (D) at one or more positions where a hydrogen (H) atom is present, and where the deuterium composition of the atom or atoms is different from the natural isotopic composition.
Also as used herein, "alkyl", "alkylene", "alkylamino", "dialkylamino", "cycloalkyl", "aryl", "arylene", "alkoxy", "amino", "carboxy", "heterocycloalkyl", "heteroaryl", "heteroarylene", "carboxy" and "amino acid" groups optionally contain carbon-13 × in amounts other than the natural isotopic composition 13 C)。
As used herein, the term "EC 50 "refers to the dose, concentration or amount of a particular test compound that responds by 50% of the priming dose-dependent response of the maximum manifestation of the particular response induced, elicited or enhanced by the particular test compound.
As used herein, and unless otherwise specified, the term "IC 50 "means the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximum response in an assay that measures the maximum response.
As used herein, the terms "subject" and "patient" are used interchangeably. The term "subject" refers to animals, such as 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 some embodiments, humans. In certain embodiments, the subject is a farm animal (e.g., horse, cow, pig, etc.) or a pet (e.g., dog or cat). In certain embodiments, the subject is a human.
As used herein, the term "therapeutic agent (therapeutic agent/therapeutic agents)" refers to any agent or agents that can be used to treat or prevent a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In certain embodiments, the therapeutic agent is an agent known to be useful, or has been used, or is currently being used, in the treatment or prevention of a disorder or one or more symptoms thereof.
"therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject to treat a disorder, is sufficient to effect such treatment of the disorder. The "therapeutically effective amount" may vary depending on, inter alia, the compound, the disease or disorder and its severity, the age, weight, etc., of the subject to be treated.
In certain embodiments, "Treating" any disease or disorder refers to ameliorating the disease or disorder present in a subject. In another embodiment, "treating" includes improving at least one physical parameter that may be imperceptible to the subject. In another embodiment, "treating" includes modulating the disease or disorder physically (e.g., stabilization of a perceived symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In another embodiment, "treating" includes delaying or preventing the onset of a disease or disorder, or delaying or preventing the recurrence of a disease or disorder. In another embodiment, "treating" or "treatment" includes reducing or eliminating a disease or disorder, or slowing the progression of a disease or disorder or one or more symptoms of a disease or disorder, or reducing the severity of a disease or disorder or one or more symptoms of a disease or disorder.
As used herein, the term "prophylactic agent (prophylactic agent/prophylactic agents)" refers to any agent or agents that can be used to prevent 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 a compound provided herein. For example, a prophylactic agent is an agent that is known to be useful, or has been used, or is currently being used, to prevent or hinder the onset, development, progression and/or severity of a condition.
As used herein, the phrase "prophylactically effective amount" refers to an amount of a therapy (e.g., a prophylactic agent) sufficient to result in the prevention or reduction of the development, recurrence, or onset of one or more symptoms associated with a disorder, or to enhance or improve one or more prophylactic effects of another therapy (e.g., another prophylactic agent).
Compounds of the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)
Provided herein are GLP-1 receptor compounds useful for modulating one or more properties of the GLP-1 receptor. The compounds may be prepared as described herein and used for therapy or diagnosis. In certain embodiments, the treatment is the treatment of a metabolic disease or disorder. In certain embodiments, the treatment is the treatment of type 2 diabetes.
Embodiments described herein include the recited compounds, as well as pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers and/or mixtures thereof.
In certain embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof; wherein A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, -NMe 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the 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 (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；L 1 Selected from the group consisting of: bond, -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -, -NH-, -N (Me) -and process for preparing the sameL 3 is-CH 2 -or-C (O) -; l (L) 4 Is absent, or L 4 And L is equal to 1 And rings A and B together form a fused tricyclic ring, and L 5 Is absent; l (L) 5 Is absent, or L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring, and L 4 Is absent; r is 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、
And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-；R 11 Is hydrogen or alkyl; r is R 12 Is hydrogen or alkyl; and R is 13 Is hydrogen or alkyl. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -andin certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -.
In certain embodiments of formula (I), when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, CHF-, -CHOH-, -NH-, -N (Me) -orOr L 3 is-C (O) -, or both. In certain embodiments, when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -or->In certain embodiments, when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 3 is-C (O) -. In certain embodiments, when L 1 is-CH 2 O-, L 4 And L is equal to 1 And rings a and B together form a fused tricyclic ring. In certain embodiments, when L 1 is-CH 2 O-, L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring. In certain embodiments, when L 1 is-CH 2 O-ring C is substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted piperidinyl.
In certain embodiments, a is a ring selected from phenyl and cyclohexyl. 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. In certain embodiments, a is phenyl and ring C is piperazine. In certain embodiments, a is phenyl and ring C is piperidine. In certain embodiments, a is phenyl, and ring C is piperazine, and ring B is phenyl. In certain embodiments, a is phenyl, and ring C is piperazine, and ring B is furan. In certain embodiments, a is phenyl, and ring C is piperidine, and ring B is phenyl. In certain embodiments, a is phenyl, and ring C is piperidine, and ring B is furan.
In certain embodiments, a is a ring selected from phenyl and cyclohexyl. In certain embodiments, ring C is selected from the group consisting of substituted piperidines, azetidines, and pyrrolidines. 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 piperazine. In certain embodiments, a is phenyl and ring C is piperidine. In certain embodiments, a is phenyl and ring C is substituted piperidine. 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 piperazine, and ring B is phenyl. In certain embodiments, a is phenyl, ring C is piperazine, and ring B is furan. In certain embodiments, a is phenyl, ring C is piperidine, and ring B is phenyl. In certain embodiments, a is phenyl, ring C is piperidine, and ring B is furan. In certain embodiments, a is phenyl, ring C is substituted piperidine, and ring B is phenyl. In certain embodiments, a is phenyl, ring C is substituted piperidine, and ring B is furan. 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, there is provided a compound of formula (Ia), or a pharmaceutically acceptable salt, tautomer thereofA isomer, stereoisomer and/or mixture of stereoisomers; wherein A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, -NMe 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the 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 (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; when W is C, an adjacent dashed line indicates a double bond, e.g. L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; l (L) 4 Is absent, or L 4 And L is equal to 1 And rings A and B together form a fused tricyclic ring, and L 5 Is absent; l (L) 5 Is absent, or L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring, and L 4 Is absent; r is 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/>And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-；R 11 Is hydrogen or alkyl; r is R 12 Is hydrogen or alkyl; and R is 13 Is hydrogen or alkyl. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -andin certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -.
In certain embodiments of formula (Ia), when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -orOr L 3 is-C (O) -, or both. In certain embodiments, when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -or- >In certain embodiments, when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-orIn certain embodiments, when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 3 is-C (O) -. In certain embodiments, when L 1 is-CH 2 O-, L 4 And L is equal to 1 And rings a and B together form a fused tricyclic ring. In certain embodiments, when L 1 is-CH 2 O-, L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring.
In certain embodiments, a is a ring selected from phenyl and cyclohexyl. 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. In certain embodiments, a is phenyl and ring C is piperazine. In certain embodiments, a is phenyl and ring C is piperidine. In certain embodiments, a is phenyl, and ring C is piperazine, and ring B is phenyl. In certain embodiments, a is phenyl, and ring C is piperazine, and ring B is furan. In certain embodiments, a is phenyl, and ring C is piperidine, and ring B is phenyl. In certain embodiments, a is phenyl, and ring C is piperidine, and ring B is furan.
In certain embodiments, there is provided a compound of formula (XXX) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof; wherein W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; when W is C, an adjacent dashed line indicates a double bond, e.g. L 2 is-C (H) =; a is that 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 ；D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；L 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；R 4 Is unsubstituted alkyl, substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heterocycloalkyl alkylene, or substituted heterocycloalkyl alkylene; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-；R 11 Is hydrogen or alkyl; r is R 12 Is hydrogen or alkyl; r is R 13 Is hydrogen or alkyl;and o is an integer of 0 to 4. In certain embodiments, the compound of formula (XXX) is selected from compounds 82, 83, 91, 92, and 110 in table 1.
In certain embodiments, there is provided a compound of formula (XXXI) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof; wherein W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; a is that 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
L 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of use
L 3 is-CH 2 -or-C (O) -;
each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 takenSubstituted heterocycloalkylalkylene;
R 5 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、And tetrazolyl;
each R 6 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; and is also provided with
And o is 1, 2, 3 or 4. In certain embodiments, the compound of formula (XXXI) is selected from compounds 97 and 107 in table 1.
In certain embodiments, the compound of formula (I) is according to formula (IIa), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
Wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein, in formula IIa, B 4 Is absent; d (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each of which isR 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl; each R 6 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; and o is 1, 2, 3 or 4.
In certain embodiments, the compound of formula (I) is according to formula (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein in formula IIb, B 4 Is absent; d (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl; each R 6 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; and o is 1, 2, 3 or 4.
In certain embodiments, the compound of formula (I) is according to formula (IIc), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein in formula IIc, B 4 Is absent; d (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl; each R 6 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; r is R 14 Is hydrogen, cyano, halo, hydroxy or methyl; and o is 1, 2, 3 or 4.
In certain embodiments, the compound of formula (I) is according to formula (IId), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein, in formula IId, B 4 Is absent; d (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；R 4 Is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylAn alkylene group, a substituted heteroarylalkylene group, an unsubstituted heterocycloalkylalkylene group, or a substituted heterocycloalkylalkylene group; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/>And tetrazolyl; each R 6 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; r is R 14 Is hydrogen, cyano, halo, hydroxy or methyl; and o is 1, 2, 3 or 4.
In certain embodiments, the compound of formula (I) is according to formula (IIg), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein, in formula IIg, B 4 Is absent; d (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；Each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl; each R 6 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, the compound of formula (I) is according to formula (IIh), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein, in formula IIg, B 4 Is absent; d (D) 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl; each R 6 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, there is provided a compound of formula (III):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, L2 is O. In certain embodiments, the compound of formula (III) is selected from compounds 2, 3, 5-7, 10-18, 21-23, 25, 29, 32, 33, 35, 45, 46, 48, 50-52, 54, 56-58, 64-70, 75-80, 86, 89, 93, 95, 98, 100, 103-105, 111, 112, 115, 116, 122, 126, 130-133, 135, 137, 148, 149, 151, 157-159, 161, 162, 165, 166, 174, 187, 188, 202-208, 215-217, 221, 231, 232, 242, 243, 254, 255, 260, 263, 288, 294, 301, 318, 319, and 321 in table 1.
In certain embodiments, there is provided a compound of formula (IIIa) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -, -NH-, -N (Me) -and process for preparing the sameL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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. In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, L2 is O. In certain embodiments, the compound of formula (IIIa) is selected from compounds 103, 104, 111, 116, 126, 130-133, 135, 137, 148, 149, 151, 157-159, 161, 162, 165, 166, 174, 187, 188, in Table 1,202-208, 215-217, 221, 231, 232, 242, 243, 254, 255, 260, 263, 288, 294, 301, 318, 319, and 321.
In certain embodiments, there is provided a compound of formula (IV):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (IV) is selected from compounds 8, 9, 19, 20, 24, 26, 30, 31, 36-43, 47, 49, 55, 59, 63, 72-74, 81, 84, 94, 96, 108, and 109 in table 1.
In certain embodiments, there is provided a compound of formula (V):
Wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting ofThe group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (V) is selected from compound 71 in table 1.
In certain embodiments, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of use；L 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkylUnsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -andin certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (VI) is selected from compounds 34, 62, and 331 in table 1.
In certain embodiments, there is provided a compound of formula (VII):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (VII) is selected from compounds 60, 102, 113, 124, 136, 138, 141, 144, 154, 156, 160, 186, 214, 256, 278, and 279 in table 1.
In certain embodiments, there is provided a compound of formula (VIII):
/>
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, not takenSubstituted arylalkylenes, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -andin certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (VIII) is selected from compound 44 in table 1.
In certain embodiments, there is provided a compound of formula (IX) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =;L 1 selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl; each R 11 Is hydrogen or alkyl; each R 12 Is hydrogen or alkyl; each R 13 Is hydrogen orAn alkyl group; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (IX) is selected from compounds 27 and 28 in table 1.
In certain embodiments, there is provided a compound of formula (X):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected fromThe group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (X) is selected from compounds 4, 272, and 284 in table 1.
In certain embodiments, there is provided a compound of formula (XI):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +. >In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (XI) is selected from compounds 53, 90, 121, 142, and 143 in table 1.
In certain embodiments, there is provided a compound of formula (XII):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl groupSubstituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (XII) is compound 108 in table 1.
In certain embodiments, there is provided a compound of formula (XIII), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (XIII) is selected from compounds 88, 178 and 179 in table 1.
In certain embodiments, there is provided a compound of formula (XIV):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (XIV) is selected from the compounds in Table 185. 139 and 220.
In certain embodiments, there is provided a compound of formula (XV), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, L2 is O. In certain embodiments, the compound of formula (XV) is selected from compounds 101, 114, 118, 120, 123, 140, 146, 152, 153, 198-200, 246-249, 251-253, 264, 268-271, 285, 290, 291, 330, and 347 in Table 1.
In certain embodiments, there is provided a compound of formula (XVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, andCH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, L2 is O. In certain embodiments, R 14 Is CH 2 F or CH 2 OH. In certain embodiments, the compound of formula (XVI) is selected from compounds 99, 128, 145, 150, 155, 163, 164, 168-171, 182, 183, 189, 227, 230, 239-241, 250, 257-259, 265-267, 274-277, 280, 283, 287, 292, 295, 297, 299, 308, 316, 321, 322, 333, 335, 337, 345, 346, 352, 354, 356-358, 362-364, 366-368, 378 and 380 in Table 1.
In certain embodiments, there is provided a compound of formula (XVIa), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -, -NH-, -N (Me) -and process for preparing the sameL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azideRadicals, alkoxy radicals, haloalkoxy radicals and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、And tetrazolyl; each R 11 Is hydrogen or alkyl; each R 12 Is hydrogen or alkyl; each R 13 Is hydrogen or alkyl; r is R 14 Is hydrogen, cyano, halo, hydroxy or methyl; n is an integer from 0 to 5; m is an integer from 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, L2 is O. In certain embodiments, the compound of formula (XVI) is selected from compounds 128, 145, 168-171, 182, 183, 227, 230, 239-241, 250, 257-259, 265-267, 274-277, 280, 283, 287, 292, 295, 297, 299, 302, 308, 316, 321, 322, 333, 335-337, 344-346, 352, 354, 356-359, 362-368, 378 and 380 in Table 1.
In certain embodiments, there is provided a compound of formula (XVII) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting ofThe group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -andin certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (XVII) is selected from compound 106 in table 1.
In certain embodiments, there is provided a compound of formula (XVIII):
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (XVIII) is compound 87 in table 1.
In certain embodiments, there is provided a compound of formula (XXV), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate a single bondThe method comprises the steps of carrying out a first treatment on the surface of the When W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -, -NH-, -N (Me) -and process for preparing the sameL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> And tetrazolyl; each R 11 Is hydrogen or alkyl; each R 12 Is hydrogen or alkyl; each R 13 Is hydrogen or alkyl; r is R 14 Is hydrogen, cyano, halo, hydroxy or methyl; n is an integer from 0 to 5The method comprises the steps of carrying out a first treatment on the surface of the m is an integer from 0 to 4; o is an integer from 0 to 4; p is an integer of 0 or 1; q is an integer of 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, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -and +.>In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, the compound of formula (XXV) is compound 286 in table 1.
In certain embodiments, there is provided a compound of formula (XXVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>. In certain embodiments, L 2 Selected from the group consisting of-NH-and-N (Me) -. In certain embodiments, L2 is O. In certain embodiments, the compound of formula (XXVI) is selected from compounds 261, 262, 296, 304, 306, 307, 311, 313, 315, 325, 326, 331, 338, 340, 342, 343, 348, 353, 354, 355, 369, 374-, 376, 475-481, 483, 485, 489, 490, 492, 493, 495, 498, 504, 510, 512, 514, and 515 in table 1.
In certain embodiments, there is provided a compound of formula (XXVII) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein A is-NMe 2 or-N (CH) 3 ) Cyclohexane; l (L) 1 Is absent; w is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =; l (L) 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -,-C(H)＝,-SO 2 -, -O-, -NH-, -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, the compound of formula (XXVII) is selected from compounds 1 and 62 in table 1.
In certain embodiments, there is provided a compound of formula (XXXIX) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
Wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl (C)Group, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/>/>And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-; 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; and r is an integer from 0 to 3. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, each R 6 Independently selected from the group consisting of F and methyl. In certain embodiments, each R 6 Is F. In certain embodiments, a compound of formula (la)The compound of (XXXIX) is selected from compounds 224, 300, 303, 309, 310, 317 and 320 in table 1.
In certain embodiments, there is provided a compound of formula (XL), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-; 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; and r is an integer from 0 to 3. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, each R 6 Independently selected from the group consisting of F and methyl. In certain embodiments, each R 6 Is F. In certain embodiments, the compound of formula (XL) is selected from compounds 302, 325, 336, 344, 359, and 365 in table 1.
In certain embodiments, there is provided a compound of formula (XLI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-; 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; and r is an integer from 0 to 3. In some implementationsIn the scheme, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, each R 6 Independently selected from the group consisting of F and methyl. In certain embodiments, each R 6 Is F. In certain embodiments, each R 6 Is methyl. In certain embodiments, the compound of formula (XLI) is selected from compounds 302, 325, 336, 344, 359, 365, 478, 482, 484, 494, 496, 500-503, 505, 508, 509, and 511 in table 1.
In certain embodiments, there is provided a compound of formula (XLII) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of use L 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, quiltSubstituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -andin certain embodiments, L 2 is-O-. In certain embodiments, the compound of formula (XLII) is selected from compounds 370, 371, 373, 375, 377, 378, 486, and 513 in table 1.
In certain embodiments, there is provided a compound of formula (XLIII), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halogenRadicals, hydroxy, alkoxy radicals, R 11 R 12 NCO and R 11 R 12 N-; 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; r is an integer from 0 to 3. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, L 2 is-O-. In certain embodiments, each R 6 Independently selected from the group consisting of F and methyl. In certain embodiments, each R 6 Is F. In certain embodiments, each R 6 Is methyl. In certain embodiments, the compound of formula (XLIII) is selected from compounds 487 and 488 in table 1.
In certain embodiments, there is provided a compound of formula (XLII) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of use L 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -andin certain embodiments, L 2 is-O-. In certain embodiments, the compound of formula (XLIV) is compound 372 in table 1.
In certain embodiments, there is provided a compound of formula (XLV), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
/>
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -andin certain embodiments, L 2 is-O-. In certain embodiments, the compound of formula (XLV) is compound 379 in table 1.
In certain embodiments, there is provided a compound of formula (XLVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> 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 of 0 to 4. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -andin certain embodiments, L 2 is-O-. In certain embodiments, the compound of formula (XLVI) is selected from compounds 125 and 129 in table 1.
In certain embodiments, there is provided a compound of formula (XLI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -, -O-, -NH-; -N (Me) -and methods of useL 3 is-CH 2 -or-C (O) -; each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-; each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 heterocycloalkyl, or substituted heterocycloalkyl; r is R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/> And tetrazolyl; each R 6 Independently selected from the group consisting of: alkyl, substituted alkylHalo, hydroxy, alkoxy, R 11 R 12 NCO and R 11 R 12 N-; 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; and r is an integer from 0 to 3. In certain embodiments, L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -and +.>In certain embodiments, each R 6 Independently selected from the group consisting of F and methyl. In certain embodiments, each R 6 Is F. In certain embodiments, each R 6 Is methyl. In certain embodiments, the compound of formula (xlviii) is compound 491 in table 1.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein each R 2 And R is 3 Is H or F.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein m is 0; and o is 0.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein W is N or CH.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein W is C.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein W is CH.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein W is N.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein W is CR 14 。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 4 Selected from the group consisting of: oxetan-2-yl-methyl, (1-ethyl-1H-imidazol-5-yl) -methyl, oxolan-3-yl-methyl and 1, 3-oxazol-2-yl-methyl.
In certain embodiments, there is provided a compound of any one of formulas (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 4 Selected from the group consisting of oxetan-2-yl-methyl and (1-ethyl-1H-imidazol-5-yl) -methyl.
In certain embodiments, there is provided a compound of any one of formulas (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 4 Is oxetan-2-yl-methyl.
In certain embodiments, a method is providedA compound of any one of the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein R 4 Is (2S) -oxetan-2-yl-methyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 4 Selected from the group consisting of: (S) -butan-4-yl-1, 3-diol, butan-1-yl-one, 1- (cyanomethyl) -cyclopropan-1-yl-methyl, 1- (fluoromethyl) -cyclopropan-1-yl-methyl, 1-hydroxy-cyclopropan-1-yl-methyl, isoxazol-5-yl-methyl, (1-methyl-1H-imidazol-5-yl) -methyl, 1-methoxy-cyclopropan-1-yl-methyl, methoxyethane-2-yl, 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl and 2-oxabicyclo [ 2.1.1.1 ]]Hex-1-yl-methyl.
In certain embodiments, there is provided a compound of formula (XXX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 4 Is H.
In certain embodiments, there is provided a compound of formula (XXX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 4 Selected from the group consisting of oxacyclopentane-3-yl-methyl and 1, 3-oxazol-2-yl-methyl.
In certain embodiments, there is provided a compound of formula (XXX) and (XXXI) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein R 4 Is (3R) -oxolane-3-yl-methyl.
In certain embodiments, there is providedA compound of formula (XXX) and (XXXI) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein R 4 Is 1, 3-oxazol-2-yl-methyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 5 is-COOH or-COOMe.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 5 is-COOH.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 5 Is tetrazolyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein R 5 Is 1H-1,2,3, 4-tetrazol-5-yl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-CH 2 -, -C (O) -or-SO 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 Is a bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-or-CH (OH) -.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-ch=or-O-.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-CF 2 -, -CHF-or-CH (OH) -.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-or-N (Me) -.
In certain embodiments, there is provided a compound of formula (XXX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 2 Is a key.
In certain embodiments, there is provided a compound of formula (XXXI) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 2 is-CH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 3 is-CH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 3 is-C (O) -.
In certain embodiments, there is provided a compound of formula (XXX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 1 is-CH 2 O-or-OCH 2 -。
In certain embodiments, there is provided a compound of formula (XXXI) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 1 is-CH 2 O-or-OCH 2 。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-CH 2 O-; and L is 2 is-CH 2 -or-CO-.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-CH 2 O-; and L is 3 is-C (O) -.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and XXXI), or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 1 is-O-.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-CH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-NH-.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-N (Me) -.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-N (Et) -.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-OCH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and XXXI), or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 1 is-OC (H, me) -.
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-CH 2 O-。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-NHCH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-N (Me) CH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 1 is-SO 2 NH-。
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; and L is 3 is-CH 2 -. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX)) In certain embodiments of any of (XXXI), (XXXIX), and (XL-XLVI), L 1 is-O-; l (L) 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLICI), L 1 is-O-; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-B)-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, exampleSuch as 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIV), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In formulae (I) - (XVIII), (XXV)In certain embodiments of any of (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-NH-. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX)) And (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-CH 2 O-；L 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 Is- -NH- -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 Is- -N (Me) - -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. Some of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In some embodiments, L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl)Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XX)XIX) and (XL-xlviii), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of any of these, L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Tetrazolyl radicals, e.g.1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, a composition of formula (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI) is provided) A compound of any one of (XXXIX) and (XL-XLVIII) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-OCH 2 -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; and L is 3 is-CH 2 -. Any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of L 1 is-OCH 2 -；L 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XXX)In certain embodiments of any of (XL-XLLVII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XX)XIX) and (XL-XLIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In the formula(I) In certain embodiments of any of (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-, and L 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-, and L 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI) In the case of L 1 is-NH-; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-NH-; l (L) 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In the case of L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxygenAzetidin-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII)In certain embodiments of any of XXX), (XXXI), (XXXIX) and (XL-XLLVII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Tetrazolyl, e.g. 1H-1,2,3, 4-tetralinOxazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (X)In certain embodiments of any of XXI), (XXXIX), and (XL-XLVIII), is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereofA compound, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In the case of L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In the formulae (I) - (XVIII), (XXV)In certain embodiments of any of (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XVII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methylThe method comprises the steps of carrying out a first treatment on the surface of the And R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Tetrazolyl, e.g. 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. Certain embodiments in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)Wherein R is 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In the formulae (I) - (XV)In certain embodiments of any of III), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLIII), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-NH-. In formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of any of (2), L 1 is-N (Et) -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVI), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. Certain of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In embodiments, L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, e.g. 1H-1,2,3, 4-tetrazole-5-A base. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In the scheme, R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
Any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of L 1 is-NHCH 2 -; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In the formulas (I) - (XVIII)In certain embodiments of any of XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methylThe method comprises the steps of carrying out a first treatment on the surface of the And R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLII), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-C (H) =. In formulae (I) - (XVIII), (XXV) - (XX)In certain embodiments of any of VII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-N (Me) CH 2 -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N%Me)CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazole-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)，R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In the formulae (I) - (XVIII)) In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -, and L 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; and L is 2 is-NH-. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XXX)In certain embodiments of any of (XL-XLLVII), L 1 is-OC (H, me) -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C%H)＝；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S)-oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is thatH；R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. Any of the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of the same, L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)，R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), or pharmaceutically acceptable salts, tautomers, stereoisomers thereofIsomers and/or mixtures of stereoisomers, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-C (O) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-SO 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XVII), L 1 is-SO 2 NH-；L 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and is also provided withR 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XVII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. Certain embodiments in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)Wherein L is 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-B)-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In formulae (I) - (XVIII), (XXV) - (XX) In certain embodiments of any of VII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-X)LVII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In the formulae (I) - (XVIII), (XXV) -In certain embodiments of any of XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), or a pharmaceutically acceptable salt, tautomer, stereoisomer thereofMixtures of stereoisomers and/or stereoisomers, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX),In certain embodiments of any of (XXXI), (XXXIX) and (XL-XLVI), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. Any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments, L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 Is-C(O)-；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl.In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI)In certain embodiments of any of XXXIX) and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. Certain implementations in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII)In the scheme, L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the (I)In certain embodiments of any of (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII)，R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of either, L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (X)In certain embodiments of any of XXIX) and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVI)I) In certain embodiments of any of these, L 1 is-NH-; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. Any of the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of that, R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, a composition of formula (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XX)XIX) and (XL-xlviii) or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. Some of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In some embodiments, L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of either, L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is a tetrazolyl group, and is preferably a tetrazolyl group,such as 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), are-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propylRadical, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of any of (2), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ] ]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI),In certain embodiments of any of (XXXIX) and (XL-XLVI), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In the case of L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In the formula(I) In certain embodiments of any of (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), or a pharmaceutically acceptable salt, tautomer thereof, is providedIsomers, stereoisomers and/or mixtures of stereoisomers, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII) In the case of L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In the formulae (I) - (XV)In certain embodiments of any of III), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI)In certain embodiments of any of XXXIX) and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVI)I) In certain embodiments of any of these, R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII)) In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI)) In certain embodiments of any of (XXXIX) and (XL-XLVI), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XL)In certain embodiments of any of VII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl group}. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (X)In certain embodiments of any of XVII), (XXX), (XXXI), (XXXIX) and (XL-XLVI), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of any of (2), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. Certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII) In embodiments, R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), or pharmaceutically acceptable salts, tautomers thereofA isomer, stereoisomer and/or mixture of stereoisomers, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX)) And (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is an oxa-typeCyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulas (I) - (XVIII)In certain embodiments of any of XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (O) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-C (H) =; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-SO 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H、Cl、F、Me、-CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-CHF-. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX)And (XL-XLVIII), L 1 is-O-; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XVII), L 1 is-O-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLIII), L 1 is-O-; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-;L 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), In certain embodiments of any of (XXXIX) and (XL-XLVI), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In the formulae (I) - (XV)In certain embodiments of any of III), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and is combined withAnd R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxaCyclobutan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In the formulae (I) - (XVIII)) In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-CH 2 O-；L 2 is-CH (OH) -; and L is 3 is-CH 2 -. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLV)In certain embodiments of any of II), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. Certain implementations in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII) In the scheme, L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVI)I) In certain embodiments of any of (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. Any of the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of that, R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidine-2-Base group]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-OCH 2 -; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -; and L is 2 is-N (Me) -. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX),In certain embodiments of any of (XXXI), (XXXIX) and (XL-XLVI), L 1 is-OCH 2 -；L 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-OCH 2 -；L 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In the formulae (I) - (XVIII), (XX)In certain embodiments of any of V) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX)In certain embodiments of any of (XXXI), (XXXIX), and (XL-XLVI), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-ylA methyl group; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI)) In certain embodiments of any of (XXXIX) and (XL-XLVI), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII)In certain embodiments of any of XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a composition of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)A compound or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-, and L 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-, and L 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; and L is 3 is-CH 2 -. In the formulae (I) - (XVIII), (XXV) - (XXVII), (X)In certain embodiments of any of XX), (XXXI), (XXXIX) and (XL-XLVI), L 1 is-NH-; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)) In certain embodiments of any of these, L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. Certain embodiments in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)Wherein L is 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX)I) In certain embodiments of any of (XXXIX) and (XL-XLVI), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-N (Me) -, and L 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -, and L 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; and L is 3 is-CH 2 -. In the formulae (I) - (XVIII), (XXV) - (XXV)In certain embodiments of any of II), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In formulae (I) - (XVIII), (XXV) - (XX)In certain embodiments of any of VII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XL)In certain embodiments of any of VII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. At the position ofIn certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. Some of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In some embodiments, L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI)In certain embodiments of any of X) and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl;and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In the formulae (I) - (XV)In certain embodiments of any of III), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-N (Et) -; and L is 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-N (Et) -; l (L) 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (ME) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et)-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and is combined withAnd R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and%XL-XLLVII) in certain embodiments of any one of the following 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formula (I) - (-) -formulaIn certain embodiments of any of XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. Any of the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of one, R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XVII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In some casesIn an embodiment, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-NHCH 2 -；L 2 is-CHF-; and L is 3 is-CH 2 -. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (X)In certain embodiments of any of XX), (XXXI), (XXXIX) and (XL-XLVI), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-X)LVII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is thatH；R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-CF 2 -。In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and is also provided withR 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI),In certain embodiments of any of (XXXIX) and (XL-XLVI), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX)And (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Tetrazolyl, e.g. 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII)In certain embodiments of any of XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I (XXXIX) and (XL-XLVI),) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ] ]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; and L is 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -, and L 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -, and L 2 is-NH-. At the position ofIn certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-OC (H, me) -, and L 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. Certain of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In embodiments, L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetane-2-methyl-alkyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC(H,Me)-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxyBase-cyclopropyl-1-base-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ] ]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or stereoisomers thereofMixtures of constructs, where L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-CF 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-CHF-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-CH (OH) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-NH-. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-; and L is 2 is-N (Me) -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -; and R is 2 And R is 3 Each is H. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (2S) -oxetan-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In formulae (I) - (XVIII), (XXV)In certain embodiments of any of (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI) In certain embodiments of any of (XXXIX) and (XL-XLVI), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XX)In certain embodiments of any of X), (XXXI), (XXXIX) and (XL-XLVI), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (2S) -oxetan-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any of the paragraphs according to this paragraphIn embodiments, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In the scheme, R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each of which is a single pieceIs H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and is combined withAnd R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In the formulae (I) - (XVIII), (XXV) - (XXVI)I) In certain embodiments of any of (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (X)L-XLVIII) in certain embodiments of any one of L-XLVIII) 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In formulae (I) - (XVI)In certain embodiments of any of II), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-O-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-O-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI)In certain embodiments of any of (XXXIX) and (XL-XLVI), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a composition of formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)A compound of any one or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (X)In certain embodiments of any of XVII), (XXX), (XXXI), (XXXIX) and (XL-XLVI), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. At the position ofIn certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments of any of (2), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methylA base; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-CH 2 O-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropylA group and a cyclopropyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. Any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII) In certain embodiments of R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XX)In certain embodiments of any of XI), (XXXIX) and (XL-XLVI), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. Certain embodiments in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)Wherein L is 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (X)In certain embodiments of any of VIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-Ketones. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In the formula(I) In certain embodiments of any of (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In formulae (I) - (XVIII), (XXV)In certain embodiments of any of (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, e.g., 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 13-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NH-; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In the formulae (I) - (XVIII), (XXV)In certain embodiments of any of (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ] ]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. Certain embodiments in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII) Wherein L is 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. Some of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In some embodiments, L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In the case of L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVI)I) In certain embodiments of any of (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX)) And (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX) and (XXXI), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII) or a pharmaceutically acceptable thereof is provided Salts, tautomers, stereoisomers and/or mixtures of stereoisomers, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. Certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In embodiments, L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, exampleSuch as 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is thatH；R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Et) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In the formulae (I) - (XVIII), (X)In certain embodiments of any of XV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. Some of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII) In some embodiments, R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. Certain embodiments in any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)Wherein L is 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In the formulae (I) - (XVIII),In certain embodiments of any of (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, e.g. 1H-1,2,3, 4-tetrazole-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-NHCH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a composition of formula (I) - (XVIII), (XXV)A compound of any one of (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and is also provided withR 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. Any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments, L 1 is-N (Me) CH 2 -；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-N (Me) CH 2 -；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In the formulas (I) - (XVIII)In certain embodiments of any of XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ] ]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC%H,Me)-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. Certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In embodiments, L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methylThe method comprises the steps of carrying out a first treatment on the surface of the And R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. Any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII)In certain embodiments, L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX)And (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is a tetrazolyl group, and is preferably a tetrazolyl group,such as 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-OC (H, me) -; l (L) 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a composition of formula (I) A compound of any one of (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is oxacyclopentane-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; and R is 4 Is 1, 3-oxazol-2-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 is-COOH. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is oxacyclopentane-3-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-O-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII)，L 1 is-SO 2 NH-；L 2 is-CF 2 -；L 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CHF-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-CH (OH) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-NH-; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), L 1 is-SO 2 NH-；L 2 is-N (Me) -; l (L) 3 is-CH 2 -；R 2 And R is 3 Each is H; r is R 4 Is 1, 3-oxazol-2-yl-methyl; and R is 5 Is tetrazolyl, for example 1H-1,2,3, 4-tetrazol-5-yl. In any embodiment according to this paragraph, R 1 Can be selected from H, cl, F, me, -CF 3 、-OMe、-CN、-C(O)NMe 2 Alkyl, propyl, isopropyl and cyclopropyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3R) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (3S) -azetidin-3-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (S) -but-4-yl-1, 3-diol. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is butan-1-yl-one. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1-hydroxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is (1-methyl-1H-imidazol-5-yl) -methyl. In certain embodiments of any of formulas (XXXIX) and (XL-XLVI), (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-XLVI), R 4 Is 1-methoxy-cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is methoxyethane-2-yl. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl. In the formulae (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL)-xlviii) in certain embodiments of any one of the following 4 Is { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl ]Methyl group. In certain embodiments of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-XLVIII), R 4 Is 2-oxabicyclo [2.1.1 ]]Hex-1-yl-methyl. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-NH-. In certain embodiments, there is provided a compound of any one of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX) and (XL-xlviii), or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof, wherein L 2 is-N (Me) -.
In certain embodiments, there is provided a compound of table 1 below, or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof.
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Optically active compound
In certain embodiments, the compounds provided herein may have several chiral centers and may exist and be isolated in optically active and racemic forms. In certain embodiments, some compounds may exhibit polymorphism. Those of skill in the art will appreciate that the compounds provided herein may exist in any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, and/or mixtures thereof. Those skilled in the art will also appreciate that such compounds described herein having useful properties also described herein are within the scope of the present disclosure. Those skilled in the art will further understand how to prepare optically active forms of the compounds described herein, e.g., by resolution of the 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-, where the L-enantiomer is in a naturally occurring configuration) and may exist as individual enantiomers.
Examples of methods to obtain optically active substances are known in the art and include at least the following:
i) Physical separation crystals-a technique whereby macroscopic crystals of individual enantiomers are separated manually. This technique can be used if crystals of the individual enantiomers are present (i.e., the material is a racemic conglomerate and the crystals are visually distinct);
ii) simultaneous crystallization-a technique whereby individual enantiomers are crystallized separately from a solution of racemates, only when the racemates are solid racemate bulk;
iii) Enzymatic resolution-a technique in which partial or complete separation of racemates is achieved by means of different reaction rates of the enantiomers in the presence of enzymes;
iv) enzymatic asymmetric synthesis-a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain enantiomerically pure or enriched synthetic precursors of the desired enantiomer;
v) chemical asymmetric synthesis-a synthetic technique in which a chiral catalyst or chiral auxiliary is used to create an asymmetry (i.e., chirality) in the product to synthesize the desired enantiomer from an achiral precursor;
vi) diastereomeric separation-a technique in which a racemic compound is treated with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers to diastereomers. The diastereomers obtained are then separated by chromatography or crystallization by means of their now more pronounced diastereomeric differences, and the chiral auxiliary is then removed to obtain each enantiomer;
vii) primary and secondary asymmetric transformations-a technique in which diastereomers of the racemate are balanced in solution to produce the desired enantiomer of the diastereomer, or in which the kinetics or thermodynamic crystallization of the desired enantiomer of the diastereomer perturbs the equilibrium so that ultimately in principle all material is converted into the crystalline diastereomer of the desired enantiomer. The desired enantiomer is then derived from the diastereomer;
viii) kinetic resolution-this technique refers to effecting partial or complete resolution of the racemate (or further resolution of a partially resolved compound) by means of unequal reaction rates of enantiomers with chiral or non-racemic reagents or catalysts under kinetic conditions;
ix) enantiospecific synthesis from a non-racemic precursor-a synthesis technique in which the desired enantiomer is obtained from a chiral starting material, and in which the stereochemical integrity is not compromised or only minimally compromised during synthesis;
x) chiral liquid chromatography-a technique in which enantiomers of racemates are separated in a liquid mobile phase by means of their different interactions with a stationary phase. The stationary phase may be made of chiral material or the mobile phase may contain another chiral material to initiate different interactions;
xi) chiral gas chromatography-a technique in which racemates are volatilized and separated by means of different interactions of enantiomers in the gas mobile phase with a column containing a fixed non-racemic adsorbed phase;
xii) extraction with chiral solvents-a technique in which enantiomers are separated by means of kinetic or thermodynamic dissolution of one enantiomer into a specific chiral solvent;
xiii) transport across chiral membranes-a technique in which racemates are placed in contact with a thin film barrier. The barrier typically separates two miscible fluids (one containing racemates) and a driving force such as a concentration differential or pressure differential results in preferential transport across the membrane barrier. Separation occurs due to the non-racemic nature of the membrane, which allows only one enantiomer of the racemate to pass through.
In some embodiments, provided herein are compositions of compounds of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-xlviii), which are substantially free of a designated stereoisomer of the compound. In certain embodiments, in the methods and compounds of the present disclosure, the compounds are substantially free of other stereoisomers. In some embodiments, the composition comprises at least 85%, 90%, 95%, 98% or 99% to 100% of the compound by weight of the compound, the remainder comprising other chemicals or enantiomers. In some embodiments, provided herein are compositions of compounds of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-xlviii).
Substantially free of the designated enantiomer of the compound. In certain embodiments, in the methods and compounds of the present disclosure, the compounds are substantially free of other enantiomers. In some embodiments, the composition comprises at least 85%, 90%, 95%, 98% or 99% to 100% of the compound by weight of the compound, the remainder comprising other chemicals or enantiomers.
Isotopically enriched compounds
Also provided herein are isotopically enriched compounds, including, but not limited to, isotopically enriched compounds of any of formulas (I) - (XVIII), (XXV) - (XXVII), (XXX), (XXXI), (XXXIX), and (XL-xlviii).
Isotopically enriched (e.g., deuterated) drugs to improve pharmacokinetics ("PK"), pharmacokinetics ("PD") and/or toxicity profiles have previously been demonstrated in some classes of drugs. See, e.g., lijinsky et al, food cosnet. Toxicol.,20:393 (1982); lijinsky et al, J.Nat.cancer Inst.,69:1127 (1982); mangold et al, station Res.308:33 (1994); gordon et al, drug 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).
Isotopic enrichment of drugs can be used, for example, (1) to reduce or eliminate undesired metabolites; (2) increasing the half-life of the parent drug; (3) reducing the number of doses required to achieve the desired effect; (4) reducing the dosage necessary to achieve the desired effect; (5) Increase formation of active metabolites (if any); and/or (6) reduce the production of harmful metabolites in specific tissues. Isotopic enrichment of a drug can also be used to create a more effective and/or safer drug for use in combination therapy, whether or not the combination therapy is intended.
Replacement of an atom with one of its isotopes will typically result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, if the c—h bond breaks during the rate-determining step (i.e., the step with highest transition state energy) in a chemical reaction, substitution of the reactive hydrogen with a (heavier) isotope will result in a reduced reaction rate. Deuterium kinetic isotope effect ("DKIE") is the most common form of KIE. (see, e.g., foster et al, adv. Drug Res., volume 14, pages 1-36 (1985); kushner et al, can. J. Physiol. Pharmacol., volume 77, pages 79-88 (1999)).
The size of DKIE can be expressed as the ratio between the rate of a given reaction in which a C-H bond breaks and the rate of the same reaction in which deuterium is substituted for hydrogen and a C-D bond breaks. DKIE can range from about 1 (no isotopic effect) to a very large value, such as 50 or more (which means that when hydrogen has been replaced with deuterium, the reaction can be slowed down to 1/50 or less).
Substitution of hydrogen with tritium ("T") results in stronger bonds than deuterium and a numerically greater isotopic effect. Similarly, the method is described as follows; substitution of isotopes for other elements, including but not limited to 13 C or 14 C is substituted for carbon; by using 33 S、 34 S or 36 S is substituted for sulfur; by using 15 N is substituted for nitrogen; by using 17 O or 18 O replaces oxygen, resulting in a similar kinetic isotope effect.
The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances such as therapeutic agents from its circulatory system. Examples of such enzymes include cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases to react with and convert these foreign substances into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve oxidation of carbon-hydrogen (C-H) bonds to carbon-oxygen (C-O) 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 relative to the parent compound. For many drugs, such oxidation is rapid. Thus, these drugs typically require multiple administrations or high daily doses.
Thus, isotopic enrichment at certain positions of the compounds provided herein will result in detectable KIE, which detectable KIE will affect the pharmacological, PK, PD and/or toxicological profile of the compounds provided herein, as compared to an analogous compound having a natural isotopic composition.
Composition and use
Pharmaceutical compositions and methods of administration
The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds provided herein may be provided in the form of a suitable pharmaceutical composition and administered by a suitable route of administration.
The methods provided herein encompass the administration of a pharmaceutical composition comprising at least one compound provided herein and one or more compatible and pharmaceutically acceptable carriers. In this context, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and in certain embodiments, in humans. The term "carrier" includes diluents, adjuvants (e.g., freund's adjuvant), excipients or vehicles with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water may be used as a carrier. Saline solutions, as well as aqueous dextrose and glycerol solutions, can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, e.w., remington's Pharmaceutical Sciences.
In clinical practice, the pharmaceutical compositions or compounds provided herein may be administered by any route known in the art. Exemplary routes of administration 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.
Compositions for parenteral administration may be in the form of emulsions or sterile solutions. Parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions may also contain wetting agents, isotonic agents, emulsifying agents, dispersing agents and stabilizing agents. Sterilization may be performed in several ways, for example using a sterilizing filter, by irradiation, or by heating. Parenteral compositions can also be prepared in the form of sterile solid compositions which may be dissolved in sterile water or any other injectable sterile medium at the time of use.
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.
The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, with one of ordinary skill in the art being able to select a suitable pharmaceutical excipient. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a subject and the particular compound in the dosage form. The composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative and not limiting. Additional pharmaceutical excipients include, for example, those described in Handbook of Pharmaceutical Excipients, rowe et al (ed.) 6 th edition (2009), which is incorporated herein by reference in its entirety.
In some embodiments, the pharmaceutical composition comprises an antifoaming agent. Any suitable defoamer may be used. In some aspects, the defoamer is selected from the group consisting of alcohols, ethers, oils, waxes, silicones, surfactants, and combinations thereof. In some aspects, the defoamer is selected from the group consisting of mineral oil, vegetable oil, ethylene bis-stearamide, paraffin wax, ester wax, fatty alcohol wax, long chain fatty alcohols, fatty acid soaps, fatty acid esters, silicone glycols, fluorosilicones, polyethylene glycol-polypropylene glycol copolymers, polydimethylsiloxane-silica, ethers, octanol, 1-octanol, sorbitan trioleate, ethanol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.
In some embodiments, the pharmaceutical composition comprises a co-solvent. Illustrative examples of co-solvents include ethanol, poly (ethylene glycol), butylene glycol, dimethylacetamide, glycerol, and propylene glycol.
In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.
In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers or bulking agents include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.
In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants include d-alpha tocopherol, benzalkonium chloride (benzalkonium chloride), benzethonium chloride (benzethonium chloride), cetrimide (cetrimide), cetylpyridinium chloride (cetylpyridinium chloride), docusate sodium (docusate sodium), glyceryl behenate, glyceryl monooleate, lauric acid, polyethylene glycol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, polyoxyethylene glyceryl esters, sodium lauryl sulfate, sorbitan esters, and vitamin E poly (ethylene glycol) succinate.
In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of the anticaking agent include calcium phosphate (trivalent), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.
Other excipients that may be used with the pharmaceutical composition include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersants, dissolution enhancers, emulsifiers, gelling agents, ointment bases, permeation 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, 6 th edition (2009), the Pharmaceutical Press, which is incorporated herein by reference in its entirety.
In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is a saline solution, such as a sterile isotonic saline solution, or dextrose solution. In some aspects, the solvent is water for injection.
In some embodiments, the pharmaceutical composition is in the form of particles, such as microparticles or nanoparticles. The microparticles and nanoparticles may be formed of any suitable material such as polymers or lipids. In some aspects, the microparticle or nanoparticle is a micelle, liposome, or polymer vesicle.
Anhydrous pharmaceutical compositions and dosage forms comprising the compounds are also provided herein, as in some embodiments, water may promote degradation of some compounds.
Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous ingredients or ingredients containing low moisture, and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine may be anhydrous if substantial contact with moisture and/or humidity during manufacture, packaging and/or storage is contemplated.
Anhydrous pharmaceutical compositions can be prepared and stored such that its anhydrous nature is maintained. Thus, anhydrous compositions may be packaged using materials known to prevent exposure to water so that they may be included in a suitable prescription kit. Examples of suitable packages include, but are not limited to, sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
Lactose-free compositions provided herein can comprise excipients well known in the art and listed, for example, in the United States Pharmacopeia (USP) SP (XXI)/NF (XVI). Generally, lactose-free compositions comprise pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredients, binders/fillers, and lubricants. Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.
Pharmaceutical compositions and dosage forms comprising one or more excipients that reduce the rate at which the compound will decompose are also provided. Such excipients, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
Parenteral dosage forms
In certain embodiments, parenteral dosage forms are provided. Parenteral dosage forms can be administered to a subject by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because parenteral dosage forms are administered generally bypass the subject's natural defenses against contaminants, they are generally sterile or can be sterilized prior to administration to the subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection; preparing a dry product for dissolution or suspension in a pharmaceutically acceptable vehicle for injection; preparing a suspension for injection; an emulsion.
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 and sodium chloride Injection, and lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethanol, 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.
Excipients that increase the solubility of one or more of the antibodies disclosed herein may also be incorporated into parenteral dosage forms.
Dosage and unit dosage forms
In human therapy, the physician will determine the most appropriate dosimetry he deems to be based on prophylactic or curative treatment, as well as on age, weight, condition and other factors specific to the subject to be treated.
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.
The amount of the compound or composition that will be effective to prevent or treat the disorder or one or more symptoms thereof will vary with the nature and severity of the disease or disorder and the route by which the compound is administered. The frequency and dosage will also vary depending on the particular factors of each subject, depending on the particular therapy (e.g., therapeutic or prophylactic agent) being administered; severity of the condition, disease or disorder; route of administration; as well as the age, body, weight, response, and prior medical history of the subject. The effective dose can be extrapolated from dose-response curves obtained from in vitro or animal model test systems.
In certain embodiments, exemplary dosages of the composition include milligrams or microgram amounts of the compound per kilogram of subject or sample weight (e.g., about 10 micrograms/kilogram to about 50 milligrams/kilogram, about 100 micrograms/kilogram to about 25 milligrams/kilogram, or about 100 micrograms/kilogram to about 10 milligrams/kilogram). In certain embodiments, the dosage of a compound provided herein that is administered to prevent, treat, manage, or ameliorate a condition or one or more symptoms thereof in a subject is 0.1mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 10mg, or 15mg or more per kg body weight of the subject, based on the weight of the compound. In another embodiment, the dosage of the composition or the composition provided herein administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is 0.1mg to 200mg, 0.1mg to 100mg, 0.1mg to 50mg, 0.1mg to 25mg, 0.1mg to 20mg, 0.1mg to 15mg, 0.1mg to 10mg, 0.1mg to 7.5mg, 0.1mg to 5mg, 0.1 to 2.5mg, 0.25mg to 20mg, 0.25 to 15mg, 0.25 to 12mg, 0.25 to 10mg, 0.25mg to 7.5mg, 0.25mg to 5mg, 0.25mg to 2.5mg, 0.5mg to 20mg, 0.5 to 15mg, 0.5 to 12mg, 0.5mg to 10mg, 0.5mg to 7.5mg, 0.5mg to 5mg, 2.5mg, 1 to 15mg, 1 to 12mg, 1 to 1.5 mg or 1 to 2 mg.
The dose may be administered according to a suitable schedule, for example once, twice, three times or four times per week. In some cases, it may be necessary to use dosages of the compounds outside the scope of the disclosure herein, as will be apparent to one of ordinary skill in the art. Furthermore, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust or terminate therapy in conjunction with the subject response.
Different therapeutically effective amounts may be suitable for different diseases and conditions, as will be readily known to those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat, or ameliorate such disorders, but insufficient to cause or reduce adverse effects associated with the antibodies or antigen binding fragments thereof provided herein are also encompassed by the dosages and dosage frequency schedules described herein. Furthermore, when multiple doses of the compositions provided herein are administered to a subject, not all doses need be the same. For example, the dose administered to a subject may be increased to improve the prophylactic or therapeutic effect of the composition, or the dose may be decreased to alleviate one or more side effects that a particular subject is experiencing.
In certain embodiments, treatment or prophylaxis may begin with one or more loading doses of a compound or composition provided herein, followed by one or more maintenance doses.
In certain embodiments, a dose of a compound or composition provided herein may be administered to achieve a steady state concentration of the compound in the blood or serum of a subject. Steady state concentrations may be determined by measurement according to techniques that may be used by a skilled artisan, or may be based on physical characteristics of the subject, such as height, weight, and age.
In certain embodiments, the same composition may be repeatedly administered, and administration may be separated by at least one day, two days, three days, five days, ten days, fifteen days, thirty days, forty-five days, two months, seventy-five days, three months, or six months. In other embodiments, the same prophylactic or therapeutic agent may be repeatedly administered, and administration may be separated by at least one, two, three, five, ten, fifteen, thirty, forty-five, two months, seventy-five, three months, or six months.
Therapeutic application
For therapeutic applications, the compounds are administered to a mammal, in some embodiments a human, by intramuscular, intraperitoneal, intracerebroventricular, subcutaneous, intra-articular, intrathecal or intratumoral routes, in pharmaceutically acceptable dosages suitable for administration forms such as those known in the art and those discussed herein, in bolus form or by continuous infusion over a period of time. The compounds are also suitably administered by the peri-tumor, intra-focal or peri-focal route to exert local as well as systemic therapeutic effects. In certain embodiments, the compounds are administered to a mammal, in certain embodiments a human, in a pharmaceutically acceptable dosage suitable for oral administration forms such as those known in the art and those discussed herein. For example, the compounds of the present disclosure may be administered orally to a human in liquid form or in solid form. Solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical entity is combined 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, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin (kallin) and bentonite (bentonite clay), and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like.
The compounds provided herein are useful for treating any of the diseases or disorders (e.g., metabolic diseases or disorders) described herein. In certain embodiments, the disease or disorder is any disease or disorder that would benefit from modulating GLP-1 receptor activity. In certain embodiments, the disease or disorder is any disease or disorder 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 β -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.
In certain embodiments, the disease or condition is obesity, or one or more diseases or conditions associated with obesity. Non-limiting examples of obesity and obesity-related disorders include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat excess). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., cushing syndrome), hypothyroidism, insulinoma, obese type II diabetes, pseudo-hypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., prader-Willi syndrome), lorens-Mu En-bipeder syndrome (laurance-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, or beta-blocker induced obesity).
Examples of such diseases and conditions associated with obesity include, but are not limited to, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obesity diabetes), abnormal lipid metabolism, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including nonalcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attacks), bone or joint diseases (e.g., knee osteoarthritis, hip osteoarthritis, ankylosing spondylitis, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome (pick-wack syndrome (Pickwickian syndrome)), menstrual disorder (e.g., abnormal menstrual cycle, abnormal menstrual flow and cycle, amenorrhea, menstrual symptoms), visceral obesity syndrome, and metabolic syndrome. In certain embodiments, the compounds described herein are useful for treating subjects exhibiting symptoms of both obesity and insulin deficiency.
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, very late type 2 diabetes, long term insulin treated type 2 diabetes), diabetes (e.g., non-insulin dependent diabetes, insulin dependent diabetes), gestational diabetes, obesity diabetes, autoimmune diabetes, and borderline diabetes.
In some embodiments, the disease or condition is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of conditions associated with diabetes include obesity, obesity-related conditions, metabolic syndrome, neuropathy, kidney disease (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, reduced bone mass, hypertonic diabetic coma, infectious diseases (e.g., respiratory tract infections, urinary tract infections, gastrointestinal infections, skin soft tissue infections, lower limb infections), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral arterial disease, cerebrovascular disease, hypertension and risk factors related to unmanaged cholesterol and/or lipid levels and/or inflammation), NASH, bone fractures and cognitive dysfunction.
Other non-limiting examples of diseases or conditions associated with diabetes include pre-diabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL cholesterol, low HDL cholesterol, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic disorder in which activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired Glucose Tolerance (IGT), insulin resistance, and sarcopenia.
In some embodiments, the disease or condition is diabetes and obesity (glycogenic disease). In certain embodiments, the compounds described herein may be used to improve the therapeutic effectiveness of metformin (metaformin).
In some embodiments, the disease or condition is a condition of metabolically important tissue.
In some embodiments, the disease or condition is fatty liver disease. Fatty liver disease includes, but is not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, beta-lipoproteinemia, glycogen storage disease, weber-christmas disease (Weber-Christian disease), walman disease (Wolmans disease), gestational acute fatty liver, and lipodystrophy.
Nonalcoholic fatty liver disease (NAFLD) represents a range of diseases that occur in the absence of alcohol abuse and is generally characterized by the presence of steatosis (fat in the liver). NAFLD is thought to be associated with a variety of disorders such as metabolic syndrome (including obesity, diabetes and hypertriglyceridemia) and insulin resistance. It can lead to liver disease in adults and children, and can ultimately lead 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 relatively benign isolated steatosis, mainly macrovesicular (i.e. non-alcoholic fatty liver disease or NAFL), to non-alcoholic steatohepatitis (NASH) (Angulo et al J Gastroenterol Hepatol2002;17 journal S186-90). In certain embodiments, the subject is a pediatric subject (e.g., 6-16 years; or 6-12 years; or 6-10 years). In certain embodiments, the subject is an adult subject.
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); cholelithiasis; a gallbladder disorder; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism, such as osteoporosis (including postmenopausal osteoporosis), poor bone strength, reduced bone mass, paget's disease, osteolytic metastasis in cancer patients, osteodystrophy in liver disease, and altered bone metabolism caused by renal failure or hemodialysis, bone fractures, bone surgery, aging, pregnancy, protection against bone fractures, and dystrophic polycystic ovary syndrome; kidney disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end stage renal disease); muscular dystrophy, angina, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndrome. In certain embodiments, the chemical entities described herein may be used to treat surgical wounds by improving recovery after surgery and/or by preventing catabolic reactions resulting from the surgical wounds.
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 arterial disease, stroke, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disorders (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130/85mm Hg or more), and thrombotic states (exemplified by high fibrinogen or plasminogen activator inhibitors in the blood).
In some embodiments, the disease or disorder 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 chorea (Huntington's chores), tardive dyskinesia, hyperkinesia, mania, parkinson's Disease, steckel-Richard syndrome (steel-Richard syndrome), myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, friedrich's ataxia, acute confusion disorders, amyotrophic Lateral Sclerosis (ALS), glaucoma and apoptosis mediated central nervous system degenerative diseases (e.g., creutzfeld-Jakob Disease), and chronic bovine spongiform Disease. See, for example, US20060275288A1.
Non-limiting examples of psychotic disorders include drug dependence/addiction (narcotics, amphetamines) and attention deficit/hyperactivity disorder (ADHD). The chemical entities described herein are useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing drug abuse relapse, and alleviating anxiety resulting from the lack of a given addictive substance. See, for example, US20120021979A1.
In certain embodiments, the chemical entities described herein may be used to improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and may also be used to maintain dopamine neuronal and motor function in parkinson's disease.
In some embodiments, the disease or disorder is Impaired Fasting Glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, a hypoglycemic condition, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagon tumor, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and concomitant coma endpoint associated with insulin.
In certain embodiments, the compounds described herein can reduce or slow progression of borderline, fasting glucose damage, or impaired fasting glucose to diabetes.
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 (Graves disease). See, for example, US20120148586A1.
In some embodiments, the disease or condition is a gastric or intestinal related disorder. Non-limiting examples of such conditions include ulcers of any etiology (e.g., peptic ulcers, zollinger-Ellison syndrome), drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption, short bowel syndrome, caecum syndrome, inflammatory bowel disease (Crohn's disease) and ulcerative colitis), sprue, hypogammaglobulinemia sprue, chemotherapy and/or radiation-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal lesions (e.g., those caused by aspirin (aspirin)), small intestinal mucosal lesions and cachexia (e.g., cancerous cachexia, tuberculosis cachexia, cachexia associated with blood diseases, cachexia associated with endocrine diseases, cachexia associated with infectious diseases, cachexia caused by acquired immunodeficiency syndrome).
In some embodiments, the compounds described herein can be used to reduce body weight (e.g., over-standard body weight), 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 an excessive intake of food or meal imbalance, or may be weight gain resulting from concomitant use of a drug (e.g., an insulin sensitizer having ppary agonist-like effects, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). Alternatively, the weight gain may be the weight gain before obesity is reached, or may be the weight gain of an obese subject. Weight gain may also be drug-induced weight gain, or weight gain after cessation of smoking.
In some embodiments, the condition, disease, or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, or compulsive eating.
In some embodiments, the disease or condition is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, lumbago, gout, post-operative or post-traumatic inflammation, swelling, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation in metabolically important tissues (including liver, fat, pancreas, kidney, and intestine), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or inflammatory markers such as C-reactive protein in the blood).
In some embodiments, the disease or condition is cancer. Suitable examples of cancers include breast cancer (e.g., invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis 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 tumor (e.g., pineal astrocytoma, hairy cell astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), renal cancer (e.g., renal cell carcinoma, renal pelvis and transitional ureteral cell carcinoma), cholangiocarcinoma, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor of low malignant potential), bladder cancer, urinary tract cancer, skin cancer (e.g., intraocular (eye) melanoma, merkel cell carcinoma), hemangiomas, malignant lymphomas, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumors (e.g., osteosarcoma, ewing's tumor, uterine sarcoma, soft tissue sarcoma), vascular fibroids, retinal sarcomas, penile cancer, testicular tumors, childhood solid tumors (e.g., wilms ' tumor, childhood renal tumor), kaposi's sarcoma (Kaposi's sarcomas), AIDS-induced Kaposi's sarcoma, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).
In certain embodiments, provided herein are methods for treatment comprising administering an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the methods encompass the step of administering to a subject in need thereof an amount of a compound described herein effective for treating a disease or disorder in combination with a second agent effective for treating or preventing the disease or disorder. In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form as described elsewhere herein.
In certain embodiments, the subject is a untreated subject. In other embodiments, the subject has previously received therapy. For example, in certain embodiments, the subject has not responded to a single dose treatment regimen.
In certain embodiments, the subject is a subject who has stopped some other therapy because of one or more adverse events associated with the other therapy. In certain embodiments, the subject has received some other therapy and stopped the therapy prior to administration of the methods provided herein. In other embodiments, the subject has received therapy and continues to receive the therapy and administration of the compounds provided herein. The compounds described herein may be co-administered with other therapies for treating a disease or disorder at the discretion of the skilled artisan. In certain embodiments, the methods or compositions provided herein may be co-administered with a reduced dose of other therapies for treating a disease or disorder.
Diagnostic applications
In some embodiments, the compounds provided herein are used in diagnostic applications. These applications may be used, for example, to diagnose and/or prognose a disease or disorder, such as a metabolic disease or disorder.
In some diagnostic and prognostic applications or embodiments, the compounds can 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 can be detected using a labeled antibody or antigen-binding fragment thereof that specifically binds to the compound.
Kit for detecting a substance in a sample
In some embodiments, the compounds provided herein are provided in the form of a kit (i.e., a packaged combination of a predetermined amount of reagents with instructions for performing a procedure). In some embodiments, the procedure is a diagnostic assay. In certain embodiments, the procedure is a therapeutic procedure.
In some embodiments, the kit further comprises a solvent for the reconstituted compound. In some embodiments, the compounds are provided in the form of pharmaceutical compositions.
In some embodiments, the kit may include a compound or composition provided herein, an optional second agent or composition, and instructions to provide the health care provider with information regarding the use of treating the 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 in the form of a web site address where such instructions are available. A unit dose of a compound or composition or a second dose or composition provided herein may include a dose that, when administered to a subject, allows for maintenance of a therapeutically or prophylactically effective plasma level of the compound or composition in the subject for at least one day. In some embodiments, the compounds or compositions may be included in the form of sterile aqueous pharmaceutical compositions or dry powder (e.g., lyophilized) compositions.
In some embodiments, suitable packages are provided. As used herein, "package" includes solid matrices or materials that are generally used in systems and are capable of containing within fixed limits the compounds provided herein and/or a second agent suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, papers, plastics, plastic-foil laminate envelopes, and the like. If electron beam sterilization techniques are used, the package should have a density low enough to allow sterilization of the contents.
Preparation and Synthesis procedures
In some embodiments, the compounds described herein are prepared as outlined in schemes 1-7. The synthesis of the compounds of the present application is not limited to these general reaction schemes described herein. For a detailed synthesis of each individual compound, please see the examples section.
Scheme 1
Scheme 1. The compounds having formula 1h' can be prepared as shown in scheme 1. The amine may be reacted with a fluoro, nitro substituted aryl or heteroaryl compound by a SNAr reaction to provide 1b'. The nitro group in 1b' will be reduced to an amino group by hydrogenation. The reaction of 1c 'with 2-chloro-1, 1-trimethoxyethane or chloroacetic anhydride will form 1d'. Alkylation of 1d 'with tert-butyl piperazine-1-carboxylate will provide 1e', where the Boc protecting group can be removed by TFA or HCl. The resulting piperazine 1f ' can be coupled with a carboxylic acid to form 1g ', which can be deprotected to give 1h '.
Scheme 2
Scheme 2 alternatively, compound 1i '(an analogue of 1 h') can be synthesized by a direct coupling reaction of acid-containing piperazine 2b 'with carboxylic acid 2 a'.
Scheme 3
Scheme 3. Some alternative carboxylic acids 3a' contain a 5 membered heteroaryl ring. They can be coupled with 1f ' to provide compound 3b ', which can be hydrolyzed to provide 3c '.
Scheme 4
Scheme 4. Compound 4a 'can be prepared from the halide and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate by a Suzuki reaction, which upon hydrogenation will yield Compound 4b'. The reduced ester group will form alcohol 4c ', which can be used to prepare compound 4d' by a Mitsunobu reaction. Alternatively, 4c 'may be converted to bromide and reacted with phenol by alkylation reaction to form 4d'. After deprotection of the Boc group, 4e ' may be alkylated to yield 4f ' and hydrolyzed to provide 4g '.
Scheme 5
Scheme 5. Hydrazine 5a 'can be reacted with tert-butyl 4-oxopiperidine-1-carboxylate by Fischer (Fischer) indole synthesis to form carboline 5b', which can be alkylated with 1d 'to yield 5c'. Compound 5d 'may be prepared by hydrolysis of 5c'.
Scheme 6
Scheme 7
Schemes 6 and 7. Coupling of piperidine or piperazine 6a ' with various carboxylic acids will result in compounds 6b ' or 7b '.
Scheme 8
Scheme 8 (B) 1 、B 2 、B 3 And B 4 One, or both of zero, one, or both are N, and the remainder are CH). Alcohol 8a ' can be used to synthesize 8b ' by a photolithographical reaction with an alcohol (e.g., phenol), or converted to a mesylate followed by alkylation with a phenol, or coupled with an aryl halide by a Buchwald reaction to form 8b '. Reduction of the ester group in 8b 'may provide alcohol 8c'. Followed by a photolithographical reaction with phenol, or formation of the mesylate of 8c 'followed by alkylation with phenol, can provide 8d'. Deprotection of the Boc group with TFA followed by 1h coupling and hydrolysis may provide 8e'.
Scheme 9
Scheme 9.9a 'can be synthesized from 8a' by alkylation. Palladium catalyzed carbonylation will provide an ester 9b 'which can be reduced to provide an alcohol 9c'. The methanesulfonylation to form alcohol 9c 'followed by alkylation with phenol may provide 9d'. Deprotection of the Boc group with TFA followed by coupling for 1h and hydrolysis afforded 9e'.
Examples
Preparation of the Compounds
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 from compounds described in the chemical literature. "commercially available chemicals" are obtained from standard commercial sources such as Acros Organics (Pittsburgh, pa.), advanced ChemBlocks, inc (Burlingame, calif.), aldrich Chemical (Milwaukee, wis, including Sigma Chemical and Fluka), AK Scientific (Union City, calif.), astaTech, inc. (Bristol, pa.), aurum Pharmatech LLC (Franklin Park, NJ), combi-Blocks, inc. (San Diego, calif.), enamine (Monmouth JC., NJ), fisher Scientific Co. (Pittsburgh, pa.), frontier Scientific (Logan, UT), TCI American (Portland, OR) and VWR (Radnor, pa.). Specific and similar reactants are optionally determined by known chemical indices from the chemical abstracts service of the american society of chemistry, which are available in most public libraries and university libraries, as well as through online databases.
Suitable references detailing the synthesis of reactants useful in preparing the compounds described herein, or providing a reference 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," 2 nd edition, academic Press, new York,1983; "T.L. Gilchrist," Heterocyclic Chemistry ", 2 nd edition, john Wiley & Sons, new York,1992; march, "Advanced Organic Chemistry:reactions, mechanisms and Structure", 4 th edition, wiley-Interscience, new York,1992; larock "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2 nd edition (1999) Wiley-VCH, ISBN:0-471-19031-4; "Organic Reactions" (1942-2000) John Wiley & Sons, in volumes above 55; and "Chemistry of Functional Groups" John Wiley & Sons, volume 73. Some compounds require the use of protecting groups. The need for such protection is within the skill in the art. For a general description of protecting groups and their use, see t.w. greene and p.g. m. nuts, protective Groups in Organic Synthesis, john Wiley & Sons, new York,1999.
Analytical method and apparatus
Proton Nuclear Magnetic Resonance (NMR) spectra were obtained on Bruker or Varian spectrometers at 400 or 600 MHz. NMR spectra are reported below with respect to residual solvent signal: chemical shift δ (ppm), multiplicity, coupling constant J (Hz), and integration. Tetramethylsilane (TMS) was used as an internal standard in some cases. Mass spectrometry data was measured using one of two systems: system a: a Waters Acquity i-like ultra-high 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 collected using Waters MassLynx 4.1 software and purity was characterized by UV wavelength 220nm, evaporative Light Scattering Detection (ELSD) and electrospray positive ions (ESI) (column Acquity UPLC BEH C18.7 μ iota 2.1×50 mm). System B: agilent LC/MS (column: agilent USGYL01131, HPH-C18.7. Mu.M, 2.1X150 mm) consisting of 1200 series LC and 6140 quadrupole MS detector. The solvent used: acetonitrile/water containing 0.1% formic acid; the flow rate was 0.7mL/min. Preparative HPLC purification was performed with a flow rate of 15mL/min and UV wavelength detection of 214nm and 254nm (column:10μM Proteo/>250X 21.2mm A, dissolvingThe preparation method comprises the following steps: acetonitrile/water, containing modifiers such as 0.1% trifluoroacetic acid, formic acid or acetic acid). Compound purity (Acquity BEH C18, 50 x 2.1mm column) was checked on analytical HPLC (class Waters Acquity UPLC H instrument) at a flow rate of 0.5 mL/min.
Abbreviations used in the examples include:
/>
unless otherwise indicated, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware are used for synthetic transformations that are sensitive to moisture and/or oxygen. The reaction time and yield were not optimized. The example numbers and compound numbers are identical.
EXAMPLE 1 (S) -2- ((4- (6- (dimethylamino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (1)
Step a. (S) -2- ((benzyloxy) methyl) oxetane (1 a)
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℃for 30min, followed by the addition of (2S) -2- [ (phenylmethyloxy) methyl]Oxiranes (5 g,30.4 mmol). The mixture was heated at 80℃for 2h. After completion, the mixture was cooled to 25 ℃ and filtered through celite. The filter cake was washed with petroleum ether (10 mL). Water (20 mL) was added to the filtrate, and petroleum ether (10 mL) was usedX 2) extraction. The combined organic layers were treated with saturated NH 4 Cl (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a crude residue that was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title product (1 a) (2.5 g, 47%) as a yellow oil. m/z (ESI, positive ion) =201.1 [ m+na ] ] + 。
(S) -oxetan-2-ylmethanol (1 b)
To a solution of 1a (7 g,39.3 mmol) in THF (90 mL) was added Pd (OH) 2 (700 mg,3.93 mmol). At 45℃under 0.4MPa H 2 The reaction mixture was stirred for 48h. After completion, the reaction was filtered through celite, and the resulting crude mixture (1 b) in THF was advanced to the next step without further purification. m/z (ESI, positive ion) =111.1 [ m+na ]] + 。
(S) -oxetan-2-ylmethyl methanesulfonate (1 c)
To a solution of 1b (6 g,68 mmol) in THF (100 mL) at 0deg.C was added methanesulfonic anhydride (17.1 g,102 mmol) and Triethylamine (TEA) (13.6 g,136.5 mmol). The reaction mixture was stirred at 20℃for 2h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title product (1 c) as a yellow oil (6 g, 53.1%). m/z (ESI, positive ion) =167.1 [ m+h ]] + 。
Step D. (S) -2- (azidomethyl) oxetane (1 d)
To a solution of 1c (6 g,36.1 mmol) in DMF (100 mL) was added NaN 3 (7.02 g,108 mmol). The reaction mixture was stirred at 80℃for 16h. Water (20 mL) was added to the reaction, and extracted with EtOAc (20 mL. Times.2). Using H for the organic layer 2 O (10 mL) was washed, dried, and concentrated to afford the crude title product (1 d), which was advanced to the next step without further purification. m/z (ESI, positive ion) =114.1 [ M+H ]] + 。
Step E. (S) -oxetan-2-ylmethylamine (1 e)
To a solution of 1d (900 mg,7.96 mmol) in THF (30 mL) was added 10% Pd/C (10 mg). The reaction mixture was stirred under hydrogen at 20 ℃ for 2h. After completion, the crude reaction mixture was filtered through celite. The filtrate (1 e) was used in the next step without further purification. m/z (ESI, positive ion) =88.2 [ M+H ]] + 。
Step F. (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester (1 f)
To a solution of 1e (700 mg,10.5 mmol) in THF (3 mL) were 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℃for 16h, followed by the addition of water (15 mL). The solution was extracted with EtOAc (10 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title product (1 f) (1.2 g, 43.9%) as a yellow solid. m/z (ESI, positive ion) =267.1 [ m+h ]] + 。
Step G methyl (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoate (1 g)
To a solution of 1f (800 mg,7.9 mmol) in THF (8 mL) was added 10% Pd/C (100 mg). At 20℃at 50psi H 2 The reaction mixture was stirred for 3h. After completion, the crude mixture was filtered through celite, and the filtrate was concentrated to give the title product (1 g) as a yellow solid (0.6 g, 43.9%). m/z (ESI, positive ion) =237.2 [ m+h ]] + 。
(S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (1H)
To 1g (700 mg,2.96 mmol) of the catalyst in CH 3 To a solution of CN (10 mL) was added 2-chloro-1, 1-trimethoxyethane (458 mg,2.96 mmol) and 4-methyl-benzenesulfonic acid (25 mg,0.14 mmol). The reaction mixture was stirred at 60℃for 2h. The residue was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title product (1 h) as a yellow solid (0.6 g, 68.9%). m/z (ESI, positive ion) =295.1 [ m+h ]] + 。
Step I. (S) -2- ((4- (tert-Butoxycarbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (1 i)
To a solution of 1h (30 mg,0.10 mmol) in DMF (2 mL) was added piperazine-1-carboxylic acid tert-butyl ester (18.9 mg,0.10 mmol) and K 2 CO 3 (22 mg,0.15 mmol). The reaction mixture was stirred at 25℃for 16h. After completion, the mixture was quenched with water (20 mL), extracted with EtOAc (20 ml×3), and washed with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (gradient elution, 0-50% etoac/petroleum ether) to afford the title as a yellow solid The title product (1 i) (20 mg, 44.4%). m/z (ESI, positive ion) =445.1 [ m+h ]] + 。
(S) -1- (oxetan-2-ylmethyl) -2- (piperazin-1-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (1 j)
To a solution of 1i (30 mg,0.067 mmol) in DCM (2 mL) was added ZnBr 2 (60.8 mg,0.27 mmol). The reaction mixture was stirred at 25℃for 12h. After completion, the residue was purified by reverse phase HPLC (gradient elution, 0-30% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (1 j) (15 mg, 65%) as a white solid. m/z (ESI, positive ion) =345.3 [ m+h ]] + 。
Step K.6- (dimethylamino) pyrimidine-4-carboxylic acid methyl ester (1 k)
A mixture of methyl 6-chloropyrimidine-4-carboxylate (500 mg,2.28 mmol), dimethylamine (390 mg,8.69 mmol) and N, N-diisopropylethylamine (1123 mg,8.69 mmol) in THF (30 mL) was stirred at 25℃for 2h. Will react with H 2 O (10 mL), saturated NaHCO 3 (10 mL) solution quenched and then extracted with DCM (150 mL. Times.3). The organic layers were combined, dried, and concentrated to afford the crude title product (1 k) (1.06 g) as a yellow solid, which was used directly in the next step without further purification. m/z (ESI, positive ion) =182.0 [ m+h ]] + 。
Step L.6- (dimethylamino) pyrimidine-4-carboxylic acid (1 l)
1k (1.0 g,5.51 mmol) and sodium hydroxide (1.1 g,27.6 mmol) were combined in MeOH: H at 25 ℃ 2 The mixture in o=10:1 (20 mL) was stirred for 2h. ThenThe reaction was extracted with EtOAc (150 mL. Times.3). The organic layers were combined, taken over Na 2 SO 4 Dried, and concentrated to give a crude residue, which was purified by reverse phase HPLC to give the title product (1 l) as a white solid (346 mg, 37.5%). m/z (ESI, positive ion) =168.0 [ m+h ]] + 。
Step m. (S) -2- ((4- (6- (dimethylamino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (1 m)
A mixture of 1l (58 mg,0.35 mmol), 1j (60 mg,0.17 mmol), 1-hydroxybenzotriazole (30 mg,0.23 mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (40 mg,0.21 mmol) and N, N-diisopropylethylamine (112 mg,0.87 mmol) was dissolved in DCM (10 mL) and stirred at 25℃for 18h. The reaction mixture was then diluted with DCM (50 mL) and with NaHCO 3 Aqueous (100 mL. Times.3) washing. The organic layer was dried, filtered, and concentrated to give a crude residue, which was purified by preparative TLC (silica gel, etOAc: petroleum ether=1:4) to afford the title product (1 m) as a yellow solid (40 mg, 66.7%). m/z (ESI, positive ion) =494.3 [ m+h ] ] + 。
Step n. (S) -2- ((4- (6- (dimethylamino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (1)
1m (35 mg,0.07 mmol) and 1,5, 7-triazabicyclo [4.4.0 ] at 50deg.C]Dec-5-ene (TBD) (77 mg,0.24 mmol) in CH 3 CN:H 2 The mixture in o=1:1 (20 mL) was stirred for 2h. The reaction mixture was then extracted with ethyl acetate (150 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, and concentrated. The crude residue was purified by reverse phase HPLC to give the title as a white solidThe title product (1) (15 mg, 34.2%). 1 HNMR(400MHz,CDCl 3 ) Delta ppm 8.57 (s, 1H), 8.20 (br s, 1H), 7.97-8.10 (m, 1H), 7.71-7.89 (m, 1H), 6.71 (s, 1H), 5.21 (br s, 1H), 4.47-4.74 (m, 3H), 4.24-4.46 (m, 1H), 4.03 (br d, j=6.14 hz, 2H), 3.79 (br s, 2H), 3.58 (br s, 2H), 3.14 (br s, 6H), 2.59-2.73 (m, 2H), 2.57 (br s, 2H), 2.34-2.50 (m, 2H). m/z (ESI, positive ion) =480.2 [ M+H ]] + 。
EXAMPLE 2 (S) -2- ((4- (3- (2-chloro-4- (trifluoromethyl) phenoxy) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (2)
(S) -1- (oxetan-2-ylmethyl) -2- (piperazin-1-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (2 a)
To 1j (30 mg,0.087 mmol) in CH 3 CN (1 mL) and H 2 1,5, 7-Triazabicyclo [4.4.0 ] is added to a solution in O (1 mL)]Dec-5-ene (24.4 mg,0.17 mmol). The reaction mixture was stirred at 45℃for 2h. After completion, the reaction was adjusted to ph=2 by 10% citric acid. The mixture was concentrated and purified by reverse phase HPLC (CH 3 CN and H 2 O,0.5% formic acid as modifier) to afford the title product (2 a) (15 mg, 52%) as a white solid. m/z (ESI, positive ion) =331.3 [ m+h ]] + 。
Step B. (S) -2- ((4- (3- (2-chloro-4- (trifluoromethyl) phenoxy) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (2)
3- (2-chloro-4-trifluoromethylphenoxy) benzoic acid (4.7 mg,0.015 mmol) was reacted withHATU (4.6 mg,0.012 mmol) and DIPEA (2.0 mg,0.02 mmol) were mixed in DMF (0.3 mL) for 10min. 2a (3.3 mg,0.01 mmol) was then added to the mixture and the reaction was stirred for 5min. The crude mixture was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to give the title product (2) (1.2 mg, 17.4%) as a white powder. 1 H NMR(600MHz,CD 3 OD) delta ppm 8.31 (s, 1H), 7.96 (dd, j=8.44, 1.47hz, 1H), 7.87 (br d, j=2.20 hz, 1H), 7.66 (d, j=8.80 hz, 1H), 7.62 (br dd, j=8.44, 1.83hz, 1H), 7.52 (br t, j=7.89 hz, 1H), 7.26 (br d, j=7.70 hz, 1H), 7.18 (d, j=8.44 hz, 1H), 7.14 (dd, j=8.07, 1.83hz, 1H), 7.06-7.09 (m, 1H), 5.25 (qd, j=7.34, 2.57hz, 1H), 4.86-4.87 (m, 1H), 4.68-4.73 (m, 1H), 4.63 (dd, j=7.89 hz, 1H), 7.74 (br 3.37 hz), 7.14 (dd, j=8.47 hz, 1H), 7.14 (dd, j=8.57 hz, 1H), 7.06-7.09 (m, 1H), 5.25 (qd, j=7.34, 2.57hz, 1H), 4.86-4.87 (m, 1H), 4.68-4.73 (m, 1H), 4.63 (br d, 3.37 hz), 3.37 (j=3.37 hz, 3.37H), 3.37 (m, 1H), 3.37.37H). m/z (ESI, positive ion) =629.3 [ M+H ] ] + 。
The example compounds 3-7, 13, 21, 22 and 70 were synthesized as described in example 2.
EXAMPLE 10 (S) -2- ((4- (3- (4-cyano-2-fluorophenoxy) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (10)
Step A.3- (4-cyano-2-fluorophenoxy) benzoic acid methyl ester (10 a)
The flask was charged with methyl 3-hydroxybenzoate (17 mg,0.11 mmol) and DMF (1 mL) followed by sodium hydride (60%, 4.4mg,0.11mmol in mineral oil). The reaction was stirred at room temperature for 30 minutes. 4-bromo-3-fluorobenzonitrile (20 mg,0.1 mmol) and CuBr (2.2 mg,0.01 mmol) were then added and the resulting mixture was heated to 100℃overnight. The crude mixture was purified by reverse phase HPLC (CH 3 CN and water, utensilPurification with 0.1% TFA as modifier) yielded the title product (10 a) (1.6 mg, 5.9%) as a white solid. m/z (ESI, positive ion) =272.1 [ m+h ]] + 。
Step B.3- (4-cyano-2-fluorophenoxy) benzoic acid (10 b)
LiOH (2.9 mg,0.12 mmol) was added to a solution of 10a (1.6 mg, 0.006mmol) in THF: water (5:1) (1.2 mL) and stirred at room temperature for 5.5h. The crude mixture was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% TFA as modifier) to give the title product (10 b) as a white solid (0.8 mg, 53.3%). m/z (ESI, positive ion) =258.2 [ m+h ] ] + 。
Step C. (S) -2- ((4- (3- (4-cyano-2-fluorophenoxy) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (10)
The title compound was prepared from 10B by a procedure similar to that described in example 2, step B. m/z (ESI, positive ion) =570.2 [ m+h ]] + 。
The example compounds 11 and 12 were synthesized as described in example 10.
EXAMPLE 14 (S) -1- (oxetan-2-ylmethyl) -2- ((4- (3- (o-tolyloxy) benzoyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (14)
Step A.3- (O-tolyloxy) benzoic acid methyl ester (14 a)
O-cresol (10.8 mg,0.1 mmol), (3- (methoxycarbonyl) phenyl) boronic acid (36 mg,0.2 mmol), cu (OAc) 2 (36.3 mg,0.2 mmol) and molecular sieves were combined in anhydrous DCM (4 mL). Addition of Et 3 N (20.2 mg,0.2 mmol) and the mixture was stirred overnight. The solvent was then removed in vacuo and the residue was purified by reverse phase HPLC (CH 3 CN and water with 0.1% TFA as modifier) to afford the title product (14 a). m/z (ESI, positive ion) =243.1 [ m+h ]] + 。
Step B.3- (O-tolyloxy) benzoic acid (14 b)
The title compound 14B was prepared from 14a by a procedure similar to that described in example 10, step B.
Step C. (S) -1- (oxetan-2-ylmethyl) -2- ((4- (3- (o-tolyloxy) benzoyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (14)
The title compound was prepared from 14B by a procedure similar to that described in example 2, step B. 1 H NMR(600MHz,CD 3 OD) delta ppm 8.30 (s, 1H), 7.96 (br d, J=8.44 Hz, 1H), 7.65 (d, J=8.80 Hz, 1H), 7.40 (t, J=7.89 Hz, 1H), 7.30 (br d, J=7.34 Hz, 1H), 7.21 (br t, J=7.52 Hz, 1H), 7.10-7.16 (m, 1H), 7.08 (d, J=7.34 Hz, 1H), 6.95-7.00 (m, 1H), 6.93 (d, J=8.07 Hz, 1H), 6.81-6.88 (m, 1H), 5.24 (qd, J=7.15, 2.75Hz, 1H), 4.86-4.87 (m, 1H), 4.67-4.73 (m, 1H), 4.59-4.67 (m, 1H), 4.44 (d, 3.48 Hz, 1H), 6.3.33 (m, 1H), 6.75 Hz, 3.32 (2H), 3.48-7.9 Hz, 1H), 3.32 (3.48 Hz, 1H), 3.32 (2.48 Hz, 1H), 3.32 (3.48 Hz, 1H). m/z (ESI, positive ion) =541.4 [ m+h ]] + 。
The example compounds 15, 16, 17, 18, 23 and 57 were synthesized as described in example 14.
EXAMPLE 19 (S) -2- ((4- (5- ((3-chloro-2-methylphenoxy) methyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (19)
Step A.5- ((3-chloro-2-methylphenoxy) methyl) furan-2-carboxylic acid ethyl ester (19 a)
The flask was filled with ethyl 5- (chloromethyl) furan-2-carboxylate (18 mg,0.1 mmol), ethyl 5- (chloromethyl) furan-2-carboxylate (16 mg,0.12 mmol), K 2 CO 3 (32 mg,0.24 mmol) and DMF (1 mL). The suspension was stirred overnight and purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to afford the title product (19 a) (28 mg, 98%) as a white solid. m/z (ESI, positive ion) =295.0 [ m+h ]] + 。
Step B.5- ((3-chloro-2-methylphenoxy) methyl) furan-2-carboxylic acid (19 b)
The title compound was prepared from 19a by a procedure similar to that described in example 59 step C.
Step C. (S) -2- ((4- (5- ((3-chloro-2-methylphenoxy) methyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (19)
The title compound was prepared from 19B by a procedure similar to that described in example 2, step B. 1 H NMR(600MHz,CD 3 OD) δppm 8.26 (s, 1H), 7.97 (dd, j=8.44, 1.10hz, 1H), 7.64 (d, j=8.44 hz, 1H), 7.08-7.13 (m, 1H), 6.97-7.04 (m, 2H), 6.94 (d, j=8.07 hz, 1H), 6.62 (d, j=3.30 hz, 1H), 5.26 (qd, j=7.15, 2.75hz, 1H), 5.14 (s, 2H), 4.86-4.89 (m, 1H), 4.69-4.75 (m, 1H), 4.63 (td, j=7.89, 5.87hz, 1H), 4.45 (dt, j=9.17, 5.87hz, 1H), 4.03 (d, j=13.57 hz, 1H), 3.95 (d, j=13.57 hz, 1H), 5.86-4.89 (m, 1H), 4.69-4.75 (s, 2H), 4.64.7 (m, 1H). m/z (ESI, positive ion) =579.2 [ m+h ] ] + 。
Compounds 24, 26, 30, 31, 41, 42, 43, 47, 49, 55, 64-69, 71 and 81 of the examples were synthesized analogously to those described in example 19.
EXAMPLE 20 (S) -1- (oxetan-2-ylmethyl) -2- ((4- ((5- (phenoxymethyl) furan-2-yl) methyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (20)
Step A.5- (phenoxymethyl) furan-2-carbaldehyde (20 a)
The title compound was prepared from phenol and 5- (chloromethyl) furan-2-carbaldehyde by a procedure analogous to the procedure described in step a of example 19.
Step B. (S) -1- (oxetan-2-ylmethyl) -2- ((4- ((5- (phenoxymethyl) furan-2-yl) methyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (20)
To a solution of 5- (phenoxymethyl) furan-2-carbaldehyde (2.0 mg,0.01 mmol) and 2a (1.7 mg,0.005 mmol) in methoxyethanol (1 mL) was added 5-ethyl-2-methylpyridine borane (1.1. Mu.L, 0.0075 mmol) and HOAc (0.4. Mu.L, 0.0075 mmol). The mixture was stirred at 60 ℃ overnight, and thenAnd (5) cooling. The crude reaction mixture was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to afford the title product (20) (2.4 mg, 75%) as a white solid. 1 H NMR(600MHz,CD 3 OD) delta ppm8.27-8.35 (m, 1H), 7.96 (dd, j=8.44, 1.47hz, 1H), 7.66 (d, j=8.44 hz, 1H), 7.20-7.26 (m, 2H), 6.93-6.98 (m, 2H), 6.87-6.91 (m, 1H), 6.45 (br d, j=2.93 hz, 1H), 6.36 (br s, 1H), 5.21 (qd, j=7.21, 2.57hz, 1H), 5.01 (s, 1H), 4.78-4.82 (m, 2H), 4.66 (br dd, j=15.41, 2.57hz, 1H), 4.61 (td, j=7.89, 5.87hz, 1H), 4.43 (m, 1H), 6.45 (br s, 1H), 4.01 (bd, j=7.21, 2.57hz, 1H), 5.01 (br, 1H), 4.78-4.72 (dd, 2.72H), 4.72.72 (dd, 1H), 3.7.7.21, 2.57hz, 1H), 4.78-4.7.72 (dd, 1H). m/z (ESI, positive ion) =517.2 [ m+h ] ] + 。
Example compounds 8, 9, 35 and 63 were synthesized as described in example 20.
EXAMPLE 27 (S) -2- ((4- ((6- (2, 4-dichlorophenyl) benzofuran-2-yl) methyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (27)
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Step A.6- (2, 4-dichlorophenyl) benzofuran-2-carboxylic acid ethyl ester (27 a)
Under nitrogen atmosphere, the [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) chloride complex with dichloromethane (1:1) (1.52 g,1.8 mmol), (2, 4-dichlorophenyl) boronic acid (2.13 g,11.1 mmol) and ethyl 6-bromo-1-benzofuran-2-carboxylate (2.5 g,9.3 mmol) were added to 1, 4-dioxane (24 mL), K 2 CO 3 (3.86 g,27.8 mmol) and water (12 mL). The reaction was heated to 80 ℃, stirred for one hour, and quenched with water (50 mL). The mixture was extracted with dichloromethane (50 mL, ×2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, and concentrated. Passing the crude residue throughSilica gel column chromatography (n-pentane: etoac=95:5) afforded the title product (27 a) (1.5 g, 43%) as a white solid. m/z (ESI, positive ion) =357.0 [ m+na ]] + 。
Step B. (6- (2, 4-dichlorophenyl) benzofuran-2-yl) methanol (27 b)
Bottling with LiAlH 4 (0.2 g,5.1 mmol) and THF (30 mL). 27a (1.5 g,4.7 mmol) in 10mL THF was then added dropwise at 20deg.C. The reaction mixture was stirred at 70 ℃ for 3h, then quenched by slow addition of ethyl acetate (5 mL) at 0 ℃. After removal of the solvent, the crude residue was diluted with water (40 mL) and extracted with ethyl acetate (40 ml×3). The organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (gradient elution, etOAc/petroleum ether, 0-20%) to afford the title product (27 b) as a white solid (386.1 mg, 27.8%). m/z (ESI, positive ion) =275.0 [ M-OH ] + 。
Step C.2- (bromomethyl) -6- (2, 4-dichlorophenyl) benzofuran (27 c)
To a stirred solution of 27b (50 mg,0.15 mmol) in dichloromethane (1.5 mL) was added phosphorus tribromide (73 mg,0.27 mmol). The mixture was stirred at 0deg.C for one hour and saturated NaHCO 3 The aqueous solution (2 mL) was diluted. The reaction mixture was then extracted with DCM (3 ml×3) and washed with brine (3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution, etOAc/petroleum ether, 0-10%) to afford the title product (27 c) as a yellow oil (53 mg, 81.6%).
Step d. (S) -2- ((4- ((6- (2, 4-dichlorophenyl) benzofuran-2-yl) methyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (27 d)
27c (20 mg,0.056 mmol) was added to a solution of 1j (19 mg,0.056 mmol) and potassium carbonate (31 mg,0.225 mmol) in DMF (0.5 ml) and stirred for 24h. The reaction was then diluted with water (2 mL) and extracted with EtOAc (2 ml×2). The organic phase was washed with saturated sodium bicarbonate solution (2 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (gradient elution, meOH/dichloromethane, 0-20%) to afford the title product (27 d) as a yellow oil (17 mg, 44.0%). m/z (ESI, positive ion) =619.2 [ m+h ] ] + 。
Step E. (S) -2- ((4- ((6- (2, 4-dichlorophenyl) benzofuran-2-yl) methyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (27)
To a mixture of 27d (17 mg,0.028 mmol) in acetonitrile (0.5 mL) and water (0.5 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a ]]Pyrimidine (8 mg,0.056 mmol). The reaction was stirred at 20℃for 16h. The mixture was concentrated and purified by reverse phase HPLC (CH 3 CN and H 2 O, with 0.05% NH 4 HCO 3 As modifier, gradient elution, 0-80%) to afford the title product 27 (3.3 mg, 18.6%) as a white solid. 1 H NMR(400MHz,CDCl 3 ) Delta ppm 8.18 (s, 1H), 8.01 (d, j=8.5 hz, 1H), 7.78 (d, j=8.4 hz, 1H), 7.56 (d, j=8.0 hz, 1H), 7.51 (d, j=5.5 hz, 2H), 7.31 (s, 2H), 7.25 (s, 1H), 6.64 (s, 1H), 5.23-5.16 (m, 1H), 4.72-4.57 (m, 3H), 4.39-4.34 (m, 1H), 3.98 (s, 2H), 3.75 (s, 2H), 2.78-2.58 (m, 8H), 2.48-2.37 (m, 2H). m/z (ESI, positive ion) =605.1 [ m+h ]] + 。
Compound 28 of the example was synthesized as described in example 27.
EXAMPLE 32 (S) -2- ((4- (3- (2-chloro-4-methylbenzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (32)
The title compound was prepared from methyl 3- (bromomethyl) benzoate and (2-chloro-4-methylphenyl) boronic acid by a procedure similar to that described in example 59, steps B and C, followed by a procedure similar to that described in example 2, step B. 1 H NMR(600MHz,CD 3 OD) delta ppm 8.29-8.33 (m, 1H), 7.94-8.00 (m, 1H), 7.63-7.69 (m, 1H), 7.34-7.40 (m, 1H), 7.28-7.33 (m, 1H), 7.20-7.26 (m, 2H), 7.14-7.20 (m, 2H), 7.05-7.10 (m, 1H), 5.24 (qd, J=7.34, 2.57Hz, 1H), 4.86-4.87 (m, 1H), 4.67-4.74 (m, 1H), 4.63 (td, J=7.89, 5.87Hz, 1H), 4.44 (dt, J=9.26, 6.01Hz, 1H), 4.10 (s, 2H), 4.03 (brd, J=13.94 Hz, 1H), 3.94 (brd, 3.86-4.87 (m, 1H), 4.67-4.74 (m, 1H), 4.63 (td, J=7.89, 5.87Hz, 1H), 4.44 (3.14-2H), 3.24 (3.24 Hz, 3.24H), 3.32 (3.24-2.7, 3.7H), 3.24 (3.7 ). m/z (ESI, positive ion) =573.2 [ m+h ]] + 。
Example compounds 33, 48 and 56 were synthesized as described in example 32.
EXAMPLE 34 (S) -1- (oxetan-2-ylmethyl) -2- ((4- (6- (p-tolyloxy) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (34)
Step A.6- (p-tolyloxy) pyrimidine-4-carboxylic acid methyl ester (34 a)
6-chloropyrimidine-4-carboxylic acid methyl ester (1 g,5.81 mmol), p-cresol (0.94 g,8.71 mmol) and Cs 2 CO 3 (1.94 g,8.71 mmol) was added successively to DMSO (20 mL). Will be reversed at 25 DEG CThe mixture was stirred for 3h. After completion, the mixture was quenched with water (20 mL) and extracted with EtOAc (20 ml×3). The organic layers were combined, dried, filtered, and concentrated to provide a crude residue that was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to give the title product (34 a) as a white solid (0.76 g, 53%). m/z (ESI, positive ion) =245.1 [ m+h ] ] + 。
Step B.6- (p-tolyloxy) pyrimidine-4-carboxylic acid (34 b)
34a (1.1 g,4.5 mmol) was dissolved in MeOH: H 2 O (20 mL:7 mL). Sodium hydroxide (1.8 g,45 mmol) was added and the reaction stirred at 25 ℃ for 6h. After completion, the reaction was quenched with water (20 mL), and the mixture was adjusted to ph=6.0 with 10% citric acid and extracted with EtOAc (20 ml×3). The organic layer was dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=1:2) to give the title product 34b (830 mg, 80%) as a white solid. m/z (ESI, positive ion) =231.1 [ M+H ]] + 。
Step C. (S) -1- (oxetan-2-ylmethyl) -2- ((4- (6- (p-tolyloxy) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (34)
The title compound was prepared from 34B by a procedure similar to that described in example 2, step B. 1 H NMR(600MHz,CD 3 OD)δppm 8.71(d,J＝0.73Hz,1H),8.30-8.34(m,1H),7.96(dd,J＝8.44,1.47Hz,1H),7.66(d,J＝8.44Hz,1H),7.27(d,J＝8.44Hz,2H),7.09-7.14(m,1H),7.03-7.09(m,2H),5.25(qd,J＝7.21,2.57Hz,1H),4.85-4.89(m,1H),4.68-4.75(m,1H),4.63(td,J＝7.89,5.87Hz,1H),4.44(dt,J＝9.17,5.87Hz,1H),4.04(br d,J＝13.57Hz,1H),3.96(br d,J＝13.94Hz,1H),3.75-383 (m, 2H), 3.50 (brdd, j=6.05, 3.85hz, 2H), 2.76-2.84 (m, 1H), 2.61-2.71 (m, 2H), 2.53-2.60 (m, 2H), 2.45-2.53 (m, 1H), 2.37 (s, 3H). m/z (ESI, positive ion) =543.3 [ M+H ]] + 。
EXAMPLE 36 (S) -2- ((4- (5- ((4-chloro-2-fluorophenoxy) methyl) furan-2-carbonyl) -piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (36)
Step a. (S) -2- ((4- (5- (chloromethyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (36 a)
The title compound was prepared from 5- (chloromethyl) furan-2-carboxylic acid and 2a by a procedure similar to the procedure described in example 2 step B.
Step B. (S) -2- ((4- (5- ((4-chloro-2-fluorophenoxy) methyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (36)
4-chloro-2-fluorophenol (1.1 mg,0.008 mmol) and 36a (3.2 mg, 0.0070 mmol) were treated with K 2 CO 3 (2.2 mg,0.016 mmol) in DMF (0.5 mL). The reaction was stirred at room temperature for 4h. The crude mixture was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% hoac as modifier) to afford the title product (36) (0.4 mg, 8.9%) as a white solid. 1 H NMR(600MHz,CD 3 OD)δppm 8.35(s,1H),7.98(br d,J＝8.44Hz,1H),7.69(d,J＝8.44Hz,1H),7.13-7.22(m,2H),7.09(ddd,J＝8.80,2.57,1.47Hz,1H),6.98-7.02(m,1H),6.64(d,J＝3.30Hz,1H),5.26(qd,J＝7.21,2.57Hz,1H),5.17(s,2H),4.86-4.90(m,1H),473 (brdd, j=15.41, 2.57hz, 1H), 4.60-4.69 (m, 1H), 4.46 (dt, j=9.17, 5.87hz, 1H), 4.06 (br d, j=13.94 hz, 1H), 3.97 (br d, j=13.94 hz, 1H), 3.76 (br s, 4H), 2.81 (m, 1H), 2.53-2.68 (br s, 4H), 2.52 (m, 1H). m/z (ESI, positive ion) =583.2 [ m+h ]] + 。
Example compounds 37, 38, 39 and 40 were synthesized as described in example 36.
EXAMPLE 44 (S) -2- ((4- (7-methyl-9-oxo-9H-xanthen-3-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (44)
Step A.2-fluoroterephthalic acid dimethyl ester (44 a)
Pd (OAc) was added to a mixture of 1, 4-dibromo-2-fluorobenzene (1.0 g,3.9 mmol) in MeOH: DMSO (20 mL, 1:1) 2 (255 mg,0.78 mmol), DPPP (321 mg,0.78 mmol) and TEA (5.4 mL,39 mmol). The mixture was stirred under a CO balloon at 85 ℃ for 16h. After completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (50 ml×3). The organic layers were combined, dried, filtered, and concentrated to provide a crude residue that was purified by silica gel column chromatography (petroleum ether: etoac=5:1) to give the title product (44 a) as a brown solid (500 mg, 58%). 1 H NMR(400MHz,CDCl 3 )δppm 8.00-7.96(m,1H),7.85(dd,J＝8.1,1.5Hz,1H),7.78(dd,J＝11.0,1.5Hz,1H),3.94(s,3H),3.93(s,3H)。
Step B.2- (p-tolyloxy) dimethyl terephthalate (44 b)
To a mixture of 44a (600 mg,2.8 mmol) in DMF (30 mL) was added p-cresol (458 mg,4.2 mmol)And K 2 CO 3 (1.1 g,8.4 mmol). The mixture was stirred at 85℃for 2h. After completion, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 ml×3). The organic layers were combined, dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=5:1) to provide the title product (44 b) as a white solid (400 mg, 47%). m/z (ESI, positive ion) =301.1 [ m+h ] ] + 。
Step C.7-methyl-9-oxo-9H-xanthene-3-carboxylic acid methyl ester (44 c)
A mixture of 44b (0.5 g,1.665 mmol) in PPA (30 mL) was stirred for 2h at 125 ℃. After completion, the reaction was quenched with water (30 mL) and taken up in saturated Na 2 CO 3 The aqueous solution was washed and extracted with EtOAc (20 mL. Times.3). The organic layers were combined, dried, filtered, and concentrated to afford the crude title product (44 c) (205 mg) as a white solid. m/z (ESI, positive ion) =269.1 [ M+H ]] + 。
Step D.7-methyl-9-oxo-9H-xanthene-3-carboxylic acid (44 d)
To 44c (250 mg,0.93 mmol) in MeOH: H 2 NaOH (373 mg,9.31 mmol) was added to the mixture in O (6 mL:2 mL). The mixture was stirred at 20℃for 5h. After completion, the reaction was quenched with water (30 mL). The mixture was then adjusted to ph=6 with 10% citric acid and extracted with EtOAc (30 ml×3). The organic layers were combined, dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=1:2) to provide the title product (44 d) as a white solid (180 mg, 76%). m/z (ESI, positive ion) =255.0 [ m+h ]] + 。
Step E. (S) -2- ((4- (7-methyl-9-oxo-9H-xanthen-3-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (44)
The title compound was prepared from 44d and 2a by a procedure similar to that described in example 2, step B. 1 H NMR(600MHz,CD 3 OD) delta ppm 8.35 (d, j=8.07 hz, 1H), 8.30 (s, 1H), 8.06-8.09 (m, 1H), 7.93-7.97 (m, 1H), 7.70 (br dd, j=8.44, 2.20hz, 1H), 7.64 (br d, j=8.44 hz, 2H), 7.54 (d, j=8.44 hz, 1H), 7.44-7.47 (m, 1H), 5.25 (qd, j=7.34, 2.57hz, 1H), 4.84-4.90 (m, 1H), 4.68-4.76 (m, 1H), 4.63 (td, j=7.89, 5.87hz, 1H), 4.45 (dt, j=9.17, 5.87hz, 1H), 4.06 (br d, j=13.57 hz, 1H), 3.44-7.47 (m, 1H), 4.25 (qd, j=7.34, 2.57 hz), 4.57 (m, 1H), 4.84-4.90 (m, 1H), 4.68-4.76 (m, 1H), 4.63 (d, 3.87 hz, 3.74H). m/z (ESI, positive ion) =567.2 [ m+h ]] + 。
Example 46.1- ((1-Ethyl-1H-imidazol-5-yl) methyl) -2- ((4- (3- (methyl (p-tolyl) amino) benzoyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (46)
Step A.3- (p-tolylamino) benzoic acid methyl ester (46 a)
To methyl 3-bromobenzoate (3 g,13.9 mmol), 4-methylaniline (2.2 g,20.85 mmol), palladium diacetate (0.62 g,2.78 mmol), BINAP (1.73 g,2.78 mmol) and Cs 2 CO 3 Toluene (50 mL) was added to a mixture of (9 g,27.8 mmol). The reaction mixture was stirred at 100℃for 3h. After completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 ml×3). The organic layer was dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=20:1) to provide the title as a yellow solid Product (46 a) (2.5 g, 80%). m/z (ESI, positive ion) =242.1 [ m+h ]] + 。
Step B.3- (methyl (p-tolyl) amino) benzoic acid methyl ester (46 b)
46a (180 mg,0.75 mmol) was dissolved in THF (3 mL) and cooled in an ice bath. NaH (60%, 60mg in mineral oil, 1.49 mmol) was added to the reaction mixture and stirred at 0 ℃ for 0.5h. MeI (210 mg,1.49 mmol) was then added. The reaction temperature was raised to room temperature and stirred for 3h. After completion, the mixture was quenched with water (3 mL) and extracted with EtOAc (3 ml×3). The organic layer was dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether) to give the title product (46 b) as a white solid (158 mg, 85%). m/z (ESI, positive ion) =256.0 [ m+h ]] + 。
Step C.3- (methyl (p-tolyl) amino) benzoic acid (46 c)
To a mixture of 46b (500 mg,1.9 mmol) and sodium hydroxide (2 g,50 mmol) was added MeOH: H 2 O (10 mL:5 mL). The reaction mixture was stirred at room temperature for 5h. After completion, the mixture was quenched with water (5 mL) and extracted with EtOAc (5 ml×3). The organic layers were combined, dried, filtered, and concentrated to provide a crude product, which was purified by silica gel column chromatography (petroleum ether: etoac=2:1) to provide the title product (46 c) as a white solid (366 mg, 80%). m/z (ESI, positive ion) =242.2 [ m+h ] ] + 。
Step D.1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- ((4- (3- (methyl (p-tolyl) amino) benzoyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (46)
The title compound was prepared from 46c and 57i by a procedure similar to that described in example 2, step B. 1 H NMR(600MHz,CD 3 OD) delta ppm 8.16 (d, j=0.73 hz, 1H), 8.01 (brdd, j=8.44, 1.47hz, 1H), 7.79 (s, 1H), 7.72 (br d, j=8.44 hz, 1H), 7.25 (brt, j=8.07 hz, 1H), 7.20 (br d, j=8.07 hz, 2H), 7.03-7.07 (m, 2H), 6.88-6.93 (m, 1H), 6.73-6.77 (m, 2H), 6.57 (s, 1H), 5.78 (s, 2H), 4.09 (q, j=7.34 hz, 2H), 3.87-3.89 (m, 2H), 3.60 (br s, 2H), 3.31-3.35 (m, 2H), 3.28 (s, 3H), 2.56 (br s, 2H), 6.73-6.77 (m, 2H), 6.57 (s, 1H), 4.09 (q, j=7.34 hz, 2H), 3.28-3.28 (m, 2H). m/z (ESI, positive ion) =592.4 [ m+h ]] + 。
Compounds 25, 29, 45, 50, 51, 52, 54, 58, 75, 76, 85 and 87 of the examples (last 2 steps according to steps D and C of example 102) were synthesized in analogy to the synthesis of examples 25, 29, 45, 50, 51, 52, 54, 58, 75, 76, 85 and 88.
Example 57.2- ((4- (3- (2-chloro-4-methylphenoxy) benzoyl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (57)
Step A.1-ethyl-1H-imidazole-5-carboxylic acid ethyl ester (57 a)
To a solution of ethyl 1H-imidazole-5-carboxylate (2.8 g,20.0 mmol) in DMF (10 mL) was added NaH (60%, 1.2g,30.0mmol in mineral oil) at 0deg.C. After stirring at the same temperature for 0.5h, ethyl iodide (3.12 g,20.0 mmol) was added and the resulting mixture was stirred at 0 ℃ for an additional 0.5h. After completion, the mixture was taken up with H 2 O (30 mL) was quenched and extracted with EtOAc (30 mL. Times.3). Using H for the organic layer 2 O (30 mL), brine (30 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to yield a crude residue. Will be disabledThe residue was purified by column chromatography on silica gel (petroleum ether: etoac=5:1) to give the title product (57 a) as a white solid (850 mg, 25%). m/z (ESI, positive ion) =169.1 [ m+h ]] + 。
Step B.1-ethyl-1H-imidazole-5-carboxamide (57 b)
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57a (3.6 g,21.4 mmol) was reacted in a sealed reactor at 80℃in 7NNH 3 The solution in MeOH (50 mL) was stirred for 36h. 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 provide the title product (57 b) (1.9 g, 64%) as a white solid. m/z (ESI, positive ion) =140.1 [ m+h ]] + 。
Step C. (1-ethyl-1H-imidazol-5-yl) methylamine (57 c)
To a solution of 57b (1.9 g,13.6 mmol) in THF (20 mL) at 0deg.C was added LiAlH 4 (1.1 g,27.2 mmol). At 60℃under N 2 The mixture was stirred for 16h. After completion, the mixture was taken up with Na 2 SO 4 ·10H 2 O quench, and filter. The filtrate was extracted with DCM (100 mL). The organic layer was concentrated in vacuo to afford the crude title product (57 c) (1.4 g) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =126.2 [ m+h ] ] + 。
Step D.3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) -4-nitrobenzoic acid methyl ester (57 d)
57c (1.4 g,11.1 mmol), methyl 3-fluoro-4-nitrobenzoate (2.4 g,12.2 mmol) and TE are added at 25℃CA mixture of A (3.3 g,33.3 mmol) in THF (20 mL) was stirred for 16h. After completion, the mixture was taken up with H 2 O (50 mL) was diluted and extracted with DCM (50 mL. Times.3). The organic layer was treated with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to yield a crude residue. The residue was purified by silica gel column chromatography (DCM: meoh=10:1) to give the title product (57 d) as a white solid (1.6 g, 47%). m/z (ESI, positive ion) =305.2 [ m+h ]] + 。
Step E.4-amino-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzoic acid methyl ester (57 e)
At 25℃at H 2 A mixture of 57d (1.6 g,5.26 mmol) and 10% Pd/C (200 mg) in MeOH (10 mL) was stirred for 2h. After completion, the mixture was filtered through a pad of celite, which was rinsed with additional MeOH (100 mL). The organic layers were combined 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 (57 e) (1.3 g, 90%) as a brown solid. m/z (ESI, positive ion) =275.2 [ m+h ] ] + 。
Step F.2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (57 f)
To 57e (100 mg,0.36 mmol) at CH at room temperature 3 To a solution of CN (3 mL) was added 2-chloro-1, 1-trimethoxyethane (67.7 mg,0.44 mmol) and p-toluenesulfonic acid monohydrate (3.4 mg,0.018 mmol). The mixture was heated to 60 ℃ and stirred overnight. The crude reaction mixture was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to give the title product (57 f) as a white solid (46.6 mg, 39.0%). m/z (ESI, positive ion) =333.1 [ m+h ]] + 。
Step G.2- ((4- (tert-Butoxycarbonyl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (57 g)
Tert-butyl piperazine-1-carboxylate (11 mg,0.06 mmol), 57f (20 mg,0.06 mmol) and K are combined in DMF (1 mL) 2 CO 3 The mixture of (18 mg,0.13 mmol) was stirred overnight. The crude mixture was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to afford the title product (57 g) (23 mg, 79%). m/z (ESI, positive ion) =483.3 [ M+H ]] + 。
Step H.1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- (piperazin-1-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (57H)
57g (23 mg,0.06 mmol) were dissolved in DCM (2 mL) and treated with trifluoroacetic acid (TFA, 2 mL) at room temperature for 10min. The solvent and TFA were removed in vacuo to afford the title product as a crude residue (57 h), which was used in the next step without further purification. m/z (ESI, positive ion) =383.2 [ m+h ]] + 。
Step I.1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- (piperazin-1-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (57 i)
Dissolve crude 57h in CH 3 CN (1 mL), and added at room temperature at H 2 LiOH (15 mg,0.6 mmol) in O (0.5 mL). The reaction mixture was stirred overnight and purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to afford the title product (57 i) (8.9 mg, 24.9%). m/z (ESI, positive ion) =369.3 [ m+h ]] + 。
Step J.2- ((4- (3- (2-chloro-4-methylphenoxy) benzoyl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (57)
The title compound was prepared from 3- (2-chloro-4-methylphenoxy) benzoic acid (prepared similarly to 14B) and 57i by a procedure similar to that described in example 2, step B. 1 HNMR(600MHz,CD 3 OD) delta ppm 8.15 (s, 1H), 7.99 (br dd, j=8.62, 1.28hz, 1H), 7.77 (s, 1H), 7.70 (d, j=8.44 hz, 1H), 7.40 (t, j=8.07 hz, 1H), 7.35 (d, j=1.83 hz, 1H), 7.16 (br dd, j=8.25, 2.02hz, 1H), 7.07 (br d, j=7.34 hz, 1H), 7.02 (d, j=8.44 hz, 1H), 6.97 (br dd, j=8.07, 2.57hz, 1H), 6.80-6.84 (m, 1H), 6.56 (s, 1H), 5.76 (s, 2H), 4.07 (q, j=7.34 hz, 2H), 3.88 (s, 2H), 3.59 (br d, j=7.34 hz, 1H), 7.97 (br dd, j=8.57 hz, 1H), 6.80-6.84 (m, 1H), 3.56 (br d, 3.34H), 3.59 (br 2H), 3.24 (br 2H, 3.55H). m/z (ESI, positive ion) =613.3 [ m+h ] ] + 。
EXAMPLE 59 (S) -2- ((4- (5- (2, 4-dichlorobenzomethyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (59)
Step A.1- (bromomethyl) -2, 4-dichlorobenzene (59 a)
At 0℃under N 2 Next, PBr was added to a solution of (2, 4-dichlorophenyl) methanol (1.0 g,5.6 mmol) in DCM (15 mL) 3 (760 mg,2.8 mmol). After 0.5h, the mixture was warmed to 25 ℃ and stirred for 1.5h. After the reaction was completed, the mixture was washed with H 2 O (10 mL) and quenched by 7% NaHCO 3 The aqueous solution is adjusted to pH 7-8. Mixing the reactionThe compound was extracted with DCM (20 mL. Times.2). The organic layer was treated with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to afford the title product (59 a) (1.0 g), which was used in the next step without further purification.
Step B.5- (2, 4-dichlorobenzyl) furan-2-carboxylic acid methyl ester (59 b)
To 59a (0.9 g,3.8 mmol) and (5- (methoxycarbonyl) furan-2-yl) boronic acid (0.65 g,3.8 mmol) in dioxane (30 mL) and H at 20deg.C 2 To a mixture of O (4 mL) was added sodium carbonate (1.21 g,11.4 mmol) and Pd (dppf) Cl 2 (0.44 g,0.3 mmol). At 80℃under N 2 The mixture was stirred for 12h. After completion, the mixture was taken up with H 2 O (50 mL) was quenched and extracted with EtOAc (50 mL. Times.3). Using H for the organic layer 2 O (30 mL), brine (30 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to afford a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=20:1) to afford the title product (59 b) (1.0 g, 86.8%) as a colorless oil. M/z (ESI, positive ion) =285.0.[ m+h ]] + 。
Step C.5- [ (2, 4-dichlorophenyl) methyl ] furan-2-carboxylic acid (59 c)
59b (1.0 g,0.0035 mol) in THF (30 mL) and H at 25 °c 2 To the mixture in O (10 mL) was added LiOH (0.25 g,0.0105 mol). At N 2 The mixture was stirred for 12h. After completion of the reaction, the mixture was adjusted to ph=7 with 1N HCl and extracted with EtOAc (10 ml×3). Using H for the organic layer 2 O (30 mL), brine (30 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to afford the title product (59 c) (700 mg, 73.8%) as a white solid, which was used in the next step without further purification.m/z (ESI, positive ion) =270.9 [ m+h ]] + 。
Step d. (S) -2- ((4- (5- (2, 4-dichlorobenzyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (59 d)
To a solution of 59c (100 mg,0.37 mmol) in DCM (10 mL) was added N, N-diisopropylethylamine (238 mg,1.8 mmol), 1-hydroxybenzotriazole (68 mg,0.48 mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (85 mg,0.44 mmol) and 1j (127 mg,0.37 mmol) at 25 ℃. At 25℃under N 2 The reaction was stirred for 16h. After completion, the reaction was filtered and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=5:1) to afford the title product (59 d) as a white solid (160 mg, 50.8%). m/z (ESI, positive ion) =597.1 [ m+h ]] + 。
Step E. (S) -2- ((4- (5- (2, 4-dichlorobenzyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (59)
To 59d (40 mg,0.067 mmol) at 25℃in CH 3 CN:H 2 To a mixture in o=1:1 (10 mL) was added TBD (56 mg,0.40 mmol). At 50℃under N 2 The mixture was stirred for 2h. After completion, the reaction mixture was adjusted to ph=7 with 1N HCl and extracted with EtOAc (10 ml×3). The organic layer was washed with water (10 mL), brine (10 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated in vacuo to afford a crude residue. The residue was purified by reverse phase HPLC (H 2 O:CH 3 Cn=1:1) to afford the title compound (59) (30 mg, 75.3%) as a white solid. 1 H NMR(400MHz,CD 3 OD)δppm 8.35(s,1H),7.98(dd,J＝8.331.32hz, 1H), 7.69 (d, j=8.33 hz, 1H), 7.46 (d, j=1.75 hz, 1H), 7.21-7.40 (m, 2H), 6.96 (d, j=3.51 hz, 1H), 6.25 (d, j=3.51 hz, 1H), 5.25 (qd, j=7.16, 2.63hz, 1H), 4.90-4.84 (m, 1H), 4.72 (dd, j=15.57, 2.41hz, 1H), 4.64 (td, j=7.89, 6.14hz, 1H), 4.45 (dt, j=9.10, 5.97hz, 1H), 4.16 (s, 2H), 4.05 (br d, j=14.03hz, 1H), 3.75 (br) 4.90-4.84 (m, 1H), 4.45 (br 2.57, 1H), 4.45 (br.7.57). m/z (ESI, positive ion) =583.2 [ m+h ] ] + 。
EXAMPLE 60 (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (60)
Step A.5- (bromomethyl) oxazole-2-carboxylic acid methyl ester (60 a)
NBS (1034 mg,5.81 mmol) and AIBN (93 mg,0.58 mmol) are added to the solution in anhydrous CCl at room temperature 4 In 5-methyl-1, 3-oxazole-2-carboxylic acid methyl ester (800 mg,5.81 mmol) in (58 mL) and the reaction was heated to 70 ℃ for one hour. Saturated NaHCO for reaction 3 The aqueous solution was quenched and extracted with DCM (20 mL. Times.3). The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtration, concentration, and purification by silica gel column chromatography (gradient elution, etOAc/hexanes, 0-40%) afforded the title product (60 a) (1000 mg, 78%) as a colorless oil. m/z (ESI, positive ion) =222.0 [ m+h ]] +
Step B.5- ((1- (tert-Butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) methyl) oxazole-2-carboxylic acid methyl ester (60 b)
At room temperature(1, 1' -bis (diphenylphosphino) ferrocene) Palladium (II) dichloride (332 mg,0.45 mmol), K 2 CO 3 (1258 mg,9.1 mmol) and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylate (1406 mg,4.55 mmol) were added to 1, 4-dioxane, H 2 In 60a (1000 mg,4.55 mmol) in O (3:1, 46 mL). The mixture was degassed with argon for 10min, then heated to 50 ℃ for 2h. The reaction mixture was taken up in EtOAc and saturated NaHCO 3 The aqueous solution is partitioned between. The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtered, concentrated, and purified by silica gel chromatography (gradient elution, etOAc/hexanes, 0-50%) to afford the title product (60 b) as an amber oil (284 mg, 40%). m/z (ESI, positive ion) =345.1 [ m+na ]] +
Step C.4- ((2- (hydroxymethyl) oxazol-5-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (60 c)
10% Pd/C (96 mg,0.09 mmol) was added to 60b (284 mg,1.81 mmol) in EtOH (18 mL) at room temperature. The reaction was degassed with hydrogen for 10min, followed by H 2 Stirring under a balloon for 16h. The mixture was filtered through a pad of celite, rinsed with EtOAc, and concentrated to give the title product (60 c) as a light brown oil (586 mg, 99%) which was used in the next step without further purification. m/z (ESI, positive ion) =347.3 [ m+na ]] + 。
Step D.4- ((2- (hydroxymethyl) oxazol-5-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (60 d)
at-78deg.C, liAlH is added 4 (1M in THF) (3.6 mL,3.6 mmol) was added to 60c (586 mg,1.81 mmol) in anhydrous THF (18 mL) and stirred at 0deg.C for 30min. The reaction was carried out by dropwise addition of H 2 O, followed by 15% NaOH to quench,and extracted with EtOAc (20 ml×3). The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtration, concentration, and chromatography on silica gel (gradient elution, meOH/CH 2 Cl 2 0-10%) to afford the title product (60 d) (57 mg, 11%) as a pale yellow oil. m/z (ESI, positive ion) =319.2 [ m+na ]] + 。
Step E.4- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (60 e)
DIAD (58 mg,0.29 mmol), PPh at 0deg.C 3 (76 mg,0.29 mmol) and 2, 4-dichlorophenol (31 mg,0.19 mmol) were added to 60d (57 mg,0.19 mmol) in dry THF (1.9 mL). After 1.5H, the reaction was carried out between EtOAc and H 2 O. The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtration, concentration, and purification by silica gel column chromatography (gradient elution, etOAc/hexanes, 0-90%) afforded the title product (60 e) as a colorless oil (65 mg, 76%). m/z (ESI, positive ion) =385.0 [ M-tBu+H ]] + 。
Step f. (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (60 f)
TFA (0.03 mL,0.41 mmol) was added to 60e (9 mg,0.02 mmol) in DCM (0.2 mL) at room temperature. The reaction was stirred for 3h, concentrated, and co-evaporated in vacuo with DCM (2 ml×3) to give the crude amine (7 mg). m/z (ESI, positive ion) =341.1 [ M+H ] ] + . The crude amine was redissolved in DCM (0.2 mL). DIPEA (0.07 mL,0.04 mmol) and 1h (4 mg,0.014 mmol) were added successively. The reaction was heated at 40 ℃ for 16h, concentrated, and purified by silica gel column chromatography (gradient elution, meOH/DCM, 0-10%)To provide the title compound (60 f) (9 mg, 75%). m/z (ESI, positive ion) =599.3 [ m+h ]] + 。
Step g. (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (60)
LiOH.H 2 O (0.6 mg,0.015 mmol) was added to the mixture in THF: H 2 In 60f (9 mg,0.015 mmol) in O (1:1, 0.3 mL) and stirred at room temperature. After 12H, additional LiOH H was added 2 O (0.3 mg, 0.0070 mmol) and the reaction was stirred for an additional 3h. The reaction was acidified with 1N HCl to ph=7 and quenched with saturated NaHCO in EtOAc 3 The aqueous solution is partitioned between. The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtered, concentrated, and purified by silica gel column chromatography (gradient elution, meOH/DCM, 0-15%) to give the title compound (60) (8 mg, 91%) as a white solid. m/z (ESI, positive ion) =585.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 8.31(s,1H),7.97(br dd,J＝8.44,1.47Hz,1H),7.65(d,J＝8.44Hz,1H),7.40(d,J＝2.57Hz,1H),7.25(br dd,J＝8.80,2.57Hz,1H),7.22-7.16(m,1H),6.87(s,1H),5.21-5.25(m,3H),4.81-4.85(m,1H),4.70-4.61(m,2H),4.45(dt,J＝9.17,5.87Hz,1H),4.01(d,J＝13.9Hz,1H),3.90(d,J＝13.9Hz,1H),3.00-2.83(m,2H),2.82-2.73(m,1H),2.66(br d,J＝6.60Hz,1H),2.50(ddt,J＝11.23,9.03,7.29,7.29Hz,1H),2.11-2.30(m,2H),1.59-1.72(m,2H),1.21-1.40(m,2H),0.81-0.96(m,2H)。
EXAMPLE 61 (S) -2- ((4- (6- (cyclohexyl (methyl) amino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (61)
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Step A6- (cyclohexyl (methyl) amino) pyrimidine-4-carboxylic acid methyl ester (61 a)
A mixture of methyl 6-chloropyrimidine-4-carboxylate (500 mg,2.89 mmol), N-methylcyclohexylamine (655 mg,5.8 mmol) and N, N-diisopropylethylamine (748 mg,5.79 mmol) in THF (50 mL) was heated to 65deg.C for 24h. Will react with H 2 O(10ml)、NaHCO 3 (10 mL) and extracted with DCM (15 mL. Times.3). The organic layers were combined, dried, filtered, and concentrated to afford the crude title product (61 a) (600 mg), which was used in the next step without further purification. m/z (ESI, positive ion) =250.2 [ m+h ]] + 。
Step B.6- (cyclohexyl (methyl) amino) pyrimidine-4-carboxylic acid (61 b)
61a (500 mg,2.00 mmol) and sodium hydroxide (401 mg,10 mmol) were combined in MeOH: H at 25 ℃ 2 The mixture in o=10:1 (20 mL) was stirred for 2h. The reaction mixture was then extracted with EtOAc (50 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (CH 3 CN:H 2 O=1:3) to afford the title product (61 b) (430 mg, 82.0%) as a white solid. m/z (ESI, positive ion) =236.0 [ M+H ]] + 。
Steps C and d. (S) -2- ((4- (6- (cyclohexyl (methyl) amino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (61)
The title compound was prepared from 61B by a procedure similar to that described in example 61 steps B and C. 1 H NMR(400MHz,CDCl 3 )δppm 8.55(s,1H),8.20(br s,1H) 8.04 (d, j=7.89 hz, 1H), 7.79 (d, j=8.33 hz, 1H), 6.68 (br s, 1H), 5.14-5.28 (m, 1H), 4.53-4.68 (m, 4H), 4.35 (br d, j=8.33 hz, 1H), 3.96-4.12 (m, 2H), 3.80 (br s, 2H), 3.59 (br s, 2H), 2.93 (br s, 3H), 2.62-2.75 (m, 2H), 2.57 (br s, 2H), 2.35-2.52 (m, 2H), 1.86 (br d, j=10.52 hz, 2H), 1.71 (br d, j=10.96 hz, 3H), 1.10-1.58 (m, 5H). m/z (ESI, positive ion) =274.7 [ m+h ]] + 。
EXAMPLE 62 (S) -2- ((4- (6- (methyl (phenyl) amino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (62)
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Step A.6- (methyl (phenyl) amino) pyrimidine-4-carboxylic acid (62 a)
The flask was charged with N-methylaniline (0.5 g,2.9 mmol) and dioxane (15 mL). 6-Chloropyrimidine-4-carboxylic acid methyl ester (463 mg,4.3 mmol), 4-methylbenzenesulfonic acid (1.47 g,8.7 mmol) and H are added 2 O (62 mg,3.5 mmol). The resulting mixture was heated to 120 ℃ and stirred for 8h. After completion, the mixture was taken up with H 2 O (10 mL) was quenched and extracted with DCM (20 mL. Times.2). The aqueous phase was separated, lyophilized, and purified by silica gel column chromatography to provide the title product (62 a) (0.41 g, 61.7%). 1 H NMR(400MHz,DMSO-d 6 )δ8.72(s,1H),7.55(t,J＝7.7Hz,2H),7.44-7.39(m,3H),6.83(s,1H),3.47(s,3H)。
Step B. (S) -2- ((4- (6- (methyl (phenyl) amino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (62 b)
From 62a and by a procedure similar to that described in step M of example 11j the title compound was prepared. m/z (ESI, positive ion) =556.3 [ m+h ]] + 。
Step C. (S) -2- ((4- (6- (methyl (phenyl) amino) pyrimidine-4-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (62)
The title compound was prepared from 62b by a procedure similar to that described in example 1, step N. 1 H NMR(400MHz,DMSO-d 6 ) Delta ppm 8.60 (d, j=0.98 hz, 1H), 8.47 (br s, 1H), 8.18 (s, 1H), 7.83 (br d, j=8.31 hz, 1H), 7.45-7.58 (m, 2H), 7.30-7.45 (m, 3H), 6.33-6.46 (m, 1H), 5.07 (m, 1H), 4.70 (br dd, j=14.92, 6.85hz, 1H), 4.57 (br d, j=13.45 hz, 1H), 4.41-4.52 (m, 1H), 4.34 (dt, j=8.86, 5.84hz, 1H), 3.91 (br d, j=13.69hz, 1H), 3.77 (br d, j=13.45 hz, 1H), 3.47-3.62 (m, 2H), 3.43 (br d, j=13.45 hz, 1H), 4.41-4.52 (m, 1H), 4.34 (br d, j=13.45 hz, 1H), 3.33-2.34 (m, 2H). m/z (ESI, positive ion) =542.3 [ m+h ]] + 。
EXAMPLE 72 (S) -2- ((4- ((5- ((2, 4-dichlorophenoxy) methyl) furan-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (72)
Step A.4- ((5- (methoxycarbonyl) furan-2-yl) methyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (72 a)
To methyl 5- (chloromethyl) furan-2-carboxylate (3.0 g,0.017 mol), tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (6.4 g,0.021 mmol) and sodium carbonate (3.7 g,0.034 mol) in dioxane H at 25 °c 2 In the mixture in o=8:1 (80 mL)Addition of Pd (dppf) Cl 2 DCM (1.4 g,0.0017 mol). At 90℃under N 2 The mixture was stirred for 18h. After completion, the mixture was taken up with H 2 O (80 mL) was quenched and extracted with EtOAc (80 mL. Times.3). Using H for the organic layer 2 O (80 mL), brine (80 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=20:1) to give the title product (72 a) (4.2 g, 68%) as a yellow oil. m/z (ESI, positive ion) =344.2 [ m+na ]] + 。
Step B.4- ((5- (methoxycarbonyl) furan-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (72 b)
The flask was filled with 72a (2.0 g,0.0062 mol). MeOH (30 mL) and Raney Nickel (Raney-Ni) (1.0 g) were added at 25 ℃. At 25℃at H 2 The mixture was stirred for 36h. After the reaction was complete, the mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to afford crude 72b (2.0 g) as a colorless oil, which was used in the next step without purification. m/z (ESI, positive ion) =346.2 [ m+na ] ] + 。
Step C.4- ((5- (hydroxymethyl) furan-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (72 c)
To a mixture of 72b (1.5 g,0.0046 mol) in THF (30 mL) was added diisobutylaluminum hydride (1.0M in hexane, 14mL,0.014 mol) at-40 ℃. At-40 ℃ under N 2 The mixture was stirred for 3h. After completion, the reaction was quenched with ice-cold aqueous NaOH (2N) and extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (72 c) (1.3 g, 87%) as a yellow oil. m/z (ESI, positive ion) =318.2 [ m+na ]] + 。
Step D.4- ((5- ((2, 4-dichlorophenoxy) methyl) furan-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (72 d)
To a mixture of 72c (1.3 g,0.0044 mol), 2, 4-dichlorophenol (0.79 g,0.0048 mol) and triphenylphosphine (1.27 g,0.0048 mol) in THF (30 mL) was added DEAD (0.84 g,0.0048 mol) at 0deg.C. The mixture was warmed to room temperature and taken up in N 2 Stirred for 16h. After completion, the mixture was concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (72 d) as a colorless oil (800 mg, 37%). m/z (ESI, positive ion) =462.1 [ m+na ] ] + 。
Step E.4- ((5- ((2, 4-dichlorophenoxy) methyl) furan-2-yl) methyl) piperidine (72 e)
To a mixture of 72d (500 mg,1.1 mmol) in DCM (20 mL) was added 2, 6-lutidine (3.7 g,34 mmol) and TMSOTF (3.8 g,17 mmol) at 0deg.C. At 0℃under N 2 The reaction was stirred for one hour. After completion, the mixture was treated with NH 4 Cl (10 mL) was quenched and extracted with EtOAc (20 mL. Times.3). Using H for the organic layer 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to afford the crude title product (72 e) (400 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =340.1 [ m+h ]] + 。
Step F. (S) -2- ((4- ((5- ((2, 4-dichlorophenoxy) methyl) furan-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (72 f)
At 25℃to 72e (400 mg,1.2 mmol) and K 2 CO 3 (325 mg,2.4 mmol) in DMF (30 mL) was added 1h (346 mg,1.2 mmol). At 25℃under N 2 The mixture was stirred for 16h. After completion, the mixture was taken up with H 2 O (30 mL) was quenched and extracted with DCM (30 mL. Times.3). Using H for the organic layer 2 O (30 mL. Times.3), brine (30 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title product (72 f) as a yellow oil (520 mg, 67%). m/z (ESI, positive ion) =598.2 [ m+h ]] + 。
Step G. (S) -2- ((4- ((5- ((2, 4-dichlorophenoxy) methyl) furan-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (72)
To 72f (50 mg,0.084 mmol) in THF (6 mL) and H 2 Lithium hydroxide (20 mg,0.84 mmol) was added to the mixture in O (2 mL) and the reaction was heated to 50deg.C. At 50℃under N 2 After stirring for 24H, the mixture was adjusted to ph=7 with 1N HCl, with H 2 O (5 mL) was diluted and extracted with EtOAc (10 mL. Times.3). Using H for the organic layer 2 O (10 mL), brine (10 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue, which was purified by reverse phase HPLC (55% CH 3 CN/H 2 O, with formic acid as modifier) to afford the title compound (72) (30 mg, 58%) as a white solid. 1 H NMR(400MHz,CD 3 OD)δppm 8.27(d,J＝0.88Hz,1H),7.96(dd,J＝8.33,1.32Hz,1H),7.63(d,J＝8.33Hz,1H),7.35(d,J＝2.63Hz,1H),7.20-7.24(m,1H),7.15-7.19(m,1H),6.37 (d, j=3.07 hz, 1H), 6.02 (d, j=3.07 hz, 1H), 5.22 (qd, j=7.16, 2.63hz, 1H), 5.05 (s, 2H), 4.81-4.87 (m, 1H), 4.55-4.74 (m, 2H), 4.44 (dt, j=8.99, 6.03hz, 1H), 4.00 (d, j=14.03 hz, 1H), 3.89 (d, j=14.03 hz, 1H), 2.96 (br d, j=10.96 hz, 1H), 2.86 (br d, j=10.96 hz, 1H), 2.71-2.82 (m, 1H), 2.56 (d, j=6.58 hz, 2H), 2.42-2.55 (m, 1H), 2.12-2.27 (m, 2H), 1.58-1.72 (m, 1H), and 18-1.37H. m/z (ESI, positive ion) =584.2 [ m+h ] + 。
Example compounds 84, 103, 104 (tert-butyl ester was used in the case of 104 and deprotected in DCM using TFA) 108 and 109 were synthesized as described in example 72.
EXAMPLE 73 (S) -2- ((4- (5- ((2, 4-dichlorobenzomethyl) oxy) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (73)
Step A.5- ((2, 4-dichlorobenzyl) oxy) furan-2-carboxylic acid methyl ester (73 a)
To a mixture of methyl 5-bromofuran-2-carboxylate (1.0 g,0.0049 mol), (2, 4-dichlorophenyl) methanol (0.87 g,0.0049 mol), 3,4,7, 8-tetramethyl-1, 10-phenanthroline (0.23 g,0.00098 mol) and CuI (0.09 g,0.0004 mol) in toluene (15 mL) was added Cs 2 CO 3 (2.4 g,0.0074 mol) and under N 2 The reaction mixture was heated to 80 ℃ for 18h. After completion, the mixture was taken up with H 2 O (20 mL) was quenched and extracted with EtOAc (20 mL. Times.3). Using H for the organic layer 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=50:1) to afford the title product (73 a) (220 mg, 13%) as a white solid. m/z (ESI, positive ion) =301.0 [ m+h ]] + 。
Step B.5- ((2, 4-dichlorobenzyl) oxy) furan-2-carboxylic acid (73 b)
The title compound was prepared from 73a by a procedure similar to that described in example 59, step C. m/z (ESI, positive ion) =287.0 [ M+H ]] + 。
Step C. (S) -2- ((4- (5- ((2, 4-dichlorobenzomethyl) oxy) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (73 c)
The title compound was prepared from 73b and 1j by a procedure similar to that described in example 59, step D. m/z (ESI, positive ion) =613.2 [ m+h ]] + 。
Step d. (S) -2- ((4- (5- ((2, 4-dichlorobenzomethyl) oxy) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (73)
To 73c (50 mg,0.082 mmol) in THF: H 2 To the mixture in o=3:1 (15 mL) was added lithium hydroxide (20 mg,0.82 mmol) and the reaction mixture was heated to 50 ℃. At 50℃under N 2 After stirring for 16h, the reaction was cooled and adjusted to ph=7 with 1N HCl. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL. Times.3). Using H for the organic layer 2 O (10 mL), brine (10 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue which was purified by reverse phase HPLC (45% ch 3 CN/H 2 O, with 0.05% NH 4 HCO 4 As modifier) to afford the title compound (7) as a white solid 3)(30mg,60％)。 1 H NMR(400MHz,CD 3 OD) delta ppm 8.31 (d, j=0.9 hz, 1H), 7.96 (dd, j=8.5, 1.4hz, 1H), 7.65 (d, j=8.5 hz, 1H), 7.53 (dd, j=6.6, 5.3hz, 2H), 7.37 (dd, j=8.3, 2.1hz, 1H), 7.01 (d, j=3.6 hz, 1H), 5.59 (d, j=3.6 hz, 1H), 5.30-5.21 (m, 3H), 4.88-4.84 (m, 1H), 4.71 (dd, j=15.4, 2.6hz, 1H), 4.63 (dt, j=14.0, 7.1hz, 1H), 4.45 (dt, j=9.1, 5.9hz, 1H), 4.03 (d, j=13.6 hz, 1H), 5.88-5.21 (m, 1H), 4.71 (d, j=3.3.8 hz, 1H), 4.8-4.8 hz, 1H), 4.8.7.7 (d, 3.8hz, 1H). m/z (ESI, positive ion) =599.1 [ m+h ]] + 。
EXAMPLE 74 (S) -2- ((4- ((5- ((2, 4-dichlorobenzomethyl) oxy) furan-2-yl) methyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (74)
Step A.5- ((2, 4-dichlorobenzyl) oxy) furan-2-carboxylic acid methyl ester (74 a)
To a mixture of methyl 5-bromofuran-2-carboxylate (1 g,4.9 mmol), (2, 4-dichlorophenyl) methanol (0.95 g,5.3 mmol), 3,4,7, 8-tetramethyl-1, 10-phenanthroline (0.23 g,0.9 mmol) and CuI (0.09 g,0.4 mmol) in toluene (12 mL) was added Cs 2 CO 3 (2.39 g,7.3 mmol), and at N 2 The reaction was heated to 80 ℃ for 18h. The mixture was then filtered and concentrated in vacuo to give a crude residue which was purified by silica gel column chromatography (EtOAc/petroleum ether, 20-30%) to afford the title product (74 a) (0.35 g, 23.9%) as a yellow solid. m/z (ESI, positive ion) =301.0 [ m+h ] ] + 。
Step B. (5- ((2, 4-dichlorobenzyl) oxy) furan-2-yl) methanol (74 b)
At-45 ℃ under N 2 DIBAL-H (3.5 mL,3.5 mmol) was added to a mixture of 74a (350 mg,1.16 mmol) in dry THF (15 mL) and the reaction stirred at-45℃for one hour. The reaction was quenched with ice-cold aqueous NaOH (2N) and extracted with EtOAc (30 ml×3). The organic layer was washed with water (20 mL), brine (20 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC (40% EtOAc/petroleum ether) to give the title product (74 b) as a colorless oil (181 mg, 51%). m/z (ESI, positive ion) =294.9 [ m+na ]] + 。
Step C.5- ((2, 4-dichlorobenzyl) oxy) furan-2-carbaldehyde (74 c)
To 74b (30 mg,0.11 mmol) in CCl 4 MnO was added to the mixture in (3 mL) 2 (47 mg,0.55 mmol) and the reaction was stirred at 25℃for 18h. The mixture was then filtered and concentrated in vacuo to afford the title product (74 c) (15 mg, 25%) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =293.0 [ m+na ]] + 。
Step d. (S) -2- ((4- ((5- ((2, 4-dichlorobenzomethyl) oxy) furan-2-yl) methyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (74 d)
To 74c (118 mg,0.435 mmol) and 1j (25 mg,0.07 mmol) in CH 3 NaBH was added to the mixture in OH (5 mL) 3 CN (9 mg,0.145 mmol). The reaction was stirred at 25℃for 36h. The mixture was quenched with ice water (5 mL) and extracted with EtOAc (15 ml×3). The organic layer was washed with water (5 mL), brine (5 mL), dried, filtered, and concentrated to give a crude residue which was purified by reverse phase HPLC (35% CH 3 CN/H 2 O, with formic acid asAs modifier) to afford the title product (74 d) (13 mg, 3.6%) as a white solid. m/z (ESI, positive ion) =599.2 [ m+h ]] + 。
Step E. (S) -2- ((4- ((5- ((2, 4-dichlorobenzomethyl) oxy) furan-2-yl) methyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (74)
To 74d (13 mg,0.0217 mmol) in CH 3 OH:H 2 To a mixture in O (6:1, 3.5 mL) was added LiOH (8 mg,0.33 mmol) and the reaction was stirred at 25℃for 18h. The mixture was adjusted to ph=7 with 1N HCl and taken up with DCM: CH 3 OH (10:1) (10 mL. Times.2) extraction. The organic layer was concentrated in vacuo to give a crude residue which was purified by reverse phase HPLC (56% CH 3 CN/H 2 O, with NH 4 HCO 3 As a modifier) to afford the title product (74) (4.4 mg, 31%) as a white solid. 1 H NMR(400MHz,CD 3 OD) delta ppm 8.16 (s, 1H), 7.93 (dd, j=8.33, 1.32hz, 1H), 7.49-7.59 (m, 3H), 7.36 (br dd, j=8.11, 1.97hz, 1H), 6.16 (d, j=3.07 hz, 1H), 5.29 (d, j=3.07 hz, 1H), 5.24 (m, 1H), 5.16 (s, 2H), 4.76-4.86 (m, 1H), 4.54-4.72 (m, 2H), 4.41-4.48 (m, 1H), 3.98 (br d, j=13.59 hz, 1H), 3.89 (br d, j=13.59 hz, 1H), 3.46 (s, 2H), 2.70-2.81 (m, 1H), 2.39-2.67 (m, 9H). m/z (ESI, positive ion) =585.2 [ m+h ] ] + 。
EXAMPLE 78 (S) -2- ((4- (3- (((2-chloro-4-methylphenyl) (methyl) amino) methyl) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (78)
Step A.3- (((2-chloro-4-methylphenyl) amino) methyl) benzoate (78 a)
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2-chloro-4-methylaniline (14.2 mg,0.1 mmol), methyl 3- (bromomethyl) benzoate (27.5 mg,0.12 mmol) and K 2 CO 3 (17.3 mg,0.125 mmol) was suspended in DMF (1 mL). The reaction mixture was stirred at 100℃for 1.5 hours. After cooling to room temperature, the crude residue was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% TFA as modifier) to afford the title product (78 a) as a pale brown solid (21 mg, 72.7%). m/z (ESI, positive ion) =290.1 [ m+h ]] + 。
Step B. (S) -2- ((4- (3- (((2-chloro-4-methylphenyl) (methyl) amino) methyl) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (78)
The title compound was prepared from 78a and 2a by a procedure similar to that described in steps B to D of example 46. 1 H NMR(600MHz,CD 3 OD) delta ppm 8.33 (s, 1H), 7.97 (dd, j=8.44, 1.47hz, 1H), 7.66 (d, j=8.44 hz, 1H), 7.47 (br d, j=7.70 hz, 1H), 7.34-7.43 (m, 2H), 7.28 (br d, j=7.70 hz, 1H), 7.16 (s, 1H), 6.94-6.99 (m, 2H), 5.25 (qd, j=7.15, 2.75hz, 1H), 4.85-4.92 (m, 1H), 4.69-4.75 (m, 1H), 4.61-4.68 (m, 1H), 4.46 (dt, j=9.17, 5.87hz, 1H), 4.21 (s, 2H), 4.04 (d, j=13.57 hz, 1H), 3.94 (d, j=13.94 hz, 1H), 3.78-3.85 (m, 1H), 3.71-3.78 (m, 1H), 3.27-3.29 (m, 2H), 2.73-2.89 (m, 1H), 2.68 (s, 3H), 2.60-2.67 (m, 2H), 2.46-2.58 (m, 1H), 2.40 (br s, 2H), 1.88-2.01 (s, 3H). m/z (ESI, positive ion) =602.4 [ m+h ] ] + 。
The example compounds 77, 79 and 80 were synthesized as described in example 78.
Example 83.4- (((6- (1- (6- (1H-tetrazol-5-yl) nicotinyl) piperidin-4-yl) pyridin-2-yl) oxy) methyl) -3-fluorobenzonitrile (83)
Step A.6-fluoro-3 ',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester (83 a)
2-bromo-6-fluoropyridine (2 g,11.36 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.86 g,12.5 mmol), sodium carbonate (4.71 g,34.08 mmol) and Pd (dppf) Cl were reacted under nitrogen at 80 ℃ 2 A solution of (831 mg,1.14 mmol) in a mixture of DMF (50 mL) and water (10 mL) was stirred for 3h. After completion, the reaction mixture was extracted with EtOAc (50 ml×2). The organic layer was washed with brine (50 mL), dried (sodium sulfate), filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (gradient elution, etOAc/hexanes, 0-10%) to afford the title product (83 a) (3.1 g, 97%) as a yellow oil. m/z (ESI, positive ion) =301.2 [ m+na ]] + 。
Step B.4- (6-Fluoropyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (83 b)
To a solution of 83a (5 g,17.96 mmol) in methanol (70 mL) was added 10% Pd/C (0.5 g). The mixture was stirred at 20℃under a hydrogen atmosphere (1 atm) for one hour. The reaction mixture was filtered through celite pad, and the filtrate was concentrated under reduced pressure to give the title product (83 b) (3.9 g) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =303.2 [ m+na ] ] + 。
Step C.4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (83 c)
At 0℃under nitrogenTo a solution of 83b (399mg, 1.39 mmol) and 3-fluoro-4- (hydroxymethyl) benzonitrile (210 mg,1.39 mmol) in anhydrous 1, 4-dioxane (2.5 mL) was added potassium tert-butoxide (156 mg,1.39 mmol) in portions over 5 min. The mixture was heated to 110 ℃ for 4h. After completion, the organic solvent was removed under reduced pressure. The crude residue was partitioned between EtOAc (5 mL) and water (5 mL). The organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase HPLC (gradient elution, CH) 3 CN/H 2 O,0-90%, with 0.1% NH 3 ·H 2 O as a modifier) to afford the title product (83 c) (305 mg, 74.2%) as a yellow oil. m/z (ESI, positive ion) =434.2 [ M+Na ]] + 。
Step D.3-fluoro-4- (((6- (piperidin-4-yl) pyridin-2-yl) oxy) methyl) benzonitrile (83 d)
A solution of 83c (305 mg,0.74 mmol) in 2N HCl:EtOAc (4 mL) was stirred at 20deg.C for 0.5h. After completion, the reaction mixture was concentrated and purified by silica gel column chromatography (gradient elution, meOH/DCM, 5-10%) to afford the title product (83 d) as a yellow solid (178 mg, 74.2%). m/z (ESI, positive ion) =312.2 [ m+h ] ] + 。
Step E.4- (((6- (1- (6- (1H-tetrazol-5-yl) nicotinyl) piperidin-4-yl) pyridin-2-yl) oxy) methyl) -3-fluorobenzonitrile (83)
The flask was charged with 83d (6.8 mg,0.022 mmol), 6- (1H-tetrazol-5-yl) nicotinic acid (3.8 mg,0.02 mmol) and HATU (11.4 mg,0.03 mmol). DMF (1 mL) was added followed by DIPEA (0.014 mL,0.08 mmol). The reaction was stirred for 10min, then directly by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to give the title compound (83) (2.5 mg, 25.8%) as a white solid. 1 H NMR(600MHz,CD 3 OD) delta ppm 8.83 (d, j=2.20 hz, 1H), 8.35 (d, j=8.07 hz, 1H), 8.10 (dd, j=8.07, 1.83hz, 1H), 7.57-7.68 (m, 3H), 7.51-7.57 (m, 1H), 6.88 (d, j=7.34 hz, 1H), 6.72 (d, j=8.44 hz, 1H), 5.46-5.59 (m, 2H), 4.69-4.76 (m, 1H), 3.80 (br d, j=12.84 hz, 1H), 3.35 (br d, j=12.84 hz, 1H), 2.93-2.99 (m, 1H), 1.95 (br d, j=10.64 hz, 1H), 1.71-1.71 (m, 3H). m/z (ESI, positive ion) =485.2 [ M+H ]] + 。
Example compounds 82, 97 (starting from 74 c) and 107 (starting from 72 e) were synthesized as described in example 83.
EXAMPLE 89 (S) -2- ((4- (3- (4-isopropyl-2-methylphenoxy) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (89)
Step A.3- (4-isopropyl-2-methylphenoxy) -4-nitrobenzoic acid methyl ester (89 a)
To a mixture of methyl 3-fluoro-4-nitrobenzoate (2.65 g,13.3 mmol) in DMF (50 mL) was added 4-isopropyl-2-methylphenol (2 g,13.3 mmol) and K 2 CO 3 (5.5 g,39.9 mmol). The mixture was stirred at 25 ℃ for one hour. After completion of the reaction, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 ml×3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=5:1) to provide the title product (89 a) (1.45 g, 56%) as a white solid. m/z (ESI, positive ion) =330.0 [ m+h ]] + 。
Step B.4-amino-3- (4-isopropyl-2-methylphenoxy) benzoic acid methyl ester (89 b)
To a mixture of 89a (3 g,9.1 mmol) in MeOH (50 mL) was added 10% Pd/C (200 mg,1.9 mmol). At 20℃at H 2 The mixture was stirred under an atmosphere for 12h. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: etoac=3:1) to afford the title product (89 b) as a white solid (2.52 g, 92%). m/z (ESI, positive ion) =300.1 [ M+H ]] + 。
Step C.3- (4-isopropyl-2-methylphenoxy) benzoic acid methyl ester (89 c)
A mixture of isobutyl nitrite (1.4 g,13.2 mmol) in DMF (20 mL) was stirred at 70℃for 10min. Then 89b (1.6 g,5.3 mmol) was added to the above mixture. The reaction mixture was stirred at 70 ℃ for one hour. After completion, the reaction was completed with H 2 O (20 mL) was quenched and extracted with EtOAc (20 mL. Times.3). The organic layer was dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=20:1) to provide the title product (89 c) as a white solid (0.7 g, 45%).
Step D.3- (4-isopropyl-2-methylphenoxy) benzoic acid (89 d)
The title compound was prepared from 89c by a procedure similar to that described in step D of example 78. m/z (ESI, positive ion) =271.1 [ M+H ]] + 。
Step E. (S) -2- ((4- (3- (4-isopropyl-2-methylphenoxy) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (89 e)
The title compound was prepared from 89D by a procedure similar to that described in example 59 step D. m/z (ESI, positive ion) =597.3 [ m+h ]] + 。
Step F. (S) -2- ((4- (3- (4-isopropyl-2-methylphenoxy) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (89)
To 89e (80 mg,0.13 mmol) in MeOH: H 2 To the mixture in O (6 mL:2 mL) was added LiOH (64 mg,2.68 mmol). The mixture was stirred at 20℃for 5h. After completion, the reaction was quenched with water (10 mL), adjusted to ph=6 by 10% citric acid, and extracted with EtOAc (10 ml×3). The organic layers were combined, dried, filtered, and concentrated to provide a crude residue, which was purified by reverse phase HPLC (CH 3 CN water with formic acid as modifier) to give the title product (89) as a white solid (20 mg, 26%). 1 HNMR(400MHz,CD 3 OD) delta ppm 8.46 (d, j=0.9 hz, 1H), 8.10-8.14 (m, 1H), 7.79 (d, j=8.3 hz, 1H), 7.36-743 (m, 1H), 7.17 (d, j=1.8 hz, 1H), 7.04-7.12 (m, 2H), 6.97 (ddd, j=8.3, 2.6,0.9hz, 1H), 6.84-6.89 (m, 2H), 5.28-5.17 (m, 1H), 4.92-4.87 (m, 1H), 4.73 (dd, j=15.3, 2.6hz, 1H), 4.65 (td, j=7.9, 5.7hz, 1H), 4.46 (dt, j=9.2, 5.9hz, 1H), 4.30-4.39 (m, 2H), 3.28-5.17 (m, 2H), brs (2.85, 2.9, 2H), 4.92-4.87 (m, 1H), 4.73 (dd, j=15.3.3 hz, 2.6H), brs (2.8.3, 2H). m/z (ESI, positive ion) =583.3 [ m+h ]] + 。
EXAMPLE 90 (S) -2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -1,3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indol-2-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (90)
Step A.1- (bromomethyl) -4-chloro-2-fluorobenzene (90 a)
To a solution of (4-chloro-2-fluorophenyl) methanol (1 g,6.2 mmol) in DCM (10 mL) at 0deg.C was added PBr 3 (0.84 g,3.1 mmol) and the reaction was stirred at the same temperature for one hour. The mixture was diluted with DCM (50 mL) and saturated NaHCO 3 Aqueous solution (10 mL), H 2 O (10 mL) washing, na 2 SO 4 Dried, filtered, and concentrated in vacuo to give the title product (90 a) (1.05 g, 73%) as a yellow oil, which was used in the next step without further purification.
Step B.4-chloro-2-fluoro-1- ((2-iodophenoxy) methyl) benzene (90 b)
90a (1.0 g,4.5 mmol), 2-iodophenol (1.0 g,4.5 mmol) and potassium carbonate (1.87 g,13.4 mmol) are combined in CH at 70 ℃ 3 The mixture in CN (20 mL) was stirred for 2h. The mixture was diluted with EtOAc (100 mL) and washed with water (30 ml×2). The organic layer was purified by Na 2 SO 4 Dried, filtered, and concentrated in vacuo to yield a crude residue. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 5-10%) to afford the title product (90 b) (1.5 g, 82%) as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δppm7.79(dd,J＝7.7,1.2Hz,1H),7.66(t,J＝8.1Hz,1H),7.52(dd,J＝10.0,1.8Hz,1H),7.42-7.34(m,2H),7.15(d,J＝8.2Hz,1H),6.79(t,J＝7.5Hz,1H),5.21(s,2H)。
Step C.2- (2- ((4-chloro-2-fluorobenzyl) oxy) phenyl) hydrazine-1-carboxylic acid tert-butyl ester (90 c)
At 80℃under N 2 Next, 90b (1.5 g,4.1 mmol) hydrazine was added Tert-butyl benzoate (700 mg,5.3 mmol), cs 2 CO 3 A mixture of (2.0 g,6.1 mmol), copper (I) iodide (80 mg,0.4 mmol) and 3,4,7, 8-tetramethyl-1, 10-phenanthroline (0.1 g,0.4 mmol) in DMF (30 mL) was stirred for 28h. The mixture was diluted with EtOAc (250 mL) and treated with H 2 O (100 mL) followed by brine (100 mL). The organic layer was purified by Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue which was purified by silica gel column chromatography (EtOAc/petroleum ether, 20-30%) to afford the title product (90 c) (0.32 g, 17%) as a pale yellow oil. m/z (ESI, positive ion) =389.2 [ m+na ]] + 。
Step d. (2- ((4-chloro-2-fluorobenzyl) oxy) phenyl) hydrazine (90 d)
To a solution of 90c (330 mg,0.9 mmol) in DCM (3 mL) was added a solution of 4NHCl in dioxane (5 mL). The mixture was stirred at 20 ℃ for 6h, then concentrated to give the title product (90 d) (220 mg) as a brown solid, which was used in the next step without further purification. m/z (ESI, positive ion) =250.1 [ M-NH ] 2 ] + 。
Step E.6- ((4-chloro-2-fluorobenzyl) oxy) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indole (90 e)
A mixture of 90d (200 mg,0.66 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (145 mg,0.73 mmol) in EtOH (15 mL) and concentrated HCl (3 mL) was stirred at 80℃for 4h. The mixture was concentrated in vacuo to give a crude residue which was purified by reverse phase HPLC (37% CH 3 CN/H 2 O,0.5% formic acid as modifier) to give the title product (90 e) as a brown solid (160 mg, 66%). m/z (ESI, positive ion) =331.1 [ m+h ]] + 。
Step F. (S) -2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -1,3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indol-2-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (90 f)
To 90e (61 mg,0.186 mmol) and K 2 CO 3 To a mixture of (70 mg,0.51 mmol) in DMF (5 mL) was added 1h (50 mg,0.17 mmol) and KI (14 mg,0.08 mmol) in DMF (5 mL). The resulting mixture was stirred at 22℃for 5h. The mixture was poured into water (20 mL) and extracted with EtOAc (20 ml×2). Using H for the organic layer 2 O (10 mL), brine (10 mL), washed with Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give a crude residue which was purified by preparative TLC (silica gel, DCM: CH 3 Oh=10:1) to give the title product (90 f) (32 mg, 20%) as a yellow oil. m/z (ESI, positive ion) =589.2 [ m+h ]] + 。
Step G. (S) -2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -1,3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indol-2-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (90)
90f (32 mg,0.056 mmol) and lithium hydroxide (27 mg,1.12 mmol) were combined in CH at 20deg.C 3 OH:H 2 The mixture in o=10:1 (6 mL) was stirred for 5h. The mixture was adjusted to ph=7 with 1N HCl. The solvent was removed and the residue was purified by reverse phase HPLC (27% ch) 3 CN/H 2 O, with 0.5% TFA as modifier) to afford the title compound (90) (9.7 mg, 23.9%) as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δppm 10.87(s,1H),8.08(s,1H),7.80(dd,J＝8.6,1.1Hz,1H),7.76(t,J＝8.1Hz,1H),7.56-7.41(m,2H),7.35(dd,J＝8.1,2.0Hz,1H),6.91(d,J＝7.9Hz,1H),6.83(t,J＝7.8Hz,1H),6.70(d,J＝7.7Hz,1H),5.25(s,2H),5.01-5.13(m,1H),4.73(dd,J＝14.9,6.9Hz,1H),4.56-4.65(m,1H),4.45(dd,J＝13.6,8.3Hz,1H),4.38-430 (m, 1H), 4.15 (d, j=13.6 hz, 1H), 4.03 (d, j=13.2 hz, 1H), 3.62-3.74 (m, 2H), 2.83-2.90 (m, 2H), 2.73-2.80 (m, 1H), 2.65-269 (m, 1H), 2.53-2.58 (m, 1H), 2.30-2.35 (m, 1H). m/z (ESI, positive ion) =575.1 [ M+H ]] + 。
Compound 53 of the example was synthesized as described in example 90.
EXAMPLE 91.5- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidine-1-carbonyl) picolinic acid (91)
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Step A.5- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidine-1-carbonyl) picolinic acid methyl ester (91 a)
To a flask containing 83d (15 mg,0.05 mmol), 6- (methoxycarbonyl) pyridine-3-carboxylic acid (14.5 mg,0.08 mmol) and HATU (36.6 mg,0.096 mmol) was added DMF (1 mL) followed by DIPEA (0.028 mL,0.16 mmol). The reaction was stirred for 10min, then directly by reverse phase HPLC (CH 3 CN and water, with 0.1% TFA as modifier) to give the title product (91 a) as a white solid (23 mg, 60.1%). m/z (ESI, positive ion) =475.2 [ m+h ] ] + 。
Step B.5- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidine-1-carbonyl) picolinic acid (91)
91a (23.0 mg,0.049 mmol) was dissolved in CH 3 CN (0.5 mL) was then added with 2N aqueous NaOH (0.5 mL). The mixture was stirred at room temperature overnight and purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to give the title compound (91) as a white solid (13.6 mg, 60.9%). 1 H NMR(600MHz,CD 3 OD) delta ppm 8.74 (s, 1H), 8.25 (d, j=8.07 hz, 1H), 8.03-8.09 (m, 1H), 7.67 (t, j=7.52 hz, 1H), 7.57-7.64 (m, 2H), 7.51-7.57 (m, 1H), 6.87 (d, j=7.34 hz, 1H), 6.71 (d, j=8.07 hz, 1H), 5.46-5.59 (m, 2H), 4.66-4.77 (m, 1H), 3.72 (br d, j=12.10 hz, 1H), 3.30-3.39 (m, 1H), 2.98-3.06 (m, 1H), 2.94 (ddd, j=11.55, 7.70,3.85hz, 1H), 1.91-1.97 (m, 1H), 1.72-1.88 (m, 3H). m/z (ESI, positive ion) =461.2 [ m+h ]] + 。
Example 92.4- (((6- (4- (6- (1H-tetrazol-5-yl) nicotinyl) piperazin-1-yl) pyridin-2-yl) oxy) methyl) -3-fluorobenzonitrile (92)
Step A.4- (((6-chloropyridin-2-yl) oxy) methyl) -3-fluorobenzonitrile (92 a)
A solution of 3-fluoro-4- (hydroxymethyl) benzonitrile (151 mg,1.0 mmol) in THF (2 mL) was cooled to 0deg.C. KOTBu (168 mg,1.5 mmol) was added in portions. The resulting mixture was stirred at 0deg.C for 5min, followed by the addition of 2, 6-dichloropyridine (123 mg,0.83 mmol). The reaction was slowly warmed to room temperature and stirred overnight. After completion, the reaction was saturated with NH 4 Aqueous Cl (5 mL) was quenched and extracted with ethyl acetate (5 mL. Times.3). The combined organic phases were washed with brine, with Na 2 SO 4 Dried, filtered, and then purified by silica gel column chromatography (hexane: etoac=5:1). The fractions containing the desired product were concentrated to give the title product (92 a) (79.4 mg, 36.4%), m/z (ESI, positive ion) =263.2 [ m+h ]] + 。
Step B.4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (92 b)
Direction 92a (7)9.4mg,0.3 mmol), piperazine-1-carboxylic acid tert-butyl ester (61.5 mg,0.33 mmol), pd 2 (dba) 3 (13.7 mg,0.015 mmol), BINAP (18.7 mg,0.3 mmol) and Cs 2 CO 3 Toluene (5 mL) was added to the mixture (195 mg,0.6 mmol). The reaction mixture was stirred at 110 ℃ overnight. After completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 ml×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered, and concentrated. The crude residue was purified by reverse phase HPLC (CH 3 CN and water, with 0.1% TFA as modifier) to give the title product (92 b) as a pale brown solid (20.7 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δppm 7.24(d,J＝3.5Hz,1H),6.46(dd,J＝3.5,0.5Hz,1H),5.54(d,J＝5.4Hz,1H),4.78-4.68(m,1H),3.79(s,3H),1.38(d,J＝6.6Hz,3H)。
Step 3.3-fluoro-4- (((6- (piperazin-1-yl) pyridin-2-yl) oxy) methyl) benzonitrile (92 c)
To a mixture of 92b (20.7 mg,0.05 mmol) in ethyl acetate (0.2 mL) was added 2N HCl (1.2 mL). The reaction was stirred for 3h and the crude product was lyophilized to give the title product (92 c) as a white solid (14.2 mg, 80%). m/z (ESI, positive ion) =313.4 [ m+h ] ] + 。
Step D.4- (((6- (4- (6- (1H-tetrazol-5-yl) nicotinyl) piperazin-1-yl) pyridin-2-yl) oxy) methyl) -3-fluorobenzonitrile (92)
To a flask containing 92c (4 mg, 0.09 mmol), 6- (1H-tetrazol-5-yl) nicotinic acid (2.0 mg,0.01 mmol) and HATU (4.3 mg,0.01 mmol) was added DMF (1 mL) followed by DIPEA (0.005 mL,0.028 mmol). The reaction was stirred for 10min and was directly purified by reverse phase HPLC (CH 3 CN and water, with 0.1% HOAc as modifier) to give the title compound (9) as a white solid2)(1.1mg,24.1％)。 1 HNMR(600MHz,CD 3 OD) δppm 8.22-8.41 (m, 2H), 8.08 (br d, j=7.70 hz, 1H), 7.65 (br t, j=7.52 hz, 1H), 7.56 (dd, j=12.10, 8.80hz, 2H), 7.50 (t, j=8.07 hz, 1H), 6.36 (d, j=8.07 hz, 1H), 6.20 (d, j=7.70 hz, 1H), 5.46 (s, 2H), 3.84 (br s, 2H), 3.65 (br s, 2H), 3.56 (br s, 4H). m/z (ESI, positive ion) =486.3 [ m+h ]] + 。
Examples 94 and 96.2- ((4- (5- ((R) -1- (2, 4-dichlorophenoxy) ethyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (94) and 2- ((4- (5- ((S) -1- (2, 4-dichlorophenoxy) ethyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (96)
Step A.5-Acetylfuran-2-carboxylic acid methyl ester (94 a)
A solution of methyl 5-bromofuran-2-carboxylate (50 mg,0.24 mmol) in anhydrous DMF (1.2 mL) was treated with tributyl- (1-ethoxyvinyl) stannane (106 mg,0.29 mmol) and bis (triphenylphosphine) palladium (II) chloride (17 mg,0.024 mmol) under nitrogen. The reaction was heated to 115 ℃ and stirred for 18h, cooled, treated with 1N HCl (5 mL) and stirred at 20 ℃ for 30min. The reaction was then diluted with water (2 mL) and extracted with EtOAc (2 ml×3). The organic layer was washed with water (2 mL), brine (2 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EtOAc/petroleum ether, 0-11%) to afford the title product (94 a) (33 mg, 74.1%) as a yellow oil. m/z (ESI, positive ion) =169.1 [ m+h ]] + 。
Step B.5- (1-hydroxyethyl) furan-2-carboxylic acid methyl ester (94 b)
To a solution of 94a (1.3 g,7.7 mmol) in anhydrous MeOH (20 mL) at 0deg.C was added NaBH in portions 4 (0.15 g,3.85 mmol). The reaction mixture was stirred at 25℃for 2H and H was used 2 O (3 mL) quench. The organic solvent was removed under reduced pressure, and the residue was extracted with EtOAc (3 ml×3). The combined organic extracts were washed with brine (5 mL), with Na 2 SO 4 Dried, filtered, and concentrated. The resulting crude residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 0-20%) to afford the title product (94 b) (1.2 g, 67.0%) as a yellow oil. m/z (ESI, positive ion) =240.1 [ m+h ] ] + 。
Step C.5- (1- (2, 4-dichlorophenoxy) ethyl) furan-2-carboxylic acid methyl ester (94 c)
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To a mixture of 94b (50 mg,0.29 mmol), 2, 4-dichlorophenol (53 mg,0.32 mmol) and triphenylphosphine (85 mg,0.32 mmol) in THF (2.5 mL) was added diethyl azodicarboxylate (56 mg,0.32 mmol) at 0deg.C. At 25℃under N 2 The mixture was stirred for 16h and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 0-10%) to afford the title product (94 c) (31 mg, 30.1%) as a yellow oil. m/z (ESI, positive ion) =337.0 [ m+na ]] + 。
Step D.5- (1- (2, 4-dichlorophenoxy) ethyl) furan-2-carboxylic acid (94 d)
A solution of 94c (15 mg,0.05 mmol) in acetonitrile (0.5 mL) was treated with lithium hydroxide (6 mg,0.24 mmol) in water (0.5 mL) at 0deg.C and stirred at 25deg.C for 2h. The mixture was concentrated, acidified to ph=2 by 1N HCl, and extracted with EtOAc (2 ml×3). The organic phase was washed with brine (2 mL) and dried over anhydrous sodium sulfateAnd concentrated to afford the title product (94 d) (11 mg) as a yellow oil, which was used directly in the next step without further purification. m/z (ESI, negative ion) =299.0 [ m-H ]] - 。
Step E.2- ((4- (5- (1- (2, 4-dichlorophenoxy) ethyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (94 e)
1j (213 mg,0.62 mmol) and 94d (186 mg,0.62 mmol) were dissolved in DMF (3 mL). At N 2 Diisopropylethylamine (319 mg,2.47 mmol) and HATU (352 mg,0.93 mmol) were added under atmosphere and the mixture was stirred at 20℃for 2h. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL. Times.3). The combined organic phases were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (MeOH/DCM, 5-10%, with 0.5% formic acid) to give the title product (94 e) as a yellow oil (180 mg, 42.5%). m/z (ESI, positive ion) =627.2 [ m+h ]] + 。
Step F.2- ((4- (5- ((R) -1- (2, 4-dichlorophenoxy) ethyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (94) and 2- ((4- (5- ((S) -1- (2, 4-dichlorophenoxy) ethyl) furan-2-carbonyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (96)
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A solution of 94e (50 mg,0.08 mmol) in MeOH (1 mL) was treated with sodium hydroxide (13 mg,0.21 mmol) in water (1 mL) at 0deg.C, and the reaction mixture was stirred at 20deg.C for 4h. The mixture was concentrated, then diluted with water (5 mL), adjusted to ph=5 with 0.1NHCl, and extracted with EtOAc (5 ml×3). The organic phase was washed with water (2 mL), brine (2 mL), Dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column chromatography (MeOH/DCM, 5-10%,0.5% formic acid) and further separated using chiral column (ChiralPak OJ,4.6 x 150mm,3 μm) using CO 2 MeOH 75:25 as mobile phase and flow rate of 2.0mL/min to afford the title compound (94, peak 1 elution) (4.1 mg, 8.03%) and (96, peak 2 elution) (5 mg, 9.3%) as a white solid. 94: 1 H NMR(400MHz,CD 3 OD) delta ppm8.34 (s, 1H), 7.98 (br d, j=8.56 hz, 1H), 7.68 (br d, j=8.56 hz, 1H), 7.34 (br d, j=2.45 hz, 1H), 7.18 (br dd, j=8.80, 2.45hz, 1H), 7.12 (br d, j=8.80 hz, 1H), 6.97 (d, j=3.42 hz, 1H), 6.54 (d, j=3.67 hz, 1H), 5.54 (q, j=6.36hz, 1H), 5.21-5.29 (m, 1H), 4.72 (br dd, j=15.28, 2.57hz, 1H), 4.60-4.68 (m, 2H), 4.46 (dt, j=9.11, 5.96hz, 1H), 4.04 (br d, 3.67hz, 1H), 5.54 (q, j=3.67 hz, 1H), 5.21-5.36 hz, 1H), 5.21-5.29 (m, 1H), 4.72 (br d, 1H), 4.94-94 (3.67 hz, 1H). m/z (ESI, positive ion) =613.2 [ m+h ]] + .96 data: 1 H NMR(400MHz,CD 3 OD) delta ppm 8.31 (s, 1H), 7.97 (br d, j=8.56 hz, 1H), 7.67 (br d, j=8.31 hz, 1H), 7.27-7.35 (m, 1H), 7.19 (dd, j=8.80, 2.69hz, 1H), 7.12 (d, j=9.05 hz, 1H), 6.97 (d, j=3.42 hz, 1H), 6.54 (d, j=3.42 hz, 1H), 5.54 (q, j=6.36 hz, 1H), 5.26 (qd, j=7.17, 2.69hz, 1H), 4.72 (br dd, j=15.41, 2.69hz, 1H), 4.56-4.68 (m, 2H), 4.45 (dt, j=9.23, 5.90hz, 1H), 4.03 (br 69, 13.69hz, 1H), 5.54 (br=3.67, 1H), 5.67 (q, j=6.36 hz, 1H), 5.26 (qd, j=7.17, 2.69hz, 1H), 4.72 (br 1H). m/z (ESI, positive ion) =613.2 [ m+h ] ] + . The stereochemistry of 94 and 96 is arbitrarily specified.
EXAMPLE 95 (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) -4-fluorobenzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (95)
Step a. (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) -4-fluorobenzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (95 a)
1j (80 mg,0.23 mmol) and 3- ((2-chloro-4-methylphenyl) (methyl) amino) -4-fluorobenzoic acid (68 mg,0.23mmol, prepared by a procedure similar to that described in example 46, steps a-C) were dissolved in DCM (2 mL). DIPEA (0.16 mL,0.93 mmol) and a solution of propylphosphonic anhydride (50 wt%, in ethyl acetate, 442mg,0.69 mmol) were added. The solution was stirred for one hour at 20 ℃ and concentrated. The mixture was purified by silica gel column chromatography (MeOH/DCM, 5-10%) to afford the title product (95 a) as a yellow solid (61 mg, 43.9%). m/z (ESI, positive ion) =620.2 [ m+h ]] + 。
Step B. (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) -4-fluorobenzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (95)
To 95a (65 mg,0.1 mmol) in MeOH: H at 0deg.C 2 To a solution in o=5:1 (1.2 mL) was added sodium hydroxide (21 mg,0.5 mmol). The reaction mixture was then warmed to room temperature and stirred for 5h. The mixture was then concentrated, diluted with water (5 mL), adjusted to ph=4 with 0.1NHCl, and extracted with EtOAc (5 ml×3). The organic phase was washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude mixture was purified by silica gel column chromatography (MeOH/DCM, 5-10%, gradient elution) to afford the title product (95) as a white solid (10.4 mg, 16.0%). 1 H NMR(400MHz,CD 3 OD)δppm 8.34(d,J＝0.98Hz,1H),7.97(dd,J＝8.56,1.47Hz,1H),7.68(d,J＝8.56Hz,1H),7.25(s,1H),7.02-7.18(m,3H),6.96(ddd,J＝8.31,4.16,1.96Hz,1H),6.85(dd,J＝8.44,2.08Hz,1H),5.24(qd,J＝7.21,2.32Hz,1H),4.78-4.85(m,1H),4.71(br dd,J＝15.41,2.69Hz,1H),4.63(td,J＝7.82,6.11hz, 1H), 4.44 (dt, j=9.05, 5.87hz, 1H), 3.99-4.06 (m, 1H), 3.90-3.96 (m, 1H), 3.72 (br s, 2H), 3.48 (br s, 2H), 3.25 (s, 3H), 2.74-2.86 (m, 1H), 2.39-2.69 (m, 5H), 2.32 (s, 3H). m/z (ESI, positive ion) =606.2 [ m+h ]] + 。
Example compounds 98 and 100 were synthesized as described in example 95.
EXAMPLE 99 (S) -2- ((4- (2- ((2-chloro-4-methylphenyl) (methyl) amino) isonicotinyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (99)
Step A.4- (2-Bromoisonicotinoyl) piperazine-1-carboxylic acid tert-butyl ester (99 a)
2-bromopyridine-4-carboxylic acid (1.0 g,0.005 mol), piperazine-1-carboxylic acid tert-butyl ester (0.93 g,0.005 mol), DIPEA (3.5 mL,0.02 mol), and propylphosphonic anhydride (T) at 20deg.C 3 A solution of P) (6.36 g,0.02 mol) in DCM (10 mL) was stirred for 3h. After completion, the reaction was completed with H 2 O (50 mL) was diluted and extracted with EtOAc (50 mL. Times.3). The organic layer was dried, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=1:2) to afford the title product (99 a) (1.85 g, 94%) as a yellow solid. m/z (ESI, positive ion) =370.1 [ m+h ]] + 。
Step B.4- (2- ((2-chloro-4-methylphenyl) amino) isonicotinyl) piperazine-1-carboxylic acid tert-butyl ester (99 b)
99a (1.27 g,3.4 mmol), 2-chloro-4-methylaniline (0.48 g,3.4 mmol), chloro (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl) were reacted at 95 ℃]Palladium (II) (0.53 g,0.6 mmol) and Cs 2 CO 3 (2.82 g,10.0 mmol) in dioxane (12 mL) was stirred for 12h. After completion, the reaction was completed with H 2 O (50 mL) was diluted and extracted with EtOAc (50 mL. Times.3). The organic layer was dried, filtered, concentrated, and purified by silica gel column chromatography (CH 2 Cl 2 Meoh=50:1) to afford the title product (99 b) (0.85 g, 56%) as a yellow oil. m/z (ESI, positive ion) =431.2 [ M+H ]] + 。
Step C.4- (2- ((2-chloro-4-methylphenyl) (methyl) amino) isonicotinyl) piperazine-1-carboxylic acid tert-butyl ester (99 c)
A solution of 99b (652 mg,1.51 mmol) and NaH (60%, 72mg in mineral oil, 3.03 mmol) in DMF (8 mL) was stirred at 0deg.C for 0.5h. MeI (258 mg,1.81 mmol) was then added. The resulting mixture was stirred at 0℃for 1.5h. After completion, the reaction was completed with H 2 O (1 mL) was quenched and extracted with EtOAc (10 mL. Times.3). The organic layer was dried, filtered, concentrated, and purified by silica gel column chromatography (DCM: meoh=50:1) to afford the title product (99 c) as a yellow solid (575 mg, 81%). m/z (ESI, positive ion) =445.2 [ m+h ]] + 。
Step D. (2- ((2-chloro-4-methylphenyl) (methyl) amino) pyridin-4-yl) (piperazin-1-yl) methanone (99 d)
A solution of 99c (295 mg,0.66 mmol) and 2N HCl in EtOAc (5 mL) was stirred for 3h at 20deg.C. After completion, the reaction was cooled in an ice bath. Saturated NaHCO 3 An aqueous solution was added to the mixture to adjust to ph=7. Will react with H 2 O (10 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The organic layer was dried, concentrated and purified by reverse phase HPLC (30% CH 3 CN/H 2 O, with 0.05% formic acid as modifier) to afford the title product (99 d) (129 mg, 52%) as a yellow solid.m/z (ESI, positive ion) =345.1 [ m+h ]] + 。
Step E. (S) -2- ((4- (2- ((2-chloro-4-methylphenyl) (methyl) amino) isonicotinyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (99 e)
99d (84 mg,0.24 mmol), 1h (72 mg,0.24 mmol) and K were combined at 20 ℃ 2 CO 3 A solution of (67 mg,0.49 mmol) in DMF (2 mL) was stirred for 5h. After completion, the reaction was completed with H 2 O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The organic layer was dried, filtered, concentrated, and purified by silica gel column chromatography (DCM: meoh=50:1) to afford the title product (99 e) as a white solid (45 mg, 29%). m/z (ESI, positive ion) =603.2 [ m+h ]] + 。
Step F. (S) -2- ((4- (2- ((2-chloro-4-methylphenyl) (methyl) amino) isonicotinyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (99)
99e (46 mg,0.076 mmol) and LiOH (9 mg,0.38 mmol) were taken up in THF: H at 20 ℃ 2 The solution in o=1:1 (1 mL) was stirred for 3h. After completion, the reaction was cooled in an ice bath and 1N HCl was added to the mixture to adjust to ph=5, and the reaction was extracted with EtOAc (50 ml×3). The organic layer was dried, filtered, concentrated, and purified by reverse phase HPLC (25% CH 3 CN/H 2 O, with 0.05% formic acid as modifier) to afford the title product (99) (9.8 mg, 21.4%) as a white solid. 1 H NMR(400MHz,CD 3 OD)δppm 8.32(s,1H),8.18(d,J＝5.14Hz,1H),7.97(br d,J＝8.31Hz,1H),7.67(d,J＝8.31Hz,1H),7.42(s,1H),7.26(d,J＝0.98Hz,2H),6.63(dd,J＝5.14,1.22Hz,1H),6.07(s,1H),5.23(qd,J＝6.89,2.08Hz,1H),4.81-4.85(m,1H),4.69(br dd,J＝15.41,2.45hz, 1H), 4.56-4.66 (m, 1H), 4.43 (dt, j=9.05, 5.87hz, 1H), 4.01 (d, j=13.69 hz, 1H), 3.91 (d, j=13.94 hz, 1H), 3.69 (br s, 2H), 3.33-3.44 (m, 5H), 2.68-2.89 (m, 1H), 2.41-2.64 (m, 5H), 2.40 (s, 3H). m/z (ESI, positive ion) =589.2 [ m+h ]] + 。
Example compounds 86, 93 and 101 were synthesized as described in example 99.
EXAMPLE 102 (S) -2- ((4- (2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (102)
Step A.2- (bromomethyl) oxazole-5-carboxylic acid methyl ester (102 a)
NBS (1 g,7.1 mmol) and AIBN (0.47 g,2.8 mmol) in CCl at 80℃C 4 To a stirred solution in (20 mL) was added methyl 2-methyl-1, 3-oxazole-5-carboxylate (1.9 g,10.6 mmol). The reaction mixture was stirred at 80℃for 16h. After completion, the reaction was completed with H 2 O (15 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc: petroleum ether=1:10) to afford the title product (102 a) (0.8 g, 49%) as a yellow oil. m/z (ESI, positive ion) =220.1 [ m+h ]] + 。
Step B.2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carboxylic acid methyl ester (102 b)
To 102a (300 mg,1.36 mmol) and 2, 4-dichlorophenol (333 mg,2.0 mmol) in CH 3 Addition of K to solution in CN (10 mL) 2 CO 3 (560 mg,4.1 mmol). The reaction was mixed at 20 ℃The mixture was stirred for 2h. After completion, the reaction solution was taken up with H 2 O (10 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc: petroleum ether=1:10) to afford the title product (102 b) as a white solid (267 mg, 62%). m/z (ESI, positive ion) =302.2 [ m+h ] ] + 。
Step C.2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carboxylic acid (102 c)
To a stirred solution of 102b (300 mg,0.99 mmol) in MeOH (5 mL) was added NaOH (198 mg,4.97 mmol) in H 2 O (1 mL). The reaction mixture was stirred at 20 ℃ for 2h and cooled in an ice bath. 1N HCl (2.0 mL) was added to adjust to ph=5. The reaction mixture was then extracted with EtOAc (5 mL. Times.3). The combined organic layers were dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc/petroleum ether, 20-30%) to afford the title product (102 c) as a white solid (210 mg, 70%). m/z (ESI, positive ion) =288.0 [ m+h ]] + 。
Step d. (S) -2- ((4- (2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (102 d)
To a stirred solution of 102c (100 mg,0.35 mmol), 1j (143 mg,0.42 mmol) and DIPEA (0.18 mL,1.04 mmol) in DCM (3 mL) at 20deg.C was added T 3 P (221 mg,0.694mmol,2 eq.). The reaction mixture was stirred at 20℃for 2h. After completion, the reaction solution was taken up with H 2 O (5 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc: petroleum Ether=1:5) to afford the title product (102 d) as a white solid (90 mg, 40%). m/z (ESI, positive ion) =614.1 [ m+h ]] + 。
Step e. (S) -2- ((4- (2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carbonyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (102)
To 102d (10 mg,0.016 mmol) at 20℃in CH 3 CN:H 2 To a stirred solution in o=1:1 (2 mL) was added TBD (5 mg,0.033 mmol). The reaction mixture was stirred for 2h and cooled in an ice bath. 1N HCl (0.1 mL) was added to adjust to ph=5. The reaction mixture was then extracted with EtOAc (5 mL. Times.3). The combined organic layers were dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc/petroleum ether, 20-30%) to afford the title product (102) (3.2 mg, 30%) as a white solid. 1 H NMR(400MHz,CD 3 OD) delta ppm 8.30 (s, 1H), 7.97 (br d, j=8.77 hz, 1H), 7.62-7.68 (m, 2H), 7.41 (d, j=2.63 hz, 1H), 7.24-7.30 (m, 1H), 7.21 (d, j=8.77 hz, 1H), 5.34 (s, 2H), 5.26 (qd, j=7.24, 2.85hz, 1H), 4.89-4.92 (m, 1H), 4.71 (br dd, j=15.57, 2.85hz, 1H), 4.60-4.67 (m, 1H), 4.41-4.49 (m, 1H), 4.00-4.07 (m, 1H), 3.92-3.99 (m, 1H), 3.69-3.80 (m, 4H), 2.79 (br d, j=5.70 hz, 2.46-1H). m/z (ESI, positive ion) =600.1 [ m+h ] ] + 。
Example compound 113 was synthesized as described in example 102.
EXAMPLE 105 (S) -2- ((4- (1- (3- ((2-chloro-4-methylphenyl) (methyl) amino) phenyl) cyclopropyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (105)
Step A.1- (1- (3-bromophenyl) cyclopropyl) -4-toluenesulfonylpiperazine (105 a)
The flask was charged with 1- (3-bromophenyl) cyclopropyl-1-amine (50 mg,0.24 mmol). DIPEA (1 mL) and N, N-bis (2-chloroethyl) -4-methylbenzenesulfonamide (77 mg,0.26 mmol) were added. The reaction mixture was stirred at 120℃for 40h. The reaction was diluted with water (10 mL) and extracted with EtOAc (10 mL. Times.3). The organic phase was washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 0-20%) to afford the title product (105 a) as a yellow solid (53 mg, 46%). m/z (ESI, positive ion) =435.1 [ m+h ]] + 。
Step B.2-chloro-4-methyl-N- (3- (1- (4-toluenesulfonylpiperazin-1-yl) cyclopropyl) phenyl) aniline (105 b)
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To a solution of 105a (18 mg,0.04 mmol), cesium carbonate (27 mg,0.08 mmol), palladium diacetate (1 mg,0.04 mmol) and rac-2, 2 '-bis (diphenylphosphino) -1,1' -binaphthyl (3 mg,0.04 mmol) in toluene (0.5 mL) was added 2-chloro-4-methylaniline (6 mg,0.04 mmol). The reaction was stirred at 100℃for 2h. After completion, the mixture was concentrated. The reaction was diluted with water (5 mL) and extracted with EtOAc (5 ml×3). The organic phase was washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue which was purified by silica gel column chromatography (EtOAc/petroleum ether, 0-20%) to afford the title product (105 b) (12 mg, 53%) as a yellow solid. m/z (ESI, positive ion) =496.2 [ m+h ] ] + 。
Step C.2-chloro-N, 4-dimethyl-N- (3- (1- (4-toluenesulfonylpiperazin-1-yl) cyclopropyl) phenyl) aniline (105 c)
NaH (60%, 72mg,1.8mmol in mineral oil) was added successively in portions to a solution of 105b (4476 mg,0.9 mmol) in anhydrous DMF (5 mL) under nitrogen atmosphere followed by the dropwise addition of methyl iodide (255 mg,1.8 mmol). The reaction mixture was stirred at 20 ℃ for one hour and quenched with water (20 mL) at 0 ℃. The mixture was extracted with EtOAc (20 ml×3), and the organic phase was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 0-20%) to afford the title product (105 c) as a yellow oil (12 mg, 58%). m/z (ESI, positive ion) =510.2 [ m+h ]] + 。
Step D.2-chloro-N, 4-dimethyl-N- (3- (1- (piperazin-1-yl) cyclopropyl) phenyl) aniline (105 d)
To a solution of 105c (240 mg,0.47 mmol) in trifluoroacetic acid (4 mL) was added concentrated H 2 SO 4 (45 mg,3.29 mmol). The mixture was heated at 75 ℃ and stirred for 3h. After completion, the reaction was diluted with water (10 mL) and with NH 3 ·H 2 O was adjusted to ph=11. The mixture was extracted with EtOAc (20 ml×3), and the organic phase was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (MeOH/dichloromethane, 5-10%,0.5% NH) 3 ·H 2 O as a modifier) to afford the impure title product (105 d) as a white solid (139 mg). m/z (ESI, positive ion) =356.2 [ m+h ]] + 。
Step E. (S) -2- ((4- (1- (3- ((2-chloro-4-methylphenyl) (methyl) amino) phenyl) cyclopropyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (105 e)
To a solution of 105d (139 mg,0.39 mmol) in DMF (3 mL) was added 1h (127 mg,0.43 mmol) and potassium carbonate (162 mg,1.17 mmol). The reaction was stirred at 20℃for 3h. The reaction was diluted with water (10 mL) and extracted with EtOAc (20 ml×3). The organic phase was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (MeOH/DCM, 0-5%, gradient elution) to provide the title product (105 e) as a white solid with 81% purity (147 mg). m/z (ESI, positive ion) =614.2 [ m+h ]] + 。
Step F. (S) -2- ((4- (1- (3- ((2-chloro-4-methylphenyl) (methyl) amino) phenyl) cyclopropyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (105)
At 0℃to 105e (80 mg,0.13 mmol) in THF: H 2 To a solution in O (1:1, 2 mL) was added lithium hydroxide (6 mg,0.26 mmol). The reaction mixture was stirred at 20℃for 16h. After completion, THF was removed in vacuo. The resulting mixture was adjusted to ph=7 with 1N HCl and extracted with DCM (5 ml×2). The combined organic phases were washed with water (2 mL), brine (2 mL), dried over magnesium sulfate, filtered, and concentrated to give a crude residue which was purified by reverse phase HPLC (gradient 35-45% CH 3 CN/H 2 O,0.1% TFA as modifier) to afford the title compound (105) (14.5 mg, 18%) as a white solid. 1 H NMR(400MHz,CD 3 OD) delta ppm 8.39 (br s, 1H), 8.04-8.12 (m, 1H), 7.75 (br d, j=8.56 hz, 1H), 7.35 (s, 1H), 7.15-7.29 (m, 3H), 6.86 (br d, j=7.58 hz, 1H), 6.59-6.67 (m, 2H), 5.13 (qd, j=7.16, 2.63hz, 1H), 4.68-4.78 (m, 1H), 4.51-4.65 (m, 2H), 4.23-4.40 (m, 3H), 3.25 (s, 3H), 2.85-3.60 (m, 8H), 2.65-2.73 (m, 1H), 2.38-2.48 (m, 1H), 2.35 (s, 3H), 1.32 (brdd, j=8.68, 7.65 (m, 2H), 4.51-4.65 (m, 2H). m/z (ESI, positive ion) =600.3 [ m+h ]] + 。
EXAMPLE 106 (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzylidene) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (106)
Step A.4- (3-bromobenzylidene) piperidine-1-carboxylic acid tert-butyl ester (106 a)
To a solution of diethyl (3-bromobenzyl) phosphonate (2 g,6.5 mmol) in THF (15 mL) was added NaH (60%, 260mg,13.0mmol in mineral oil) at 0 ℃. After stirring at 0deg.C for 30min, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.59 g,13.0 mmol) in THF (5 mL) was added. The resulting mixture was stirred at the same temperature for 0.5h, followed by a reaction at 20℃under N 2 Stirring is carried out for 8 hours under the atmosphere. The mixture was treated with H 2 O (10 mL) was quenched and extracted with EtOAc (10 mL. Times.2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated, and purified by silica gel column chromatography (EtOAc: petroleum ether=1:10) to give the title product (106 a) as a white solid (2.2 g, 96%). m/z (ESI, positive ion) =374.1 [ m+na ]] + 。
Step B.4- (3- ((2-chloro-4-methylphenyl) amino) benzylidene) piperidine-1-carboxylic acid tert-butyl ester (106 b)
At N 2 Next, to a solution of 106a (1.0G, 2.84 mmol) in 1, 4-dioxane (5 mL) was added 2-chloro-4-methylaniline (480 mg,3.41 mmol), ruphos-Pd-G2 (241 mg,0.31 mmol), cs 2 CO 3 (1.85 g,5.68 mmol). The mixture was stirred at 95 ℃ for 7h, then concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc: petroleum ether=1:10) to give the title product (106 b) as a light brown oil (760 mg, 65%). m/z (ESI, positive ion) =435.1 [ m+na ]] + 。
Step C.4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzylidene) piperidine-1-carboxylic acid tert-butyl ester (106 c)
To a solution of 106b (45 mg,0.11 mol) in DMF (1 mL) was added KOH (78 mg,0.54 mol) and methyl iodide (232 mg,1.6 mol). The mixture was stirred at 20℃for 16h. The reaction was diluted with water (10 mL) and extracted with EtOAc (5 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated, and purified by preparative TLC (EtOAc: petroleum ether=1:5) to give the title product (106 c) as a colorless oil (32 mg, 68%). m/z (ESI, positive ion) =449.2 [ m+na ]] + 。
Step D.2-chloro-N, 4-dimethyl-N- (3- (piperidin-4-ylidenemethyl) phenyl) aniline (106 d)
To a mixture of 106c (45 mg,0.105 mmol) in DCM (3 mL) was added a solution of 4N HCl in dioxane (0.3 mL). The mixture was stirred at 14℃for 2h. After completion, the reaction mixture was concentrated in vacuo to give the title product (106 d) (46 mg, hcl salt) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =327.1 [ M+H ]] + 。
Step E. (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzylidene) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (106 e)
A mixture of 106d (41 mg,0.10 mmol) and potassium carbonate (56 mg,0.41 mmol) in DMF (3 mL) was stirred for 0.5h at 16 ℃. Potassium iodide (2 mg,0.01 mmol) and 1 in DMF (0.5 mL) were then addedh (30 mg,0.10 mmol) was added to the above mixture. After stirring for 2.5h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 ml×2). The combined organic layers were taken up over Na 2 SO 4 Drying, filtration, concentration, and purification by reverse phase HPLC (53% CH 3 CN/H 2 O, with 0.05% TFA as modifier) to give the title product (106 e) as a white solid (29 mg, 39%). m/z (ESI, positive ion) =585.3 [ m+h ]] + 。
Step F. (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzylidene) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (106)
106e (29 mg,0.05 mmol) in CH 3 OH:H 2 LiOH H was added to a solution in a mixed solvent (3.5 mL) of O=5:1 2 O (40 mg,0.95 mmol). The reaction was stirred at 16 ℃ for 18h, adjusted to ph=7 with 1N HCl, and extracted with EtOAc (10 ml×2). The combined organic layers were taken up over Na 2 SO 4 Drying, filtration, concentration, and purification by reverse phase HPLC (42% CH 3 CN/H 2 O, with 0.5% TFA as modifier) to afford the title compound (106) (16.8 mg, 48.4%) as a white solid. 1 H NMR(400MHz,CD 3 OD) delta ppm 8.35 (d, j=0.88 hz, 1H), 8.02-8.09 (m, 1H), 7.82 (d, j=8.77 hz, 1H), 7.36 (s, 1H), 7.11-7.23 (m, 3H), 6.59 (d, j=7.45 hz, 1H), 6.46-6.55 (m, 2H), 6.29 (s, 1H), 5.22 (qd, j=7.16, 2.63hz, 1H), 4.61-4.83 (m, 5H), 4.42 (dt, j=9.43, 5.81hz, 1H), 3.55 (br s, 2H), 3.42 (br s, 2H), 3.21 (s, 3H), 2.72-2.89 (m, 3H), 2.67 (br t, j=5.92 hz, 2H), 2.44-2.55 (m, 1H), 2.36 (m, 3H). m/z (ESI, positive ion) =571.1 [ m+h ] + 。
Example 110.1'- ((6- (2H-tetrazol-5-yl) pyridin-3-yl) methyl) -6- ((2, 4-dichlorobenzyl) oxy) -1',2',3',6 '-tetrahydro-2, 4' -bipyridine (110)
Step A.6- ((2, 4-dichlorobenzyl) oxy) -3',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester (110 a)
(1, 1' -bis (diphenylphosphino) ferrocene) Palladium (II) dichloride (12.7 mg,0.017 mmol), cs at room temperature 2 CO 3 (113 mg,0.35 mmol) and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylate (53 mg,0.17 mmol) were added to 2-chloro-6- [ (2, 4-dichlorophenyl) methoxy in anhydrous 1, 4-dioxane (0.9 mL)]Pyridine (50 mg,0.17 mmol). The mixture was purged with argon for 10min, then heated to 90 ℃ for 2h. The reaction was carried out between EtOAc and saturated NaHCO 3 The aqueous solution is partitioned between. The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtration, concentration, and purification by silica gel column chromatography (gradient elution, etOAc/hexanes, 0-50%) afforded the title product (110 a) as a white oil (48 mg, 64%). m/z (ESI, positive ion) =435.2 [ m+h ]] + 。
Step B.5- ((6- ((2, 4-dichlorobenzomethyl) oxy) -3',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -yl) methyl) pyridine carbonitrile (110 b)
TFA (0.15 mL,2.0 mmol) was added to 110a (44 mg,0.1 mmol) in DCM (1 mL) at room temperature and stirred for 30min. The reaction was concentrated to give the crude TFA salt, which was redissolved in anhydrous THF (0.1 m,1.0 ml). 5-formylpyridine-2-carbonitrile (45 mg,0.15 mmol) was added. After stirring for 10min, sodium triacetoxyborohydride (42 mg,0.2 mmol) was added and the reaction was stirred for 3h. The reaction was carried out between EtOAc and saturated NaHCO 3 The aqueous solution is partitioned between. The organic layer was washed with brine, dried (Na 2 SO 4 ) Concentrating, and passingPurification by silica gel column chromatography (gradient elution, meOH/DCM, 0-5%) afforded the title product (110 b) as a white oil (15 mg, 21%). m/z (ESI, positive ion) =451.2 [ M+H ]] + 。
Step C.1'- ((6- (2H-tetrazol-5-yl) pyridin-3-yl) methyl) -6- ((2, 4-dichlorobenzyl) oxy) -1',2',3',6 '-tetrahydro-2, 4' -bipyridine (110)
NaN was added at room temperature 3 (2 mg,0.032 mmol) and NH 4 Cl (2 mg,0.032 mmol) was added to 110b (13 mg,0.029 mmol) in anhydrous DMF (0.3 mL). After stirring for 10min, the reaction was heated to 100 ℃ for 40h, followed by cooling. The crude mixture was purified directly by reverse phase HPLC (gradient elution, 0-90% CH 3 CN/water with 0.1% TFA as modifier) to afford the title compound (110) (2.6 mg, 15%) as a white solid. 1 H NMR(600MHz,CD 3 OD) δppm 8.94 (br s, 1H), 8.38 (d, j=8.07 hz, 1H), 8.23 (dd, j=7.89, 1.28hz, 1H), 7.72 (t, j=7.89 hz, 1H), 7.45-7.50 (m, 2H), 7.31 (dd, j=8.25, 2.02hz, 1H), 7.18 (d, j=7.70 hz, 1H), 6.84 (d, j=8.44 hz, 1H), 6.70 (br s, 1H), 5.48 (s, 2H), 4.62 (s, 2H), 4.01 (br s, 2H), 3.65 (br s, 2H), 2.97 (br s, 2H). m/z (ESI, positive ion) =494.2 [ m+h ]] + 。
EXAMPLE 111 (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) phenoxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (111)
Step A.4- {3- [ (2-chloro-4-methylphenyl) (methyl) amino ] phenoxy } piperidine-1-carboxylic acid tert-butyl ester (111 a)
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At room temperature, 4- (3-bromophenoxy) piperidine-1-carboxylic acid tert-butyl ester (137 mg,0.39 mmol), pd (OAc) 2 (1.4 mg, 0.006mmol), BINAP (4 mg, 0.006mmol) and Cs 2 CO 3 (157 mg,0.48 mmol) was added to a flask containing 2-chloro-N, 4-dimethylaniline (50 mg,0.32 mmol) in anhydrous toluene (0.2M, 1.6 mL). The mixture was degassed with argon for 10min, then heated to 120 ℃ for 2h. The reaction was carried out between EtOAc and saturated NaHCO 3 The aqueous solution is partitioned between. The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtration, concentration, and purification by silica gel column chromatography (gradient elution, etOAc/hexanes, 0-20%) afforded the impure title product (111 a) (122 mg) as a white oil. m/z (ESI, positive ion) =432.2 [ m+h ] ] + 。
Step B.2-chloro-N, 4-dimethyl-N- (3- (piperidin-4-yloxy) phenyl) aniline (111 b)
The flask was burned in DCM (0.7 mL) at room temperature to 111a (30 mg, impure). TFA (0.1 mL,1.4 mmol) was added. The reaction was stirred for 30min, then concentrated. The crude residue was taken up in EtOAc and saturated NaHCO 3 The aqueous solution is partitioned between. The organic layer was washed with brine, dried (Na 2 SO 4 ) And concentrated to give the crude title product (111 b) (23 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =331.2 [ m+h ]] + 。
Step C. (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) phenoxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (111)
DIPEA (0.0125 mL,0.07 mmol) and 1h (12 mg,0.04 mmol) were added to 111b (23 mg,0.07 mmol) in DCM (1.4 mL) at room temperature and heated to 40deg.C for 16 minh. The reaction was concentrated to provide the crude ester, which was redissolved in THF: H 2 O (1:1, 0.4 mL). Adding LiOH H 2 O (2 mg,0.045 mmol). After stirring at room temperature for 12h, the reaction was acidified with 1N HCl. The mixture was stirred with EtOAc and saturated NaHCO 3 The aqueous solution is partitioned between. The organic layer was washed with brine, dried (Na 2 SO 4 ) Filtered, concentrated, and purified by reverse phase HPLC (0-70% CH 3 CN and water, with 0.1% hoac as modifier, gradient elution) to afford the title product (111) as a white solid (2.5 mg,6%, over 3 steps). 1 H NMR (600MHz,CD 3 OD) delta ppm 8.50 (s, 1H), 8.27 (s, 1H), 7.95 (dd, j=8.44, 1.47hz, 1H), 7.62 (d, j=8.44 hz, 1H), 7.34 (s, 1H), 7.12-7.21 (m, 1H), 7.01 (t, j=8.25 hz, 1H), 6.31 (dd, j=8.07, 1.83hz, 1H), 6.14 (dd, j=8.07, 2.20hz, 1H), 6.03 (t, j=2.38 hz, 1H), 5.25 (qd, j=7.15, 2.38hz, 1H), 4.85-4.90 (m, 1H), 4.70 (dd, j=15.41, 2.93hz, 1H), 4.63 (td, j=7.89, 5.87 hz), 4.46 (dd, 2.20 hz), 6.03 (t, j=2.38 hz), 6.03 (t, 2.38hz, 1H), 4.25 (qd, j=7.15, 2.38hz, 1H), 4.85-4.90 (m, 1H), 4.7.70 (m, 1H), 3.37 (3.37H), 3.7.7, 3-2.37 hz, 2.7H), 3.7 (m, 2.37H), 2.7.7 (2.37H), 2.7 (m, 1H). m/z (ESI, positive ion) =575.3 [ m+h ]] + 。
Example 112.2- ((4- (3- (1- (2-chloro-4-methylphenyl) ethyl) benzoyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (112)
Step A.3- (2-chloro-4-methylbenzoyl) benzoic acid methyl ester (112 a)
To methyl 3-iodobenzoate (400 mg,1.53 mmol), (2-chloro-4-methylphenyl) boronic acid (260 mg,1.53 mmol), K under a carbon monoxide (CO) atmosphere 2 CO 3 (527 mg,3.82 mmol) and Pd (dppf) Cl 2 To a mixture of DCM (125 mg,0.15 mmol) was added anisole (12 mL). At 80 DEG CThe mixture was stirred for 12h. After completion, the mixture was filtered, concentrated, and purified by silica gel column chromatography (EtOAc: petroleum ether=1:10) to afford the title product (112 a) as a yellow solid (29 mg, 59%). m/z (ESI, positive ion) =289.0 [ m+h ]] + 。
Step B.3- (2-chloro-4-methylbenzoyl) benzoic acid (112 b)
The flask was filled with 112a (150 mg,0.52 mmol) and CH 3 OH:H 2 O=10:1 (8 mL), followed by sodium hydroxide (104 mg,2.6 mmol). The mixture was stirred at 16℃for 3h. The mixture was then adjusted to ph=7 with 1N HCl and extracted with EtOAc (30 ml×2). The combined organic layers were treated with H 2 O (5 mL), brine (5 mL), washed with Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give the title product (112 b) (130 mg) as a grey solid, which was used in the next step without further purification. m/z (ESI, positive ion) =274.9 [ m+h ]] + 。
Step C.3- (1- (2-chloro-4-methylphenyl) -1-hydroxyethyl) benzoic acid (112 c)
CH was added to a mixture of 112b (130 mg,0.47 mmol) in THF (10 mL) at 0deg.C 3 MgBr (3M in hexane, 0.6mL,1.66 mmol). The mixture was stirred at 0 ℃ for one hour. After completion, the mixture was treated with saturated NH 4 Aqueous Cl (10 mL) was quenched with H 2 O (10 mL) was diluted and extracted with EtOAc (20 mL. Times.2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give the title product (112 c) (116 mg, crude) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =273.1 [ M-OH] + 。
Step D.3- (1- (2-chloro-4-methylphenyl) ethyl) benzoic acid (112 d)
To a flask containing 112c (116 mg,0.4 mmol) was added triethylsilane (2 mL) followed by TFA (1 mL). The mixture was stirred at 16℃for 3h. After completion, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 ml×2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (61% CH) 3 CN/H 2 O, with 0.5% TFA as modifier) to give the title product (112 d) as a white solid (69 mg, 60%). m/z (ESI, positive ion) =275.1 [ m+h ]] + 。
Step E.2- ((4- (3- (1- (2-chloro-4-methylphenyl) ethyl) benzoyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (112 e)
The title compound was prepared from 112D and 1j by a procedure similar to that described in example 102 step D. m/z (ESI, positive ion) =601.1 [ m+h ] ] + 。
Step F.2- ((4- (3- (1- (2-chloro-4-methylphenyl) ethyl) benzoyl) piperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (112)
The title compound was prepared from 112e by a procedure similar to that described in example 106 step F. 1 H NMR(400MHz,CD 3 OD)δppm 8.47(s,1H),8.14(dd,J＝8.33,1.32Hz,1H),7.81(d,J＝8.33Hz,1H),7.34-7.45(m,2H),7.22-7.31(m,3H),7.19(s,1H),7.12(br d,J＝7.89Hz,1H),5.23(qd,J＝7.16,2.19Hz, 1H), 4.92 (br d, j=3.51 hz, 1H), 4.74 (br dd, j=15.35, 2.63hz, 1H), 4.58-4.70 (m, 2H), 4.32-4.51 (m, 3H), 3.87 (br s, 2H), 3.57 (br s, 2H), 2.77-3.02 (m, 5H), 2.47-2.58 (m, 1H), 2.28 (s, 3H), 1.62 (d, j=7.45 hz, 3H). m/z (ESI, positive ion) =587.2 [ m+h ]] + 。
EXAMPLE 114 (S) -2- ((4- ((6- ((2-cyano-4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (114)
(E) -2-hydroxy-5-methylbenzaldehyde oxime (114 a)
A solution of 2-hydroxy-5-methylbenzaldehyde (5 g,36.7 mmol), hydroxylamine hydrochloride (12.75 g,183.5 mmol) and pyridine (5.81 g,73.4 mmol) in EtOH (50 mL) was stirred at 60℃for 3h. After completion, the reaction mixture was concentrated to about 10mL. EtOAc (150 mL) and 1N HCl (50 mL) were added. The organic phase was washed with water (50 mL. Times.2), brine (50 mL) and with Na 2 SO 4 Dried, filtered and concentrated to afford the title product (114 a) (5.1 g, 87%) as a white solid. m/z (ESI, positive ion) =152.2 [ m+h ] ] + 。
Step B.2-hydroxy-5-methylbenzonitrile (114 b)
At 17℃to 114a (100 mg,0.66 mmol) and PPh 3 (433 mg,1.65 mmol) in CH 2 Cl 2 To the solution in (2 mL) was added dropwise diethyl azodicarboxylate (334 mg,1.65 mmol). The resulting mixture was stirred at 17℃for 3h. After completion, the reaction mixture was taken up in CH 2 Cl 2 Partition between (10 mL) and 0.1N NaOH (10 mL). The aqueous layer was treated with CH 2 Cl 2 (50 mL. Times.3) and acidified with 1N HCl (10 mL). The acidic aqueous layer was treated with CH 2 Cl 2 (50 mL. Times.2) extraction. The combined organic layers were dried, filtered, and concentrated to afford the title product (114 b) as a white solid (51 mg, 52%). m/z (ESI, positive ion) =134.2 [ M+H ]] + 。
Step C. (6- (chloromethyl) pyridin-2-yl) methanol (114 c)
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To a solution of pyridine-2, 6-diyldimethanol (20 g,143 mmol) in DMF (100 mL) was added NaH (60%, 5.75g,143mmol in mineral oil) at 0deg.C. The mixture was stirred at 0℃for 0.5h. Tert-butyl (chloro) dimethylsilane (26 g,172 mmol) was then added dropwise. The mixture was stirred at 17℃for 16h. The reaction was diluted with EtOAc (200 ml) and saturated NaHCO 3 (50 mL) and brine (50 mL). The EtOAc layer was dried, filtered, concentrated and the resulting crude residue was purified by silica gel column chromatography (5% meoh/DCM) to provide the title product (114 c) (3.5 g, 14.7%) as a colorless oil. m/z (ESI, positive ion) =158.1 [ m+h ] ] + 。
Step D.4- ((6- (hydroxymethyl) pyridin-2-yl) methyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (114 d)
The flask was charged with 114c (3.3 g,20.9 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (7.13 g,22.9 mmol), K 2 CO 3 (8.67 g,62.6 mmol) and Pd (dppf) Cl 2 DCM (0.85 g,1.0 mmol) and add 3mL of 1, 4-dioxane/H 2 O (4:1). The mixture was degassed with nitrogen and stirred at 90 ℃ under nitrogen for 3h. After completion, the reaction was completed with H 2 O (100 mL) was diluted and extracted with EtOAc (100 mL. Times.3). The organic layer was dried, filtered and concentrated. The crude residue was purified by silica gel column chromatographyPurification by method (petroleum ether: etoac=3:2) afforded the title product (114 d) (3.8 g, 57%) as a yellow oil. m/z (ESI, positive ion) =305.2 [ m+h ]] + 。
Step E.4- ((6- (hydroxymethyl) pyridin-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (114 e)
A solution of 114d (3.8 g,12.5 mmol) and 10% Pd/C (380 mg) in MeOH (30 mL) was stirred under hydrogen at 17℃for 12h. After completion, the reaction was filtered through a pad of celite and rinsed with MeOH (50 ml×3). The organic layer was concentrated to afford the title product (114 e) (3.5 g, 87%) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =307.3 [ m+h ] ] + 。
Step F.4- ((6- ((2-cyano-4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (114 f)
The flask was filled with 114b (332 mg,2.50 mmol), 114e (510 mg,1.66 mmol) and PPh 3 (65mg, 2.50 mmol). Anhydrous THF (10 mL) was added and the reaction cooled in an ice bath. Diethyl azodicarboxylate (435 mg,2.50 mmol) was added dropwise and the resulting mixture was stirred at 0℃for 1h, followed by stirring at 17℃under nitrogen for 11h. After completion, the organic layer was concentrated and purified by silica gel column chromatography (petroleum ether: etoac=4:1) to afford the title product (114 f) as a yellow oil (600 mg, 79%). m/z (ESI, positive ion) =422.2 [ m+h ]] + 。
Step G.2- ((2-chloro-4-methylphenoxy) methyl) -6- (piperidin-4-ylmethyl) pyridine (114 g)
At 0 DEG CA solution of 114f (323 mg,1.24 mmol) and 2, 6-lutidine (2.66 g,24.8 mmol) in anhydrous DCM (10 mL) was stirred for 0.5h. TMSOTF (2.76 g,12.4 mmol) was added and the resulting mixture was stirred at 0deg.C for 2h. After completion, the reaction was quenched with saturated ammonium chloride solution (1 mL). The reaction mixture was treated with H 2 O (10 mL) was diluted and extracted with EtOAc (10 mL. Times.3). The organic layer was dried, filtered and concentrated to afford the title product (114 g) as a yellow oil (400 mg, 95%) which was used in the next step without further purification. m/z (ESI, positive ion) =322.2 [ m+h ] ] + 。
Step H. (S) -2- ((4- ((6- ((2-cyano-4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (114H)
114g (98 mg,0.30 mmol), 1h (90 mg,0.30 mmol) and K are combined at 17 ℃ 2 CO 3 A solution of (126 mg,0.91 mmol) in DMF (2 mL) was stirred for 6h. After completion, the reaction was completed with H 2 O (10 mL) was diluted and extracted with EtOAc (10 mL. Times.3). The organic layer was dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (DCM: meoh=50:1) to afford the title product (114 h) as a white solid with some impurities (158 mg). m/z (ESI, positive ion) =580.3 [ m+h ]] + 。
Step I. (S) -2- ((4- ((6- ((2-cyano-4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (114)
114H (79 mg,0.136 mmol) and LiOH (10 mg,0.41 mmol) were taken up in THF: H at 30 ℃ 2 The solution in o=1:1 (2 mL) was stirred for 6h. After completion, 1N HCl was added to the mixture in an ice bath to adjust ph=5. The reaction mixture is then reactedExtracted with EtOAc (50 mL. Times.3). The organic layer was dried, filtered and concentrated, and the crude residue was purified by reverse phase HPLC (25% CH 3 CN/H 2 O, with 0.05% TFA as modifier) to afford the TFA salt of the title product (114) as a white solid (16.4 mg, 18%). 1 H NMR(400MHz,CD 3 OD) delta ppm 8.33 (d, j=0.88 hz, 1H), 8.04 (dd, j=8.55, 1.53hz, 1H), 7.88-7.94 (m, 1H), 7.80 (d, j=9.21 hz, 1H), 7.57 (d, j=7.45 hz, 1H), 7.42-7.48 (m, 2H), 7.38 (d, j=7.02 hz, 1H), 7.13-7.17 (m, 1H), 5.29 (s, 2H), 5.20 (qd, j=7.09, 2.41hz, 1H), 4.76-4.82 (m, 2H), 4.71-4.75 (m, 1H), 4.60-4.69 (m, 2H), 4.41 (dt, j=9.43, 5.81, 1H), 3.73-3.84 (m, 2H), 3.28-3.28 (m, 2H), 5.20 (qd, j=7.09, 2.41hz, 1H), 4.41-4.41 (m, 2H), 4.41 (d, 2H), 4.41 (2H), 2.41-2H), 2.74 (d, 2.74H). m/z (ESI, positive ion) =566.2 [ m+h ]] + 。
Example compounds 118, 120, 140 were synthesized in a similar procedure as described in example 114. Example 123 was then synthesized from methyl 5-fluoro-6-methylpyridine carboxylate as described in example 60, step A, B, followed by example 72, step C, and examples 114, steps E-I. Examples 126 and 133 were synthesized in the same synthesis procedure as example 123. Example 135 was synthesized as described in example 60, steps a through C, followed by example 72, step C, and example 114, steps F through I. Example 162 was then synthesized as described in example 60 steps a through C, examples 72 steps C through D, example 116 step D, and examples 114 steps H through I.
EXAMPLE 115 (S) -2- ((4- (3- ((4-cyclopropyl-2-methylphenyl) (methyl) amino) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (115)
Step A.4-cyclopropyl-2-methylaniline (115 a)
1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (44 mg,0.05 mmol) was added to 4-bromo-2-methylaniline (50 mg,0.27 mmol), cesium carbonate (350 mg,1.07 mmol), cyclopropylboronic acid (46 mg,0.54 mmol) in 1, 4-dioxane (2 mL) and H 2 In solution in O (0.1 mL). The resulting mixture was stirred at 100 ℃ for 5h and concentrated. The reaction was then diluted with water (5 mL) and the mixture was extracted with EtOAc (5 ml×3). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution, etOAc/petroleum ether, 0-10%) to afford the title product (115 a) as a yellow oil (30 mg, 68.3%). m/z (ESI, positive ion) =148.2 [ m+h ]] + 。
Step B.3- ((4-cyclopropyl-2-methylphenyl) amino) benzoic acid methyl ester (115 b)
Chloro (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Palladacycle) (16 mg,0.02 mmol) was added to a solution of 115a (30 mg,0.2 mmol), cesium carbonate (332 mg,1 mmol), methyl 3-bromobenzoate (44 mg,0.2 mmol) in 1, 4-dioxane (3 mL). The resulting reaction mixture was stirred at 90 ℃ for 16h and concentrated. The reaction was diluted with water (5 mL) and extracted with EtOAc (5 mL. Times.3). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution, etOAc/petroleum ether, 0-10%) to afford the impure title product (115 b) as a yellow oil (32 mg,80% purity). m/z (ESI, positive ion) =282.1 [ M+H ] ] + 。
Step C.3- ((4-cyclopropyl-2-methylphenyl) (methyl) amino) benzoic acid (115 c)
The title product (115C) was prepared from 115B by a procedure similar to that described in example 46, steps B and C.
Step d. (S) -2- ((4- (3- ((4-cyclopropyl-2-methylphenyl) (methyl) amino) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (115 d)
Intermediate 1j (122 mg,0.36 mmol) and 115c (100 mg,0.36 mmol) were dissolved in DCM (3 mL). Diisopropylethylamine (184 mg,1.42 mmol) and HATU (203 mg,0.53 mmol) were added and the reaction stirred at 20℃for 1h. After removal of volatiles, the crude residue was purified by preparative TLC (MeOH/DCM, 5-10%, 0.5% NH) 3 .H 2 O as a modifier) to afford the impure title product (115 d) (107 mg,83% purity) as a yellow oil. m/z (ESI, positive ion) =608.2 [ m+h ]] + 。
Step E. (S) -2- ((4- (3- ((4-cyclopropyl-2-methylphenyl) (methyl) amino) benzoyl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (115)
To impure 115d (65 mg,0.1 mmol) in MeOH: H at 0deg.C 2 To a solution in o=5:1 (2.4 mL) was added sodium hydroxide (39 mg,0.97 mmol). The reaction mixture was warmed to room temperature and stirred at 20 ℃ for 16h. After concentration, the mixture was diluted with water (5 mL), adjusted to ph=4 with 0.1N HCl, and extracted with EtOAc (5 ml×3). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (gradient elution, 40-50% CH 3 CN/H 2 O, with 0.1% formic acid as modifier) to afford the title product (115) as a white solid (19.2 mg). 1 H NMR(400MHz,CD 3 OD)δppm 8.46(s,1H),8.12 (dd, j=8.56, 1.47hz, 1H), 7.80 (d, j=8.56 hz, 1H), 7.17-7.26 (m, 1H), 7.05 (s, 1H), 6.91-7.02 (m, 2H), 6.68 (d, j=7.34 hz, 1H), 6.62 (dd, j=8.31, 2.20hz, 1H), 6.44 (s, 1H), 5.16-5.29 (m, 1H), 4.87-4.91 (m, 1H), 4.60-4.78 (m, 2H), 4.46 (dt, j=9.11, 6.08hz, 1H), 4.27-4.43 (m, 2H), 3.50-3.89 (m, 4H), 3.21 (s, 3H), 2.74-3.01 (m, 5H), 2.52 (dd, j=16-4.91 (m, 1H), 4.60-4.78 (m, 1H), 4.27-4.43 (m, 1H), 4.27-3.7.38 (m, 1H), 1.38 (m, 7.38, 7hz, 1H), 1.7.7.7 (m, 1H). m/z (ESI, positive ion) =594.3 [ m+h ]] + 。
Example 122 was synthesized in a similar procedure to that described in example 115.
EXAMPLE 116 (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (116)
Step a. (3- ((2-chloro-4-methylphenyl) (methyl) amino) phenyl) methanol (116 a)
To a solution of methyl 3- ((2-chloro-4-methylphenyl) (methyl) amino) benzoate (650 mg,2.2mmol, prepared by a similar procedure to that described in example 115 step B) in 10mL anhydrous THF at 0 ℃ was added LiAlH 4 (256 mg,6.7 mmol). At 0℃under N 2 The reaction was stirred for 1h and taken up with Na 2 SO 4 .10H 2 And O quenching. The mixture was filtered and the filter cake was rinsed with DCM (100 mL). The organic layer was concentrated to afford the title product (116 a) (487 mg, 85%) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =262.2 [ m+h ]] + 。
Step B.N- (3- (bromomethyl) phenyl) -2-chloro-N, 4-dimethylaniline (116 b)
To a solution of 116a (487 mg,1.9 mmol) in DCM (20 mL) at 0deg.C was added PBr 3 (506 mg,1.9 mmol). The mixture was stirred at 17℃for 2h. After completion, the mixture was taken up with H 2 O (30 mL) was diluted and extracted with EtOAc (30 mL. Times.3). Using H for the organic layer 2 O (30 mL), brine (30 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give the crude title product (116 b) (591 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =324.0 [ m+h ]] + 。
Step C.4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzyl) piperidine-1-carboxylic acid tert-butyl ester (116 c)
The title product (116C) was prepared by a procedure similar to that described in example 60, steps B and C.
Step D.2-chloro-N, 4-dimethyl-N- (3- (piperidin-4-ylmethyl) phenyl) aniline (116 d)
To a solution of 116c (56 mg,0.13 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture was stirred at 17℃for 1h. After completion, the mixture was concentrated in vacuo to afford the crude title product (116 d) (62 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =329.2 [ m+h ] ] + 。
Step E. (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (116 e)
At 17℃to 116d (62 mg,0.19 mmol) and K 2 CO 3 To a mixture of (78 mg,0.57 mmol) in DMF (5 mL) was added 1h (56 mg,0.19 mmol). The mixture was stirred at 17℃for 16h. After completion, the reaction was completed with H 2 O (5 mL) was quenched and extracted with DCM (20 mL. Times.3). The organic layer was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (2% MeOH/DCM) to provide the title product (116 e) as a white solid (45 mg, 40%). m/z (ESI, positive ion) =587.3 [ m+h ]] + 。
Step F. (S) -2- ((4- (3- ((2-chloro-4-methylphenyl) (methyl) amino) benzyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (116)
At room temperature, 116e (45 mg,0.07 mmol) in THF (3 ml) and H 2 Lithium hydroxide (18 mg,0.70 mmol) was added to the mixture in O (1 mL) and heated at 30deg.C for 2h. After completion, the mixture was adjusted to ph=7 with 1N HCl. The residue was purified by reverse phase HPLC (CH 3 CN/water with 0.1% TFA as modifier) to afford the TFA salt of the title product (116) as a white solid (17.1 mg, 32%). 1 H NMR(400MHz,CD 3 OD) delta ppm 8.32 (s, 1H), 8.03 (dd, j=8.56, 1.47hz, 1H), 7.80 (d, j=8.31 hz, 1H), 7.34 (s, 1H), 7.12-7.20 (m, 2H), 7.08 (t, j=7.83 hz, 1H), 6.55 (d, j=7.09 hz, 1H), 6.43 (dd, j=8.31, 2.20hz, 1H), 6.33 (s, 1H), 5.15-5.27 (m, 1H), 4.74-4.80 (m, 2H), 4.72 (d, j=6.85 hz, 1H), 4.58-4.69 (m, 2H), 4.39 (dt, j=9.29, 5.87hz, 1H), 3.76 (br s, 2H), 3.12-3.27 (m, 5.27 (m, 2H), 5.15-5.27 (m, 1H), 4.74-4.80 (m, 2H), 4.72 (d, j=6.85 hz, 1H), 4.58-4.69 (m, 2H), 3.12-3.27 (m, 2H, 3.43, 2H). m/z (ESI, positive ion) =573.3 [ m+h ]] + 。
Example 117 was synthesized in a similar procedure as described in example 116.
EXAMPLE 121 (S) -2- ((8- ((4-chloro-2-fluorobenzyl) oxy) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (121)
Step A.7-methoxy-1H-indole-3-carbaldehyde (121 a)
Phosphorus oxychloride (2.9 g,19 mmol) was added dropwise to a stirred mixture of 7-methoxy-1H-indole (2.5 g,17 mmol) in DMF (25 ml) at 0deg.C. The reaction was warmed to room temperature and at 25 ℃ under N 2 Stirred for 16h. After completion, the reaction mixture was poured into crushed ice and neutralized with 2N NaOH solution. The mixture was extracted with EtOAc (20 ml. Times.6). Using H for the organic layer 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=3:1) to afford the title product (121 a) (2.2 g, 70%) as a colorless oil. m/z (ESI, positive ion) =176.1 [ m+h ]] + 。
(Z) -7-methoxy-3- (2-nitrovinyl) -1H-indole (121 b)
Ammonium acetate (2.9 g,0.038 mol) was added to a mixture of 121a (2.2 g,0.013 mol) in nitromethane (23 g,0.38 mol) at 25 ℃. At 100℃under N 2 The reaction was stirred for 90min. After completion, the reaction was completed with H 2 O (20 mL) was quenched and extracted with EtOAc (20 mL. Times.3). Using H for the organic layer 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel chromatography (petroleum ether: etoac=3:1) to afford the title as a yellow solidProduct (121 b) (2.5 g, 87%). m/z (ESI, positive ion) =219.1 [ m+h ]] + 。
Step C.2- (7-methoxy-1H-indol-3-yl) ethan-1-amine (121 c)
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At 0℃under N 2 Next, liAlH in THF (20 mL) was added to a mixture of 121b (3.0 g,14 mmol) in dry THF (50 mL) 4 (3.3 g,82 mmol). The reaction was heated to reflux for 1h, followed by N at 25 ℃ 2 It was stirred for 16h. After completion, the reaction was completed with H 2 O (50 mL) was quenched, followed by addition of 15% NaOH solution. The mixture was extracted with EtOAc (50 mL. Times.4). Using H for the organic layer 2 O (50 mL), brine (50 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (1% MeOH/DCM) to provide the title product (121 c) as a black oil (2.6 g, 89%). m/z (ESI, positive ion) =191.1 [ m+h ]] + 。
Step D.8-methoxy-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (121 d)
To a solution of 121c (2.0 g,11 mmol) in MeOH (2 mL) at 0deg.C was added HCHO (975 mg,13mmol,40% in water) and HOAc (20 mL). At 0℃under N 2 The reaction was stirred for 1h. After completion, the mixture was adjusted to ph=8 with 2N NaOH and extracted with EtOAc (20 ml×3). Using H for the organic layer 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (5% MeOH/DCM) to afford the title product (121 d) as a brown solid (2.0 g, 85%). m/z (ESI, positive ion) =203.1 [ m+h ]] + 。
Step E.2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-8-ol (121 e)
The flask was charged with 121d (2.0 g,9.9 mmol) and 40% HBr H was added at 25 ℃ 2 O solution (5 mL). At 100℃under N 2 The reaction was stirred for 2h. After completion, the reaction mixture was filtered and concentrated in vacuo to give a crude residue, which was purified by reverse phase HPLC (100% H 2 O) to afford the title product (121 e) (1.0 g, 46%) as a black solid. m/z (ESI, positive ion) =189.1 [ M+H ]] + 。
Step F.8-hydroxy-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole-2-carboxylic acid tert-butyl ester (121 f)
At 0℃to 121e (400 mg,2.1 mmol) in THF/H 2 To the solution in O (30 mL) was added (Boc) 2 O (232 mg,1.1 mmol) and NaHCO 3 (178 mg,2.1 mmol). At 0℃under N 2 The mixture was stirred for 0.5h. After completion, the reaction was completed with H 2 O (20 mL) was diluted and extracted with EtOAc (30 mL. Times.3). Using H for the organic layer 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title product (121 f) as a white solid (90 mg, 13%). m/z (ESI, positive ion) =289.1 [ m+h ]] + 。
Step G.8- ((4-chloro-2-fluorobenzyl) oxy) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole-2-carboxylic acid tert-butyl ester (121 g)
To 121f (50 mg,0.17 mmol) and 1- (bromomethyl) -4-chloro-2-fluorobenzene (43 mg,0.19 mmol) in acetone (8 mL) at 25 ℃ K is added to the solution of (2) 2 CO 3 (24 mg,0.17 mmol). Then at 30 ℃ under N 2 The reaction was heated for 48h. After completion, the reaction was completed with H 2 O (8 mL) was quenched and extracted with EtOAc (10 mL. Times.3). Using H for the organic layer 2 O (10 mL), brine (10 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (121 g) as a colorless oil (35 mg, 44%). m/z (ESI, positive ion) =431.0 [ M+H ]] + 。
Step H.8- ((4-chloro-2-fluorobenzyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (121H)
To a solution of 121g (35 mg,0.081 mmol) in DCM (3 mL) was added TFA (0.3 mL) at 0deg.C. At 0℃under N 2 The mixture was stirred for 1h. After completion, the reaction was concentrated to afford the title product (121 h) (20 mg, 71%) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =331.1 [ m+h ]] + 。
Step I. (S) -2- ((8- ((4-chloro-2-fluorobenzyl) oxy) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid tert-butyl ester (121 i)
To 121h (30 mg,0.091 mmol) and 2- (chloromethyl) -3- [ (2S) -oxetan-2-ylmethyl at 25 ℃ ]To a solution of tert-butyl-1, 3-benzodiazole-5-carboxylate (34 mg,0.10mmol, prepared as described for 1 h) in DMF (5 mL) was added K 2 CO 3 (25 mg,0.18 mmol) and KI (15 mg,0.091 mmol). At 25℃under N 2 The reaction was stirred for 1h. After completion, the reaction was completed with H 2 O (5 mL) was quenched and extracted with EtOAc (5 mL. Times.3)Taking. Using H for the organic layer 2 O (5 mL), brine (5 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=3:1) to afford the title product (121 i) as a yellow oil (15 mg, 24%). m/z (ESI, positive ion) =631.2 [ m+h ]] + 。
Step J. (S) -2- ((8- ((4-chloro-2-fluorobenzyl) oxy) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (121)
To a solution of 121i (10 mg,0.016 mmol) in DCM (4 mL) was added TFA (0.8 mL) at 0deg.C. The reaction was warmed to room temperature and at 25 ℃ under N 2 Stirred for 16h. After completion, the reaction was concentrated to give a crude residue, which was purified by reverse phase HPLC (40% CH 3 CN/H 2 O, with 0.05% TFA as modifier) to afford the TFA salt of the title compound (121) (6 mg, 55%) as a yellow solid. 1 H NMR(400MHz,CD 3 OD) δppm 8.35 (d, j=0.88 hz, 1H), 8.01-8.09 (m, 1H), 7.82 (d, j=8.77 hz, 1H), 7.62 (t, j=8.11 hz, 1H), 7.19-7.30 (m, 2H), 7.14 (d, j=7.89 hz, 1H), 7.00 (t, j=7.67 hz, 1H), 6.81 (d, j=7.89 hz, 1H), 5.26 (s, 2H), 5.17 (qd, j=7.16, 2.19hz, 1H), 4.97 (s, 2H), 4.73-4.81 (m, 1H), 4.62-4.69 (m, 3H), 4.56 (dd, j=16.01, 5.92hz, 1H), 4.27-4.33 (m, 1H), 3.81-3.89 (m, 2H), 5.17 (qd, j=7.89 hz, 1H), 4.73-4.19 hz (m, 1H), 4.97 (s, 2H). m/z (ESI, positive ion) =575.1 [ M+H ]] + 。
Examples 124, 125, 129, 141 were synthesized in a similar procedure as described in example 60.
Example 128.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (128)
Step A.4- ((1- (tert-Butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) methyl) picolinate (128 a)
To 4- (chloromethyl) pyridine-2-carboxylic acid methyl ester (116 mg,0.63 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (194 mg,0.63 mmol), pd (dppf) Cl 2 (46 mg,0.063 mmol) and K 3 PO 4 To a mixture of (266 mg,1.25 mmol) was added THF (6 mL) and water (6 mL). The resulting suspension was heated at reflux overnight. After cooling to room temperature, the mixture was extracted with ethyl acetate (10 ml×3) and washed with brine. The combined organic phases were treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated. The crude residue obtained was purified by reverse phase HPLC (gradient elution, 20-100% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (128 a) as a white solid (42 mg, 20%). m/z (ESI, positive ion) =333.1 [ m+h ]] + 。
Step B.4- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) methyl) picolinate (128 b)
A solution of 128a (42 mg,0.12 mmol) and 10% Pd/C (8.4 mg) in MeOH (6 mL) was stirred under hydrogen at room temperature for 22h. After completion, the reaction was filtered through a celite pad and washed with MeOH (6 ml×3). The organic layer was concentrated to afford the title product (128 b) (34 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =335.3 [ m+h ]] + 。
Step C.4- ((2- (hydroxymethyl) pyridin-4-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (128 c)
128b (34 mg,0.1 mmol) CaCl 2 (23 mg,0.2 mmol) and NaBH 4 To a mixture of (15 mg,0.4 mmol) was added THF (10 mL). The resulting suspension was stirred at 60 ℃ overnight and cooled. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 ml×3) and washed with brine. The combined organic phases were treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (128 c) (7 mg,19%,2 steps) m/z (ESI, positive ion) =307.2 [ m+h ] + 。
Step D.4- ((2, 4-dichlorophenoxymethyl) pyridin-4-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (128 d)
The flask was filled with 2, 4-dichlorophenol (7 mg,0.043 mmol), 128c (12 mg,0.039 mmol) and PPh 3 (12 mg,0.047 mmol). Anhydrous THF (5 mL) was added and the reaction cooled in an ice bath. Diethyl azodicarboxylate (9.5 mg,0.047 mmol) was added dropwise and the resulting mixture was stirred at 0 ℃ for 0.5h, followed by overnight at room temperature. After completion, the reaction was quenched with water (20 mL), extracted with EtOAc (20 ml×3) and washed with brine. The combined organic layers were treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated to provide a crude residue which was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (128 d) (12.6 mg) as a colorless oil with some impurities, which was used in the next step without further purification. m/z (ESI, positive ion) =451.3 [ M+H ]] + 。
Step E.2- ((2, 4-dichlorophenoxy) methyl) -4- (piperidin-4-ylmethyl) pyridine (128 e)
A solution of 128d (12.6 mg,0.02 mmol) in DCM (0.5 mL) was treated with TFA (0.5 mL) for 10min at room temperature. After completion, the solvent was removed in vacuo and the resulting crude residue was purified by reverse phase HPLC (gradient elution, 20-100% CH 3 CN/water with 0.1% formic acid as modifier) to afford the title product (128 e) (5.9 mg, 44%) as a white solid. m/z (ESI, positive ion) =351.3 [ M+H ]] + 。
Step F.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (128 f)
128e (4.8 mg,0.014 mmol), 57f (5.5 mg,0.016 mmol) and Et were added at room temperature 3 A solution of N (14 mg,0.14 mmol) in DMF (1 mL) was stirred for 24h. After completion, the reaction was purified by reverse phase HPLC (gradient elution, 0-90% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (128 f) (14 mg) as a white solid with some impurities. m/z (ESI, positive ion) =647.3 [ m+h ]] + 。
Step G.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (128)
A solution of 128f (14 mg, impure) in THF (0.5 mL) was treated with 2N NaOH (0.5 mL) and MeOH (2 drops). The resulting mixture was stirred at room temperature for 6h. After completion, the reaction was purified by reverse phase HPLC (gradient elution, 0-90% CH 3 CN/water with 0.1% formic acid as modifier) to afford the title product (128) (4.5 mg, 51%) as a white solid. 1 H NMR(600MHz,CD 3 OD)δppm 8.41(d,J＝5.14Hz,1H),8.13(br d,J＝1.10Hz,1H) 7.99 (dd, j=8.62, 1.47hz, 1H), 7.87 (s, 1H), 7.68-7.72 (m, 1H), 7.41-7.44 (m, 1H), 7.40 (s, 1H), 7.22 (dd, j=8.80, 2.57hz, 1H), 7.18 (brdd, j=5.14, 1.47hz, 1H), 7.07 (d, j=8.80 hz, 1H), 6.60 (s, 1H), 5.76 (s, 2H), 5.24 (s, 2H), 4.08 (q, j=7.34 hz, 2H), 3.84 (s, 2H), 2.81 (brd, j=11.37 hz, 2H), 2.57 (brd, j=6.97 hz, 2H), 2.04-2.12 (m, 2H), 1.57-1.80 hz, 1H), 6.76 (s, 2H), 4.08 (q, j=7.34 hz, 2H), 3.84 (s, 2H), 2.81 (br d, 2H), 2.57 (1.37 hz, 1.64H), 1.64-7H (1H). m/z (ESI, positive ion) =633.2 [ m+h] + 。
Example compounds 137, 139, 148, 149, 151, 158, 159, 165, 166, 187 and 188 were synthesized in a similar procedure as described in example 128.
Example 130.2- ((4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) (hydroxy) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (130)
Step A.1- [ (3-bromophenyl) methoxy ] -2-chloro-4-methylbenzene (130 a)
To (3-bromophenyl) methanol (3.0 g,0.016 mol), 2-chloro-4-methylphenol (2.7 g,0.019 mol) and PPh at 0deg.C 3 (4.6 g,0.018 mol) to a mixture of THF (50 mL) was added DEAD (3.1 g,0.018 mol). At 25℃under N 2 The mixture was stirred for 8h. After completion, the mixture was concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (130 a) as a yellow oil (4.5 g, 86%). 1 H NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.50-7.56(m,1H),7.46(d,J＝7.7Hz,1H),7.36(t,J＝7.8Hz,1H),7.26(s,1H),7.09(d,J＝0.9Hz,2H),5.18(s,2H),2.23(s,3H)。
Step B.4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) (hydroxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (130 b)
To a mixture of 130a (3.0 g,9.6mmol,1.0 eq.) in THF (50 mL) was added nBuLi (2.6M in hexane) (5 mL,13 mmol) at-65 ℃. After 30min, tert-butyl 4-formylpiperidine-1-carboxylate (2.1 g,9.6 mmol) was added dropwise and at-65℃under N 2 The reaction was stirred for 1h. After completion, the mixture was treated with NH 4 Cl (40 mL) was quenched and extracted with EtOAc (30 mL. Times.3). Using H for the organic layer 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (130 b) (3.6 g, 75%) as a yellow oil. m/z (ESI, positive ion) =468.2 [ m+na ]] + 。
Step C.2- ((4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) (hydroxy) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (130 c)
To 130b (13 mg,0.03 mmol) in dry CH at room temperature 2 Cl 2 TFA (0.12 mL) was added to the solution in (0.3 mL). After 1h, the mixture was concentrated and saturated NaHCO was added 3 (0.5 mL). The reaction was extracted with EtOAc (2 mL. Times.3). The organic layer was purified by Na 2 SO 4 Dried, filtered, and concentrated to provide crude amine (13 mg). To this crude amine (13 mg) in dichloroethane (0.3 mL) was added 57f (12 mg,0.036 mmol) and DIPEA (0.01 mL) at room temperature. The reaction was then heated at 60℃for 20h. After cooling to room temperature, the reaction was concentrated and purified by silica gel column chromatography (gradient elution, 0-10% meoh/DCM) to afford the title product (130 c) as a colorless film (16 mg, impure). m/z (ESI, positive ion) =642.3 [ m+h] + 。
Step D.2- ((4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) (hydroxy) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (130)
130c (16 mg, impure) was dissolved in THF and H at room temperature 2 O in a mixed solvent (2:1, 0.25 mL). LiOH (2.1 mg,0.05 mmol) was added. After stirring for 16h, the reaction was acidified with 1N HCl to ph=7 and concentrated. The crude residue was purified by reverse phase HPLC (gradient elution, 0-70% CH 3 CN/water with 0.1% TFA as modifier) to afford the TFA salt of the title product (130) as a white solid (12.5 mg,58%, over 2 steps, racemic). 1 H NMR(600MHz,CD 3 OD) δppm 8.92 (s, 1H), 8.22 (d, j=0.92 hz, 1H), 8.05 (dd, j=8.54, 1.53hz, 1H), 7.82 (d, j=8.54 hz, 1H), 7.46 (s, 1H), 7.35-7.41 (m, 2H), 7.30 (br d, j=6.41 hz, 1H), 7.18 (d, j=1.53 hz, 1H), 6.96-7.04 (m, 3H), 5.80 (s, 2H), 5.14 (s, 2H), 4.57 (br s, 2H), 4.47 (br d, j=6.71 hz, 1H), 4.29 (q, j=7.22 hz, 2H), 3.56-3.75 (m, 2H), 2.86-3.02 (m, 2H), 2.22 (s, 3.83-2H), 2.11.83 (m, 3H), 1.52-3.52 (m, 1H), 1.52 (m, 3H). m/z (ESI, positive ion) =628.3 [ m+h ] ] + 。
Example 131.2- ((4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (131)
Step A.4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) fluoromethyl) piperidine-1-carboxylic acid tert-butyl ester (131 a)
At 0At C, 130b (53 mg,0.12 mmol) in dry CH 2 Cl 2 To a solution in (1.2 mL) was added Deoxo-Fluor (70 mg,0.14mmol,45% in THF). After 0.5h, the reaction was warmed to room temperature and stirred for 16h. Then saturated NaHCO is added 3 . The mixture was extracted with EtOAc (5 ml×3) and the organic layer was dried over Na 2 SO 4 Dried, filtered, and concentrated. The resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc/hexanes) to afford the title product (131 a) (19 mg, 35%) as a colorless film. m/z (ESI, positive ion) =470.1 [ M+H ]] + 。
Step B.2- ((4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (131)
The title product (131) was synthesized as a racemic mixture from 131a in analogy to the procedure described in example 130 steps C and D. 1 H NMR(600MHz,CD 3 OD) delta ppm 9.04 (d, j=1.10 hz, 1H), 8.20-8.26 (m, 1H), 8.06 (dd, j=8.62, 1.65hz, 1H), 7.80-7.90 (m, 1H), 7.35-7.51 (m, 3H), 7.25-7.35 (m, 1H), 7.19 (d, j=1.83 hz, 1H), 6.92-7.08 (m, 3H), 5.79-5.90 (m, 2H), 5.37 (dd, j=46.8, 6.24hz, 1H), 5.13-5.17 (m, 2H), 4.59-4.69 (m, 2H) 4.33 (q, j=7.34 hz, 2H) 3.65-3.85 (m, 2H), 3.06 (brs, 2H), 2.12-2.25 (m, 2H), 5.37 (dd, j=46.8, 6.24hz, 1H), 5.13-5.17 (m, 2H), 4.65-3.85 (m, 2H), 3.06 (m, 3H). m/z (ESI, positive ion) =630.3 [ m+h ] ] + 。
Example 132.2- ((4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) difluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (132)
Step A.4- (3- ((2-chloro-4-methylphenoxy) methyl) benzoyl) piperidine-1-carboxylic acid tert-butyl ester (132 a)
To a solution of 130b (2.0 g,4.5 mmol) in DCM (50 mL) was added Dess-Martin (Dess-Martin) periodate (3.8 g,8.9 mmol) at 0deg.C. At 30℃under N 2 The reaction was heated for 16h. After completion, the mixture was treated with NaHCO 3 The aqueous solution (40 mL) was quenched and extracted with DCM (50 mL. Times.3). Using H for the organic layer 2 O (50 mL), brine (50 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=3:1) to afford the title product (132 a) (1.2 g, 58%) as a white solid. m/z (ESI, positive ion) =466.2 [ m+na ]] + 。
Step B.4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) difluoromethyl) piperidine-1-carboxylic acid tert-butyl ester (132 b)
Deoxo-Fluor (112 mg,0.50mmol,45% in THF) was added to 132a (150 mg,0.34 mmol) and heated to 80 ℃. After 40h, the reaction was concentrated and the crude residue was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc/hexanes) to afford the title compound (132 b) as a colorless film (34 mg, 21%). m/z (ESI, positive ion) =466.2 [ M+H ] ] + 。
Step C.2- ((4- ((3- ((2-chloro-4-methylphenoxy) methyl) phenyl) difluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (132)
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The title product (132) was synthesized from 132b in a similar procedure as described in example 130, steps C and D.
1 H NMR (600 mhz, meod) delta ppm 9.01 (d, j=1.10 hz, 1H), 8.21 (d, j=1.10 hz, 1H), 8.05 (dd, j=8.80 hz, 1.47hz, 1H), 7.82 (d, j=8.80 hz, 1H), 7.58-7.62 (m, 2H), 7.51 (t, j=7.70 hz, 1H), 7.42 (br d, j=7.70 hz, 1H), 7.20 (d, j=1.47 hz, 1H), 6.99-7.07 (m, 3H), 5.82 (d, j=0.73 hz, 2H), 5.19 (s, 2H), 4.46 (br s, 2H), 4.32 (q, j=7.34 hz, 2H), 3.48-3.58 (m, 2H), 2.76-2.87 (m, 2.44 (m), 2.31-2H), 1.99-7.07 (m, 3H), 5.82 (d, j=0.73 hz, 2H), 5.19 (s, 2H). m/z (ESI, positive ion) =648.3 [ m+h ]] + 。
Example 161 was prepared in a similar procedure as described in example 132.
EXAMPLE 136 (S) -2- ((4- ((2- (((3-chloro-5-cyclopropylpyridin-2-yl) oxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (136)
Step A.2, 3-dichloro-5-cyclopropylpyridine (136 a)
At 80℃under N 2 Next, 5-bromo-2, 3-dichloropyridine (2.2 g,10.0 mmol), cyclopropylboronic acid (1.0 g,12.0 mmol), pd (OAc) 2 (112 mg,0.5 mmol), tris (o-tolyl) phosphine (304 mg,1.0 mmol) and K 2 CO 3 (4.1 g,30.0 mmol) in 20mL toluene and 5mL H 2 The mixture in O was stirred for 4h. After completion, the reaction was completed with H 2 O (20 mL) was diluted and extracted with EtOAc (30 mL. Times.3). The organic layer was treated with anhydrous Na 2 SO 4 Dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (5% etoac/petroleum ether) to afford the title product (136 a) (1.7 g, 91%) as a colorless oil. m/z (ESI, positive ion) =188.1 [ m+h ]] + 。
Step B.4- ((2- (((3-chloro-5-cyclopropylpyridin-2-yl) oxy) methyl) oxazol-5-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (136 b)
136a (260 mg,1.4 mmol), 60d (411 mg,1.4 mmol) and Cs were combined at 80 ℃C 2 CO 3 A mixture of (1.4 g,4.2 mmol) in DMF (5 mL) was stirred for 16h. After completion, the reaction was completed with H 2 O (30 mL) was diluted and extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (30 mL. Times.3), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (5% MeOH/DCM) to afford the title product (136 b) as a colorless oil (340 mg, 54%). m/z (ESI, positive ion) =448.2 [ m+h ]] + 。
Step C.2- (((3-chloro-5-cyclopropylpyridin-2-yl) oxy) methyl) -5- (piperidin-4-ylmethyl) oxazole (136 c)
To a mixture of 136b (100 mg,0.22 mmol) in DCM (10 mL) was added 2, 6-lutidine (323 mg,4.4 mmol) and TMSOTF (488 mg,2.2 mmol) at 0deg.C. The mixture was stirred at 0℃for 1h. After completion, the reaction was reacted with NH 4 Cl (10 mL) was quenched and extracted with EtOAc (20 mL. Times.3). The combined organic layers were treated with H 2 O (20 mL), brine (20 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to provide the crude title product (136 c) (230 mg) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =348.2 [ m+h ]] + 。
Step d. (S) -2- ((4- ((2- (((3-chloro-5-cyclopropylpyridin-2-yl) oxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (136 d)
At 15℃to 136c (230 mg,0.22 mmol) and K 2 CO 3 To a stirred solution of (93 mg,0.66 mmol) in DMF (3 mL) was added 1h (65 mg,0.22 mmol). The mixture was stirred at 15℃for 16h. After completion, the reaction was completed with H 2 O (5 mL) was quenched and extracted with DCM (20 mL. Times.3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (2% MeOH/DCM) to afford the title product (136 d) as a white solid (78 mg, 59%). m/z (ESI, positive ion) =606.3 [ m+h ] ] + 。
Step e. (S) -2- ((4- ((2- (((3-chloro-5-cyclopropylpyridin-2-yl) oxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (136)
136d (78 mg,0.1 mmol) in THF (3 mL) and H 2 To the mixture in O (1 mL) was added lithium hydroxide (24 mg,1.0 mmol). The reaction was stirred at 17℃for 16h. After completion, the reaction was adjusted to ph=7 with 1N HCl and extracted with EtOAc (20 ml×3). The organic layer was dried, filtered and concentrated, and the crude residue was purified by reverse phase HPLC (CH 3 CN/H 2 O, with 0.1% TFA as modifier) to afford the TFA salt of the title product (136) as a white solid (26.0 mg, 29%). 1 H NMR(400MHz,CD 3 OD) delta ppm 8.33 (d, j=0.73 hz, 1H), 8.04 (dd, j=8.56, 1.47hz, 1H), 7.86 (d, j=1.96 hz, 1H), 7.80 (d, j=8.56 hz, 1H), 7.45 (d, j=1.96 hz, 1H), 6.92 (s, 1H), 5.44 (s, 2H), 5.14-5.25 (m, 1H), 4.80 (d, j=3.42 hz, 2H), 4.71-4.78 (m, 1H), 4.56-4.71 (m, 2H), 4.40 (dt, j=9.23, 5.78hz, 1H), 3.78 (br s, 2H), 3.15-3.32 (m, 2H), 2.68-2.86 (m, 3H), 2.42-2.55 (m, 1H), 1.90-2.86 (m, 1H), 1.70-1.70H), 4.70-4.71 (m, 2H), 4.40 (dt, j=1.9.78 (m, 1H). m/z (ESI, positive ion) =592.3 [ m+h ]] + 。
Example 144 was synthesized in a similar procedure to that described in example 136.
Example 138 was synthesized in a similar procedure to that described in example 60.
Example 142 and example 143 were then synthesized from 4-iodophenol and (2, 4-dichlorophenyl) methanol by similar procedures as in example 114, step F, steps C to E, and examples 134, steps a to B.
Example 145.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (145)
Step A.4- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) oxy) picolinic acid methyl ester (145 a)
To a stirred solution of methyl 4-hydroxypicolinate (400 mg,2.61 mmol), 1-Boc-4-hydroxypiperidine (526 mg,2.61 mmol) and triphenylphosphine (856 mg,3.27 mmol) in THF (15 mL) was added dropwise diisopropyl azodicarboxylate (660 mg,3.27 mmol) at room temperature. The mixture was heated at 55℃for 23h. After cooling to room temperature, it was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 10% to 60% acetone/hexane) to afford the title product (145 a) as a yellow gum (454 mg, 52%). m/z (ESI, positive ion) =337.4 [ m+h ]] + 。
Step B.4- ((2- (hydroxymethyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (145 b)
CaCl was added to a stirred solution of 145a (420 mg,1.25 mmol) in EtOH (6.2 mL) at 0deg.C 2 (416 mg,3.75 mmol) followed by the addition ofNaBH 4 (134 mg,3.75 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 2.5h. It was cooled back to 0 ℃ and the reaction quenched by addition of saturated ammonium chloride. The reaction mixture was treated with H 2 O was diluted and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 0-10% meoh/DCM) to provide the title product (145 b) as a colourless gum (313 mg, 81%). m/z (ESI, positive ion) =309.5 [ m+h ]] + 。
Step C.4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (145 c)
To a stirred solution of 145b (50.0 mg,0.162 mmol), 2, 4-dichlorophenol (27.8 mg,0.170 mmol) and triphenylphosphine (63.8 mg,0.243 mmol) in THF (1.0 mL) at room temperature was added dropwise diisopropyl azodicarboxylate (49.2 mg,0.243 mmol). The mixture was stirred at room temperature for 6h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 20-40% acetone/hexane) to afford the title product (145 c) as a white solid (62.2 mg, 85%). m/z (ESI, positive ion) =453.3 [ m+h ] ] + 。
Step D.2- ((2, 4-dichlorophenoxy) methyl) -4- (piperidin-4-yloxy) pyridine (145 d)
A solution of 145c (60 mg,0.132 mmol) in DCM/TFA (2:1, 2.0 mL) was stirred at room temperature for 2h. The mixture was concentrated under reduced pressure and the residue was diluted with DCM and washed with saturated sodium bicarbonate and brine. The organic layer was purified by Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to afford the title product (145 d) (51.1 mg) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion)＝353.3[M+H] + 。
Step E.1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- (hydroxymethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (145 e)
A mixture of 57e (150 mg,0.547 mmol) and glycolic acid (62.4 mg,0.82 mmol) in 1,3, 5-trimethylbenzene (1.5 mL) was heated at 140℃for 19h. It was cooled to room temperature and stirred at the same temperature for 3h. The yellow solution was decanted to give an orange residue, which was dissolved in MeOH (5 mL) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 0-15% MeOH/DCM) to provide the title product (145 e) as a white foam solid (32.4 mg, 19%). m/z (ESI, positive ion) =315.1 [ m+h ]] + 。
Step F.1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2-formyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (145 f)
To a stirred suspension of 145e (32.0 mg,0.102 mmol) in DCM (2 mL) was added dess-martin periodate (47.5 mg,0.112 mmol) at room temperature. The mixture was stirred at the same temperature for 1h. The reaction was carried out by adding 10% Na 2 S 2 O 3 Aqueous solution (1 mL) and saturated sodium bicarbonate (0.6 mL). The resulting mixture was stirred at room temperature for 5min, diluted with water and extracted with DCM (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to afford the title product (145 f) (40 mg) as a white foamy solid, which was used in the next step without further purification. m/z (ESI, positive ion) =313.2 [ m+h ]] + 。
Step G.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (145 g)
AcOH (5.8 mg,0.096 mmol) was added to a stirred solution of 145d (10.0 mg,0.032 mmol) and 145f (13.6 mg,0.038 mmol) in 1, 2-dichloroethane (0.3 mL) at room temperature followed by sodium triacetoxyborohydride (10.1 mg,0.048 mmol). After stirring at the same temperature for 1h, the reaction was quenched with saturated sodium bicarbonate and extracted with DCM (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-20% MeOH/DCM, gradient elution) to afford the title product (145 g) as an off-white foam solid (15.4 mg, 74%). m/z (ESI, positive ion) =651.3 [ m+h] + 。
Step H.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (145)
At room temperature, 145g (12.3 mg,0.0189 mmol) in THF/MeOH/H 2 To a stirred solution of O (2:1:1, 0.4 mL) was added lithium hydroxide monohydrate (2.4 mg,0.57 mmol). It was stirred for 4h, then 1N HCl was added to the mixture to adjust to ph=3. The solution was purified by reverse phase HPLC (gradient elution, 20-60% CH 3 CN/H 2 O, with 0.1% TFA as modifier) to give a TFA salt of the title compound (145) as a white solid (8 mg,56% yield). 1 H NMR(600MHz,CD 3 OD) δ9.07 (d, j=1.3 hz, 1H), 8.56 (d, j=6.6 hz, 1H), 8.22 (d, j=0.7 hz, 1H), 8.06 (dd, j=8.4, 1.5hz, 1H), 7.81 (d, j=8.6 hz, 1H), 7.50-7.53 (m, 2H), 7.31-7.36 (m, 2H), 7.19 (d, j=9.0 hz, 1H), 7.08 (d, j=1.1 hz, 1H), 5.91 (s, 2H), 5.35 (s, 2H), 4.93 (br s, 1H), 4.31-4.40 (m, 4H), 3.15-3.20 (m, 2H), 2.91-3.04 (m, 2H), 2.15-2.20 (m, 2H), 1.94 (br 2.3.56 (t, 3H). m/z (ESI, positive) Ion) =635.0 [ m+h] + 。
EXAMPLE 146 (S) -2- ((4- ((6- ((2- (hydroxymethyl) -4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (146)
Step A.4- ((6- ((2- (methoxycarbonyl) -4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (146 a)
At 0deg.C, 114e (800 mg,2.61 mmol), methyl 2-hydroxy-5-methylbenzoate (404 mg,2.61 mmol) and PPh 3 (1.02 g,3.92 mmol) in THF (20 mL) was added dropwise to a solution of DEAD (682 mg,3.92 mmol). The resulting mixture was stirred at 15℃for 16h. The reaction was diluted with EtOAc (50 mL) and washed with brine (50 mL). The EtOAc layer was taken up in Na 2 SO 4 Dried, filtered and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc/petroleum ether) to afford the title product (146 a) (260 mg, 21.8%) as a colorless oil. m/z (ESI, positive ion) =455.2 [ m+h ]] + 。
Step B.4- ((6- ((2- (hydroxymethyl) -4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (146 b)
To a solution of 146a (180 mg,0.40 mmol) in THF (10 ml) was added LiBH 4 (43 mg,1.98 mmol). The reaction was stirred at 15℃for 16h with saturated NH 4 Cl (30 ml) was quenched and extracted with EtOAc (50 ml. Times.2). The combined EtOAc layers were dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (15% meoh/DCM) to give the title product (146 b) as a white solid (150 mg, 91.7%). m/z (ESI, positive ion) =427.3 [ m+h ] ] + 。
Step C. (S) -2- ((4- ((6- ((2- (hydroxymethyl) -4-methylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (146)
The title compound (146) was prepared as described in example 114, step G-I from 146 b. 1 HNMR(400MHz,CD 3 OD) δppm 8.18 (s, 1H), 7.93 (dd, j=8.33, 1.32hz, 1H), 7.73 (t, j=7.89 hz, 1H), 7.55 (d, j=8.77 hz, 1H), 7.40 (d, j=7.45 hz, 1H), 7.13-7.24 (m, 2H), 6.99 (dd, j=8.55, 1.97hz, 1H), 6.83 (d, j=7.89 hz, 1H), 5.24 (qd, j=7.09, 2.85hz, 1H), 5.16 (s, 2H), 4.80-4.87 (m, 1H), 4.55-4.74 (m, 4H), 4.45 (dt, j=9.10, 5.97hz, 1H), 3.94 (d, j=13.59 hz, 1H), 3.82 (d, j=9.55, 1.97 hz), 6.83 (d, j=1.82 (m, 1H), 5.24 (qd, j=7.09, 2.85hz, 1H), 5.80-4.87 (m, 1H), 4.55-4.55 (m, 4H), 4.45 (1H), 1.80-4.45 (1H), 1.45-1.59 (1H), 1.80-4.7.45 (1H), 1.7.7.59 (1H). m/z (ESI, positive ion) =571.3 [ m+h] + 。
Example 150.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4- (hydroxymethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (150)
Step A.2- ((2, 4-dichlorophenoxy) methyl) isonicotinic acid methyl ester (150 a)
To 2- (hydroxymethyl) pyridine-4-carboxylic acid methyl ester (0.5 g,2.99 mmol), 2, 4-dichlorophenol (0.51 g,2.99 mmol) and PPh 3 (1.18 g,4.49 mmol) in THF (15 mL) was added dropwise DIAD (0.88 mL,4.49 mmol). The resulting mixture was stirred at room temperature for 4h. After completion, the reaction was concentrated and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 40-70% EtOAc/hexanes) to afford a white solidThe title product (150 a) was isolated (0.84 g, 90%). m/z (ESI, positive ion) =312.1 [ m+h ]] +
Step B. (2- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methanol (150 b)
To an ice-cold suspension of 150a (1.9 g,6.09 mmol) in EtOH (25 mL) and THF (25 mL) was added CaCl 2 (2.03 g,18.3 mmol) and NaBH 4 (0.65 g,18.3 mmol). The resulting reaction mixture was warmed to room temperature and stirred for 2h. After completion, the reaction was cooled to 0 ℃ and saturated NH 4 Cl (20 mL) quench. EtOH and THF were removed under reduced pressure. The resulting aqueous phase was extracted with EtOAc (20 mL. Times.3). The combined organic layers were washed with brine (20 mL), and dried over Na 2 SO 4 Dried, concentrated and purified by silica gel column chromatography (gradient elution, 70-100% EtOAc/hexanes) to afford the title product (150 b) as a white solid (1.02 g, 59%). m/z (ESI, positive ion) =284.3 [ m+h ]] +
Step C.4- (bromomethyl) -2- ((2, 4-dichlorophenoxy) methyl) pyridine (150 c)
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PBr is put into 3 (0.18 mL,1.94 mmol) was added dropwise to an ice-cold solution of 150b (0.5 g,1.76 mmol) in THF (8.8 mL). The resulting white suspension was stirred at room temperature for 1h. After completion, the reaction was cooled to 0 ℃ and ice water (10 mL) was added. The reaction mixture was extracted with EtOAc (10 mL. Times.3). The combined organic layers were washed with saturated NaHCO 3 Solution (50 mL), brine (10 mL) washed with Na 2 SO 4 Dried, filtered, and concentrated to afford the title product (150 c) (0.63 g) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =346.0 [ m+h ]] +
Step D.4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidine-1, 4-dicarboxylic acid 1- (tert-butyl) ester 4-methyl ester (150 d)
To a solution of diisopropylamine (0.44 mL,3.12 mmol) in THF (4 mL) at-78deg.C was added dropwise a hexane solution of n-butyllithium (1.37 mL,3.42 mmol). The resulting solution was warmed to room temperature and stirred for 30min, then cooled again to-78 ℃. A solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-methyl ester (0.54 g,2.23 mmol) in THF (3 mL) was added dropwise, and the reaction was stirred for an additional 30min, followed by dropwise addition of 150c (0.52 g,1.49 mmol) in THF. The reaction was slowly warmed to room temperature and stirred overnight. Then the reaction was saturated with NH 4 The Cl solution (10 mL) was quenched and extracted with EtOAc (10 mL. Times.3). The combined organic layers were washed with brine (10 mL), and dried over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 60-100% EtOAc/hexanes) to afford the title product (150 d) as a colorless oil (0.47 g, 62%). m/z (ESI, positive ion) =509.3 [ m+h ]] +
Step E.4- ((2, 4-dichlorophenoxymethyl) pyridin-4-yl) methyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (150 e)
A solution of lithium aluminum hydride in THF (0.77 mL,1.85 mmol) was added dropwise to an ice-cold solution of 150d (0.47 g,0.92 mmol) in THF (4.6 mL). The reaction was stirred at 0deg.C for 10min and quenched with water (5 mL). The resulting mixture was filtered through a pad of celite. The filtrate was extracted with EtOAc (×3). The combined organic layers were washed with brine (5 mL), and dried over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 80-100% etoac/hexanes) to afford the title product (150 e) (0.26 g, 59%) as a colorless oil. m/z (ESI, positive ion) =481.3 [ m+h ]] +
Step F. (4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidin-4-yl) methanol (150 f)
A solution of 150e (15 mg,0.031 mmol) in DCM (1 mL) and TFA (0.5 mL) was stirred at room temperature for 10min. After completion, the reaction solvent was removed under reduced pressure and the resulting residue was diluted with EtOAc (3 mL). The organic layer was saturated with NaHCO 3 (5 mL), brine (3 mL), washed over Na 2 SO 4 Dried, filtered and concentrated to afford the title product (150 f) (12 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =381.1 [ m+h ]] +
Step G.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4- (hydroxymethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (150 g)
A solution of 150f (11.5 mg,0.03 mmol), 57f (16.7 mg,0.045 mmol) and DIPEA (0.026 mL,0.15 mmol) in DMF (0.5 mL) was stirred overnight at room temperature. After completion, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL. Times.2), brine (3 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-20% meoh/DCM) to provide the title product (150 g) as a pale yellow oil (6.4 mg, 31%). m/z (ESI, positive ion) =677.2 [ m+h ]] + 。
Step H.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4- (hydroxymethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (150)
150g (6.4 mg,0.009 mmol) and LiOH (1.2 mg,0.028 mmol) were combined at 30℃in THF, meOH, H 2 The solution in o=2:1:1 (0.4 mL) was stirred overnight. After completion, the reaction mixture was diluted to 1mL with water and purified by reverse phase HPLC (gradient elution, 20-100% CH 3 CN/H 2 O, with 0.1% formic acid as modifier) to afford the title product (150) (3.1 mg, 49%) as a white solid. 1 H NMR(600MHz,CD 3 OD) δppm 8.42 (d, j=5.1 hz, 1H), 8.13 (s, 1H), 8.00 (dd, j=8.6, 1.7hz, 1H), 7.80 (s, 1H), 7.73 (d, j=8.4 hz, 1H), 7.41 (s, 1H), 7.35 (d, j=2.6 hz, 1H), 7.22 (dd, j=5.1, 1.5hz, 1H), 7.19 (dd, j=9.2, 2.6hz, 1H), 7.05 (d, j=9.2 hz, 1H), 6.57 (s, 1H), 5.73 (s, 2H), 5.25 (s, 2H), 4.04 (q, j=7.2 hz, 2H), 3.87 (s, 2H), 3.21 (s, 2H), 2.72 (s, 2H), 2.49-2.56 (m-2.2.46 (m-2.34, 1H), 7.34-2 m (2 m-2.46). m/z (ESI, positive ion) =663.3 [ m+h ]] + 。
Examples 168, 169 and 170 were synthesized from 145d in a similar procedure to that described in example 150, steps G and H. Examples 171, 174, 182, 183 were synthesized in a similar procedure to that described in example 168.
EXAMPLE 152 (S) -2- ((4- ((6- ((2-chloro-4-cyclopropylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (152)
Step A.4- ((6- ((2-chloro-4-cyclopropylphenoxy) methyl) pyridin-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (152 b)
152a (800 mg,1.6mmol, prepared in a similar procedure to that described in the synthesis of 114 f), cyclopropylboronic acid (69mg, 8 mmol), pd (dppf) Cl 2 A mixture of (130 mg,0.1 mmol) in toluene (26 mL) was degassed with nitrogen and stirred at 10 ℃. Addition of Cs 2 CO 3 (1.04 g,3.2 mmol) inH 2 O (4 mL) and at 100deg.C under N 2 Next, the resulting mixture was heated for 2 hours. After cooling, the reaction was filtered and diluted with EtOAc (50 mL), with H 2 O (15 mL) and brine (15 mL). The organic layer was concentrated and purified by silica gel column chromatography (EtOAc: petroleum ether=1:4) to afford the title product (152 b) as a yellow oil (0.52 g, 62.5%). m/z (ESI, positive ion) =457.3 [ M+H ]] + 。
Step B.2- ((2-chloro-4-cyclopropylphenoxy) methyl) -6- (piperidin-4-ylmethyl) pyridine (152 c)
To a mixture of 152b (40 mg,0.09 mmol) in DCM (3 mL) was added TFA (0.5 mL) at 0deg.C. The reaction was stirred at 0deg.C for 1h, then diluted with DCM (15 mL) and taken up in NaHCO 3 Aqueous solution (8 mL. Times.2), H 2 O (10 mL) and brine (10 mL). The organic layer was purified by Na 2 SO 4 Dried, filtered and concentrated to give the title product (152 c) as a yellow oil (25 mg, 72%). m/z (ESI, positive ion) =357.1 [ m+h ]] + 。
Step c. (S) -2- ((4- ((6- ((2-chloro-4-cyclopropylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (152 d)
K was added to a mixture of 152c (50 mg,0.14 mmol), 1h (41 mg,0.14 mmol) in DMF (5 mL) at 0deg.C 2 CO 3 (58 mg,0.42 mg) and potassium iodide (12 mg,0.7 mmol). The reaction was warmed to room temperature and stirred for 1h. Will react with H 2 O (50 mL) was quenched and extracted with ethyl acetate (50 mL. Times.3). The organic layer was purified by Na 2 SO 4 Dried, filtered and concentrated to provide a crude residue which was purified by reverse phase HPLC (65% CH 3 CN/H 2 O with 0.05% TFA as modifier) to be purifiedTo afford the title product (152 d) (60 mg, 62.7%) as a white solid. m/z (ESI, positive ion) =615.3 [ M+H ]] + 。
Step d. (S) -2- ((4- ((6- ((2-chloro-4-cyclopropylphenoxy) methyl) pyridin-2-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (152)
To 152d (30 mg,0.05 mmol) in MeOH/H 2 To a solution in o=10:1 (5 ml) was added lithium hydroxide (23 mg,0.98 mmol). The mixture was stirred at 30℃for 48h. Will react with H 2 O (50 mL) was quenched, followed by extraction with EtOAc (50 mL. Times.3). The organic layer was purified by Na 2 SO 4 Dried and concentrated to provide a crude residue which was purified by reverse phase HPLC (65% ch) 3 CN/H 2 O, with 0.05% TFA as modifier) to afford the TFA salt of the title compound (152) (15 mg, 51%) as a white solid. 1 H NMR(400MHz,CD 3 OD) δ8.32 (d, j=0.91 hz, 1H), 8.03 (dd, j=8.55, 1.51hz, 1H), 7.85 (t, j=7.75 hz, 1H), 7.79 (d, j=8.56 hz, 1H), 7.55 (d, j=7.56 hz, 1H), 7.30 (d, j=7.66 hz, 1H), 7.09 (d, j=2.06 hz, 1H), 6.96 (dt, j=8.50, 5.25hz, 2H), 5.19 (s, 2H), 4.60-4.80 (m, 6H), 4.39 (dt, j=9.3, 5.9hz, 1H), 3.69-3.84 (m, 2H), 3.19-3.25 (m, 2H), 2.85 (d, j=7.04 hz, 2H), 2.73-2.82 (m, 2H), 2.82-2.82 (m, 2.25 hz), 5.19 (s, 2H), 4.60-4.80 (m, 6H), 4.39 (dt, j=9.3, 5.9hz, 1H), 3.19 (m, 2H), 2.82 (2H), 2.82-4.82 (m, 2H), 2.52-4.52 (2H), 4.38 (m, 2H), 1.52, 1H), 4.38 (2H), 1.38 (2H). m/z (ESI, positive ion) =601.2 [ m+h ]] + 。
Example 153 was synthesized in a similar procedure as described in example 152.
EXAMPLE 154 (S) -2- ((4- ((2- (((4-chloro-6-cyclopropylpyridin-3-yl) oxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (154)
Step A.2-bromo-5-methoxypyridine 1-oxide (154 a)
To a solution of 2-bromo-5-methoxypyridine (15 g,79.8 mmol) in DCE (200 ml) was added m-CPBA (20.6 g,119.7 mmol). The reaction was stirred at 60℃for 16h. The reaction mixture was then cooled and taken up in saturated Na 2 CO 3 (200 mL. Times.3) washing. The DCE layer was dried, filtered, and concentrated to provide the title product (154 a) (15.8 g, 96.9%) as a white solid. m/z (ESI, positive ion) =206.0 [ m+h ] ] + 。
Step B.2-bromo-5-methoxy-4-nitropyridine 1-oxide (154 b)
The flask was charged with sulfuric acid (40 mL) and 154a (8 g,39.2 mmol) was added followed by dropwise addition of nitric acid (4.8 mL,108 mmol). The reaction was then cooled to 60 ℃ and the remaining nitric acid (19.2 ml,432 mmol) was added. The resulting mixture was stirred at 60 ℃ for 30min, then cooled and poured into an ice/water mixture (800 mL). The solid was collected by filtration, washed with EtOAc (50 mL) and dried in an oven to afford the title compound (154 b) (5.0 g, 49%) as a yellow solid, which was used in the next step without further purification. m/z (ESI, positive ion) =248.9 [ m+h ]] + 。
Step C.2-bromo-5-methoxypyridin-4-amine (154 c)
To a solution of 154b (4.5 g,18.07 mmol) and iron powder (10.1 g,180.72 mmol) in 75% EtOH/H2O (60 mL) was added NH 4 Cl (9.7, 180.72 mmol). The mixture was stirred at 70℃for 3h. The reaction mixture was then filtered and the residue was washed with EtOH (50 mL. Times.3). The combined filtrates were concentrated and redissolved in EtOAc (100 mL). The EtOAc layer was washed with water (20 mL), brine (20 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated to provide the title compound (154 c) (2.9 g, 75.3%) as a yellow solid, which was used in the next step without further purification. m/z (ESI, positive ion) =205.1 [ m+h ] ] + 。
Step D.2-bromo-4-chloro-5-methoxypyridine (154 d)
To a solution of 154c (3.3 g,16.3 mmol) and 37% HCl (30 mL) was added dropwise a solution of sodium nitrite (1.2 g,17.1 mmol) in water (5 mL) at 0deg.C. The resulting mixture was stirred at 0deg.C for 15min, followed by dropwise addition of a solution of copper (I) chloride (1.96 g,19.51 mmol) in 37% HCl (60 mL) at the same temperature. The resulting mixture was warmed to room temperature and stirred for 2h. Then, the reaction mixture was diluted with water (500 ml), and a solid was precipitated. The solid was collected by filtration, washed with water (50 mL), and redissolved in EtOAc (100 mL). The EtOAc layer was saturated with NaHCO 3 (100 mL. Times.2), brine (200 mL), washed with Na 2 SO 4 Dried, and filtered. The filtrate was concentrated and the crude residue was purified by silica gel column chromatography (15% EtOAc/petroleum ether) to afford the title compound (154 d) (1.9 g, 52.3%) as a yellow solid. 1 H NMR(400MHz,CD 3 OD)δ8.15(s,1H),7.67(s,1H),4.00(s,3H)。
Step E.6-bromo-4-chloropyridin-3-ol (154 e)
To 154d (550 mg,2.47 mmol) in CHCl 3 BBr was added to the solution in (15 mL) 3 (1.25 g,4.95 mmol). The reaction was stirred at 50deg.C for 16h, cooled, and quenched with saturated NaHCO 3 (20 ml) and brine (20 ml). The organic layer was purified by Na 2 SO 4 Drying, filtering, and concentrating to provide a crude residue, and It was purified by silica gel column chromatography (5% meoh/DCM) to give the title product (154 e) as a white solid (350 mg, 67.8%). m/z (ESI, positive ion) =210.0 [ m+h ]] + 。
Step F.4- ((2- (((6-bromo-4-chloropyridin-3-yl) oxy) methyl) oxazol-5-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (154 f)
To a solution of 60d (498 mg,1.69 mmol) and DIPEA (524 mg,4.06 mmol) in DCM (10 mL) was added MsCl (232 mg,2.03 mmol) at 0deg.C. The reaction was stirred at 0deg.C for 0.5h, followed by washing with water (10 mL). The DCM layer was taken up in Na 2 SO 4 Dried, filtered and concentrated to provide residue a. Separately flask was charged with 154e (350 mg,1.69 mmol), K 2 CO 3 (463 mg,3.38 mmol). DMF (10 mL) was added. To this mixture was added a solution of residue a in DMF. The reaction was stirred at 50℃for 2h. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 ml×2). The EtOAc layer was dried, filtered, and concentrated to provide a crude residue which was purified by silica gel column chromatography (30% EtOAc/petroleum ether) to provide the title product (154 f) as a white solid (540 mg, 65.7%). m/z (ESI, positive ion) =510.1 [ m+na ]] + 。
Step g. (S) -2- ((4- ((2- (((4-chloro-6-cyclopropylpyridin-3-yl) oxy) methyl) oxazol-5-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (154)
The title product (154) was synthesized in a similar procedure as described in example 114, steps G to I. 1 H NMR(400MHz,CD 3 OD)δppm 8.34(d,J＝0.88Hz,1H),8.28(s,1H),7.98-8.09(m,1H),7.80(d,J＝8.77Hz,1H),7.38(s,1H),6.96(s,1H),5.30(s,2H),5.14-5.25(m,1H),4.61-4.83(m,5H),4.40(dt,J＝9.43,5.81Hz,1H),3.72-3.88 (m, 2H), 3.18-3.29 (m, 2H), 2.73-2.86 (m, 3H), 2.41-2.56 (m, 1H), 1.89-2.13 (m, 4H), 1.61 (br s, 2H), 0.97-1.06 (m, 2H), 0.85-0.97 (m, 2H). m/z (ESI, positive ion) =592.2 [ m+na ]] + 。
Example 155.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methylene) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (155)
Step A.4- ((1- (tert-Butoxycarbonyl) piperidin-4-ylidene) methyl) picolinic acid methyl ester (155 a)
The flask was charged with (2- (methoxycarbonyl) pyridin-4-yl) boronic acid (66 mg,0.37 mmol), tert-butyl 4- (bromomethylene) piperidine-1-carboxylate (101 mg,0.37 mmol), cs 2 CO 3 (238 mg,0.73 mmol) and Pd (dppf) Cl 2 (27 mg,0.037 mmol) and THF: H were added 2 Mixed solvent of o=2:1 (18 mL). The mixture was degassed with nitrogen and stirred under argon at 50 ℃ for 18h. After completion, the reaction was extracted with EtOAc (10 ml×3). The organic layer was dried, filtered and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (155 a) as a colorless oil (16.5 mg, 14%). m/z (ESI, positive ion) =333.2 [ m+h ]] + 。
Step B.4- ((2- (hydroxymethyl) pyridin-4-yl) methylene) piperidine-1-carboxylic acid tert-butyl ester (155 b)
155a (17 mg,0.05 mmol) of CaCl 2 (11 mg,0.1 mmol) and NaBH 4 THF (10 mL) was added to a mixture of (7 mg,0.2 mmol). The resulting suspension was stirred at 60 ℃ overnight. After cooling, the reaction water was used(10 mL) was quenched, extracted with ethyl acetate (10 mL. Times.3) and washed with brine. The combined organic phases were treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (155 b) as a colorless oil (9.5 mg, 63%). m/z (ESI, positive ion) =305.1 [ m+h ]] + 。
Step C.4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methylene) piperidine-1-carboxylic acid tert-butyl ester (155 c)
The beaker was filled with 2, 4-dichlorophenol (5.6 mg,0.034 mmol), 155b (9.5 mg,0.031 mmol) and PPh 3 (9.8 mg,0.038 mmol). Anhydrous THF (5 mL) was added and the reaction cooled in an ice bath. Diethyl azodicarboxylate (7.6 mg,0.038 mmol) was added dropwise and the resulting mixture was stirred at 0 ℃ for 0.5h, followed by stirring overnight at room temperature. After completion, the reaction was quenched with water (5 mL), extracted with ethyl acetate (5 ml×3) and washed with brine. The combined organic phases were treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated to provide a crude residue which was purified by silica gel column chromatography (EtOAc/hexanes) to provide the title product (155 c) as a colorless oil with some impurities, which was used in the next step without further purification. m/z (ESI, positive ion) =451.1 [ M+H ] ] + 。
Step D.2- ((2, 4-dichlorophenoxy) methyl) -4- (piperidin-4-ylidenemethyl) pyridine (155 d)
A solution of 155c (impure) in DCM (2 mL) was treated with TFA (1 mL) for 10min at room temperature. After completion, the solvent was removed in vacuo and the resulting crude residue was purified by reverse phase HPLC (gradient elution, 0-90% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (155 d) (6.3 mg) as a white solid44%,2 steps). m/z (ESI, positive ion) =351.2 [ M+H ]] + 。
Step E.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methylene) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (155 e)
155d (6.2 mg,0.018 mmol), 57f (5.9 mg,0.018 mmol) and Et are added at room temperature 3 A solution of N (18 mg,0.18 mmol) in DMF (0.8 mL) was stirred for 18h. After completion, the reaction was purified by reverse phase HPLC (gradient elution, 0-90% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (155 e) (4.4 mg, 39%) as a white solid. m/z (ESI, positive ion) =645.3 [ m+h ]] + 。
Step F.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methylene) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (155)
155e (4.4 mg, 0.0070 mmol) in CH 3 The solution in CN (0.4 mL) was treated with 2N NaOH (0.4 mL). The resulting mixture was stirred at room temperature for 24h. After completion, the reaction was purified by reverse phase HPLC (gradient elution, 0-75% CH 3 CN/water with 0.1% formic acid as modifier) to afford the title product (155) as a white solid (2.7 mg, 63%). 1 H NMR(600MHz,CD 3 OD)δppm 8.44(d,J＝5.14Hz,1H),8.16(br d,J＝0.73Hz,1H),8.00(br dd,J＝8.62,1.65Hz,1H),7.79(s,1H),7.69-7.73(m,1H),7.42(br d,J＝2.57Hz,1H),7.38(s,1H),7.23(br dd,J＝8.80,2.57Hz,1H),7.16(br dd,J＝5.14,1.10Hz,1H),7.07(br d,J＝9.17Hz,1H),6.58(br d,J＝0.73Hz,1H),6.30(s,1H),5.80(s,2H),5.25(s,2H),4.11(q,J＝7.34Hz,2H),3.86(s,2H),2.55-2.60(m,2H),2.40-2.44(m,2H),2.29(dt,J＝9.81,5.18Hz,4H),1.32(t,J＝7.34Hz, 3H) m/z (ESI, positive ion) =631.3 [ M+H ]] + 。
Example 156 was synthesized from 102c and 57i as described in example 57, step J. Example 160 was synthesized in a similar procedure as described in example 156.
Example 157.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (157)
Step A.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (157 b)
To a stirred solution of 157a (13.6 mg,0.0386mmol, prepared as described for the synthesis of 145 d) and 145f (14.5 mg,0.0463 mmol) in 1, 2-dichloroethane (0.3 mL) was added HOAc (7.0 mg,0.116 mmol) followed by sodium triacetoxyborohydride (12.2 mg,0.058 mmol) at room temperature. The mixture was stirred at the same temperature for 1h. The reaction was quenched by addition of saturated sodium bicarbonate and extracted with DCM (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 1-8% MeOH/DCM) to provide the title product (157 b) as a colourless gum (11.5 mg, 46%). m/z (ESI, positive ion) =648.3 [ m+h ]] + 。
Step B.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (157)
At room temperature, 157b (11.5 mg,0.0177 mmol) in THF/MeOH/H 2 To a stirred solution of O (2:1:11, 0.4 mL) was added lithium hydroxide monohydrate (2.23 mg,0.053 mmol). After stirring the mixture at the same temperature for 2h, additional lithium hydroxide monohydrate (2.23 mg,0.053 mmol) was added. After another 1.5h, 1N HCl was added to the mixture to adjust to ph=3. The solution was subjected to reverse phase preparative HPLC (gradient elution, 20-60% MeCN/H 2 O, with 0.1% TFA as modifier) to afford TFA salt of title compound 157 as a white solid (11.4 mg, 86%). 1 H NMR(600MHz,CD 3 OD) δ9.04 (s, 1H), 8.23 (d, j=0.9 hz, 1H), 8.06 (dd, j=8.4, 1.5hz, 1H), 7.83 (d, j=8.4 hz, 1H), 7.42 (d, j=2.6 hz, 1H), 7.31 (t, j=7.9 hz, 1H), 7.23 (dd, j=8.8, 2.6hz, 1H), 7.02-7.12 (m, 4H), 6.94 (dd, j=8.1, 2.0hz, 1H), 5.87 (s, 2H), 5.15 (s, 2H), 4.64 (br s, 1H), 4.54 (br s, 2H), 4.35 (q, j=7.3 hz, 2H), 3.19-3.41 (m, 4H), 2.13-2.20 (m, 2.88-2.1 hz, 1H), 5.87 (s, 2H), 4.64 (br s, 2H), 3.19-3.3 hz, 1H). m/z (ESI, positive ion) =634.3 [ m+h ] ] + 。
Example 163.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4-methylpiperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (163)
Step A.4- (((1H-imidazole-1-thiocarbonyl) oxy) methyl) -4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (163 a)
Thiocarbonyldiimidazole (42.6 mg,0.24 mmol) was added to a solution of 150e (23 mg,0.048 mmol) in THF (0.24 mL) at room temperature. The resulting solution was heated at 60℃for 2h. After completion, the reaction was cooled, diluted with water (1 mL) and EtOAc (1 mL), and extracted with EtOAc (1 ml×3). The combined organic layersWashed with brine (1 mL), over Na 2 SO 4 Dried, filtered, and concentrated to provide the crude title product (163 a) (28 mg) as a yellow solid, which was used in the next step without further purification. m/z (ESI, positive ion) =591.3 [ m+h ]] +
Step B.4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (163 b)
AIBN (2.33 mg,0.0142 mmol) and tributyltin hydride (0.064 mL,0.24 mmol) were added to a solution of 163a (0.028 g,0.047 mmol) in toluene (2.4 mL) at room temperature under Ar. The resulting solution was heated at 100 ℃ overnight. After completion, the reaction solvent was removed under reduced pressure to afford the crude title product (163 b) (7.5 mg), which was used in the next step without further purification. m/z (ESI, positive ion) =465.3 [ m+h ] ] +
Step C.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4-methylpiperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (163)
The title product (163) was synthesized in analogy to the procedure described in example 150, steps F-H. 1 H NMR(600MHz,CD 3 OD) δppm 8.42 (d, j=5.1 hz, 1H), 8.13 (d, j=0.7 hz, 1H), 8.00 (dd, j=8.4, 1.5hz, 1H), 7.81 (s, 1H), 7.72 (d, j=8.4 hz, 1H), 7.36-7.38 (m, 2H), 7.20 (dd, j=8.8, 2.6hz, 1H), 7.15 (dd, j=5.1, 1.5hz, 1H), 7.06 (d, j=8.8 hz, 1H), 6.57 (s, 1H), 5.73 (s, 2H), 5.26 (s, 2H), 4.05 (q), j=7.3 hz, 2H), 3.88 (s, 2H), 2.54-2.66 (m, 4H), 2.35-2.42 (m, 2H), 1.24-1.35 (m, 1.5hz, 1H), 1.35 (s, 2H), 1.83 (s, 2H). m/z (ESI, positive ion) =647.3 [ m+h ]] +
Example 164.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4- (fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (164)
Step A.4- ((2, 4-dichlorophenoxymethyl) pyridin-4-yl) methyl) -4- (fluoromethyl) piperidine-1-carboxylic acid tert-butyl ester (164 a)
Deoxo-fluor (0.104 mL,0.254 mmol) was added dropwise to a solution of 150e (0.102 g,0.212 mmol) in DCM (1.1 mL) at room temperature. The reaction was then heated to 45 ℃ overnight. After completion, the reaction was quenched with saturated NaHCO 3 The solution (5 mL) was quenched and extracted with EtOAc (5 mL. Times.3). The combined organic layers were washed with brine (5 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (gradient elution, 40-80% EtOAc/hexanes) to afford the title product (164 a) (45.0 mg, 44%) as a yellow oil. m/z (ESI, positive ion) =483.3 [ M+H ]] +
Step B.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) -4- (fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (164)
The title product (164) was synthesized from 164a in a similar procedure as described in example 150, steps F-H. m/z (ESI, positive ion) =665.3 [ m+h ]] + 。
EXAMPLE 178 (S) -2- ((4- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (178)
Step A.4- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) oxy) picolinic acid methyl ester (178 a)
Pd was added at 120℃to 2 (dba) 3 A solution of (46 mg,0.05 mmol) and BINAP (62 mg,0.1 mmol) in toluene (2 mL) was heated for 5min and subsequently transferred to methyl 2-bromopyridine-4-carboxylate (216 mg,1.0 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (241 mg,1.2 mmol) and Cs 2 CO 3 (652 mg,2.0 mmol) in 18mL of toluene. The mixture was degassed with argon and stirred under argon at 120 ℃ for 16h. After completion, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (178 a) as a colorless oil with impurities, which was used in the next step without further purification. m/z (ESI, positive ion) =337.3 [ m+h ]] + 。
Step B.4- ((2- (hydroxymethyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (178 b)
178a (77 mg,0.23 mmol) CaCl 2 (51 mg,0.46 mmol) and NaBH 4 To a mixture of (35 mg,0.91 mmol) was added THF (10 mL). The resulting suspension was stirred at 60 ℃ overnight. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 ml×3). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (178 b) as a colorless oil (35 mg,23%,2 steps). m/z (ESI, positive ion) =309.3 [ m+h ]] + 。
Step C.4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (178 c)
The flask was filled with 2, 4-dichlorophenol (27 mg,0.17 mmol), 178b (17 mg,0.06 mmol) and PPh 3 (44 mg,0.17 mmol). Anhydrous THF (5 mL) was added and the reaction cooled in an ice bath. Diethyl azodicarboxylate (34 mg,0.17 mmol) was added dropwise and the resulting mixture was stirred at 0 ℃ for 0.5h, followed by stirring overnight at room temperature. After completion, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 ml×3). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (178 c) as a colorless oil with some impurities, which was used in the next step without further purification. m/z (ESI, positive ion) =453.3 [ m+h ]] + 。
Step D.2- ((2, 4-dichlorophenoxy) methyl) -4- (piperidin-4-yloxy) pyridine (178 d)
A solution of 178c (15 mg, impure) in DCM (2 mL) was treated with TFA (1 mL) for 10min at room temperature. After completion, the solvent was removed in vacuo and the resulting crude product was purified by reverse phase HPLC (gradient elution, 0-75% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (178 d) as a white solid (17 mg,62%,2 steps). m/z (ESI, positive ion) =353.1 [ m+h ]] + 。
Step E. (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (178 e)
A solution of 178d (4.6 mg,0.01 mmol), 1h (3.2 mg,0.01 mmol) and DIPEA (25.5 mg,0.2 mmol) in DMF (1 mL) was stirred at room temperature for 22h. After completion, the reaction was purified by reverse phase HPLC (gradient elution, 20-100% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (178 e) (5.6 mg, impure) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =611.3 [ m+h ]] + 。
Step F. (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (178)
178e (5.6 mg,0.008mmol, impure) in CH 3 The solution in CN (0.5 mL) was treated with 2N NaOH (0.5 mL). The resulting mixture was stirred at room temperature for 26h. After completion, the reaction was purified by reverse phase HPLC (gradient elution, 0-90% CH 3 CN/water with 0.1% formic acid as modifier) to afford the title product (178) as a white solid (3.5 mg,59%,2 steps). 1 H NMR(600MHz,CD 3 OD) delta ppm 8.32-8.37 (m, 1H), 8.10 (d, j=5.13 hz, 1H), 7.97 (brdd, j=8.44, 1.47hz, 1H), 7.68 (d, j=8.44 hz, 1H), 7.46 (d, j=2.57 hz, 1H), 7.26 (brdd, j=8.80, 2.57hz, 1H), 7.08 (d, j=8.80 hz, 1H), 6.98-7.03 (m, 1H), 6.88 (s, 1H), 5.26 (qd, j=7.34, 2.57hz, 1H), 5.18 (s, 2H), 5.09 (m, 1H), 4.85-4.90 (m, 1H), 4.72 (brdd, j=15.59, 2.75hz, 1H), 4.65 (td), 7.89, 5.7 hz, 1H), 6.88 (s, 1H), 5.26 (qd, j=7.34, 2.57hz, 1H), 5.18 (s, 2H), 5.09 (s, 1H), 4.85-4.90 (m, 1H), 4.75 hz, 1H), 4.75 (d, 1H), 4.98-7.7.7.7 (m, 1H), 6.7.7 (1H), 6.88 (J), 1H), 6.88 (s, 1H), 1.18 (1H), 1.7.7.7 (J, 1H), 1H (1H), 1.7.7.7.7 (J, 1H). m/z (ESI, positive ion) =597.3 [ m+h ] ] + 。
Example 179 was synthesized in a similar procedure as described in example 178.
Example 186.2- (((S) -4- (2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carbonyl) -2-methylpiperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (186)
Step a. (S) -4- (2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carbonyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (186 a)
To 102c (49 mg,0.17 mmol), (2S) -2-methylpiperazin-1-yl carboxylic acid tert-butyl ester (34 mg,0.17 mmol) and T 3 To a solution of P (178 mg,0.26 mmol) in DMF (2 ml) was added triethylamine (51 mg,0.51 mmol). The mixture was stirred at 15℃for 16h, diluted with EtOAc (20 mL) and washed with brine (20 mL. Times.3). The organic layer was dried, filtered and evaporated to dryness to afford the title product (186 a) (80 mg) as a colourless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =470.1 [ M+H ]] + 。
Step B. (S) - (2- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) (3-methylpiperazin-1-yl) methanone (186 b)
To a solution of 186a (100 mg,0.21 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred for 2h at 20 ℃ and concentrated. Redissolving the crude in DCM and using saturated NaHCO 3 (5 mL. Times.2) washing. The DCM layer was dried, filtered, and concentrated to provide the title product (186 b) (78 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =370.1 [ m+h ] ] + 。
(S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (186 c)
To 1H (390 mg,1.33 mmol) in 2mL THF/H 2 To the solution in O (1:1) was added LiOH (64 mg,2.66 mmol). The mixture was stirred at 25℃for 2h. After completion, the mixture was adjusted to ph=5-6 with 1N HCl and extracted with EtOAc (20 ml×3). The combined organic layers were dried, filtered and concentrated. The crude residue was purified by preparative TLC (10% meoh/DCM) to give the title product (186 c) as a white solid (290 mg, 74%). m/z (ESI, positive ion) =281.1 [ m+h ]] + 。
Step D.2- (((S) -4- (2- ((2, 4-dichlorophenoxy) methyl) oxazole-5-carbonyl) -2-methylpiperazin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (186)
To a solution of 186b (78 mg,0.21 mmol) and 186c (61 mg,0.22 mmol) in DMF (3 mL) was added DIPEA (85 mg,0.66 mmol). The mixture was stirred at 50℃for 16h. The mixture was purified by reverse phase HPLC (45% CH 3 CN/H2O with 0.05% TFA as modifier) to afford the TFA salt of the title product (186) as a white solid (6.5 mg, 4.2%). 1 H NMR(400MHz,CD 3 OD) delta 8.49 (s, 1H), 8.17 (dd, j=8.6, 1.3hz, 1H), 7.83 (d, j=8.6 hz, 1H), 7.70 (s, 1H), 7.42 (s, 1H), 7.26 (dt, j=22.0, 5.6hz, 2H), 5.36 (s, 2H), 5.31-5.17 (m, 1H), 4.77-4.85 (m, 2H), 4.61-4.70 (m, 2H), 4.45 (dt, j=9.2, 5.9hz, 1H), 4.22 (d, j=16.4 hz, 1H), 3.98-4.17 (m, 2H), 3.65 (br s, 1H), 3.48 (br s, 1H), 2.91-3.16 (m, 2H), 2.77-2.90 (m, 1H), 2.65 (dd, 2.65, 1.4 hz, 1H), 3.20 (d, 1H). m/z (ESI, positive ion) =614.1 [ m+h ] ] + 。
Example 189.2- ((4-cyano-4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (189)
Step A.4-cyano-4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (189 a)
To a solution of diisopropylamine (0.20 mL,1.39 mmol) in THF (2 mL) at-78deg.C was added dropwise a hexane solution of n-butyllithium (0.61 mL,1.52 mmol). The resulting solution was warmed to room temperature and stirred for 30min, then cooled again to-78 ℃. A solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.21 g,0.99 mmol) in THF (1.5 mL) was added dropwise. The reaction was stirred for 30min, followed by the careful addition of 150c (0.23 g,0.66 mmol). The reaction was allowed to slowly warm to room temperature and stirred overnight. Adding saturated NH 4 Cl solution (10 mL) and the reaction was extracted with EtOAc (10 mL. Times.3). The combined organic layers were washed with brine (10 mL), and dried over Na 2 SO 4 Dried, concentrated and purified by silica gel column chromatography (gradient elution, 60-100% etoac/hexanes) to afford the title product (150 d) as a colorless oil (0.027 g, 9%). m/z (ESI, positive ion) =476.3 [ m+h ]] + 。
Step B.4- ((2, 4-dichlorophenoxymethyl) pyridin-4-yl) methyl) piperidine-4-carbonitrile (189 b)
A solution of 189a (9.3 mg, 0.020mmol) in DCM (1 mL) and TFA (0.5 mL) was stirred at room temperature for 10min. After completion, the solvent was removed under reduced pressure. The resulting residue was diluted with EtOAc (3 mL) and saturated NaHCO 3 (5 mL), brine (3 mL), washed with Na 2 SO 4 Dried, filtered, and concentrated to provide the crude title product (189 b) (6.8 mg) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =376.3 [ m+h ]] + 。
Step C.2- ((4-cyano-4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (189)
The title product (189) was prepared in analogy to the procedure described in example 150, steps G and H. 1 H NMR(600MHz,CD 3 OD) delta ppm 9.06 (d, j=1.5 hz, 1H), 8.56 (d, j=5.1 hz, 1H), 8.22 (d, j=1.1 hz, 1H), 8.06 (dd, j=8.6, 1.7hz, 1H), 7.80 (d, j=8.1 hz, 1H), 7.63 (s, 1H), 7.42 (d, j=2.6 hz, 1H), 7.41 (dd, j=5.3, 1.7hz, 1H), 7.25 (dd, j=8.8, 2.6hz, 1H), 7.11 (d, j=8.8 hz, 1H), 7.10 (d, j=1.5 hz, 1H), 5.90 (s, 2H), 5.30 (s, 2H), 4.34 (q, j=7.3 hz, 2H), 4.17 (s, 2H), 3.13 (dd, j=5.3, 1.7hz, 1H), 7.25 (dd, j=8.8 hz, 1H), 7.10 (d, j=1.5.5 hz, 1H), 7.11 (d, j=8.8 hz, 1H), 7.11 (j=3.7.7 hz, 1H), 7.11 (j=1.3, 1H). m/z (ESI, positive ion) =658.3 [ m+h ] ] + 。
EXAMPLE 198 (S) -2- ((4- ((6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (198)
Step A.2-bromo-6- ((2, 4-dichlorophenoxy) methyl) pyridine (198 a)
To a solution of (6-bromopyridin-2-yl) methanol (1.57 g,8.35 mmol) in anhydrous THF (16.7 mL) at 0deg.C was added DIAD (2.53 g,12.5 mmol), PPh 3 (3.29 g,12.5 mmol) and 2, 4-dichlorophenol (1.36 g,8.35 mmol). The resulting mixture was stirred at room temperature for 1.5h and saturated NaHCO was added 3 (10 mL). The mixture was extracted with EtOAc (10 mL. Times.3), washed with brine (10 mL), and dried over Na 2 SO 4 Dried, filtered, concentrated and the crude residue was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc/hexanes) to afford the title product (198 a) (378 mg, 27%). m/z (ESI, positive ion) =334.0 [ M+H ]] + 。
Step B.4- ((6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (198 b)
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (44 mg,0.22 mmol) in anhydrous DMF (1.1 mL) was added NaH (13 mg,0.33mmol,60% dispersion in mineral oil) at 0deg.C. After stirring for 10min, the reaction was heated to 50 ℃ and a solution of 198a (80 mg,0.24 mmol) in DMF (0.6 mL) was added dropwise. After stirring for 8H, the reaction mixture was cooled to room temperature and quenched with H 2 O (1 mL) quench. The crude mixture was extracted with EtOAc (3 mL. Times.2), washed with brine (3 mL), and dried over Na 2 SO 4 Dried, filtered, concentrated and the crude residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc/hexanes) to afford the title product (198 b) (39 mg, 40%). m/z (ESI, positive ion) =453.3 [ m+h ]] + 。
Step C.2- ((2, 4-dichlorophenoxy) methyl) -6- (piperidin-4-yloxy) pyridine (198 c)
At room temperature, 198b (37 mg,0.082 mmol) in dry CH 2 Cl 2 To a solution of (0.8 mL) was added TFA (0.3 mL,4.1 mmol). After stirring for 1h, the reaction was concentrated and saturated NaHCO was added 3 (0.5 mL) to neutralize TFA. The mixture was extracted with EtOAc (2 ml×3) and the combined organic layers were dried over Na 2 SO 4 Dried, filtered, and concentrated to provide the crude title product (198 c) (28 mg), which was used in the next step without further purification. m/z (ESI, positive ion) =353.3 [ m+h ]] + 。
Step d. (S) -2- ((4- ((6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (198 d)
To a solution of crude 198c (8 mg,0.023 mmol) in dichloroethane (0.2 mL) was added 1h (8 mg,0.027 mmol) and DIPEA (0.01 mL,8.8mg,0.068 mmol) at room temperature. The reaction was heated to 60 ℃. After 20h, the reaction was cooled to room temperature and concentrated to afford the crude title product (198 d), which was used in the next step without further purification. m/z (ESI, positive ion) =611.3 [ m+h ] ] + 。
Step E. (S) -2- ((4- ((6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (198)
At room temperature, crude 198d was dissolved in THF/H 2 O (1:1, 0.4 mL). LiOH.H 2 O (5 mg,0.11 mmol) and a few drops of MeOH were added to the mixture and heated to 50 ℃. After stirring for 1h, the reaction was acidified with 1N HCl to adjust to ph=5. The mixture was concentrated and purified by reverse phase HPLC (gradient elution, 0-70% CH 3 CN/water with 0.1% TFA as modifier) to afford the title product (198) (13.8 mg,86%, over 3 steps) as a white solid. m/z (ESI, positive ion) =597.3 [ m+h ]] + 。 1 HNMR(600MHz,CD 3 OD)δppm 8.35(s,1H),8.05(dd,J＝8.62,1.28Hz,1H),7.81(d,J＝8.44Hz,1H),7.74(t,J＝7.89Hz,1H),7.44(d,J＝2.57Hz,1H),7.25(dd,J＝8.99,2.38Hz,1H),7.17(d,J＝6.97Hz,1H),7.11(d,J＝8.80Hz,1H),6.79(br d,J＝8.07Hz,1H),5.36(br s,1H),5.22(ddd,J＝14.49,7.15,2.20Hz,1H),5.17(s,2H),4.87(s,2H),4.63-4.71(m,3H),4.43(dt,J＝9.17,5.87Hz,1H),3.57-3.78(m,4H),2.77-2.84(m,1H),2.50(ddd,J＝16.69,11.55,7.34Hz,1H),2.16-2.36(m,4H)。
Examples 199, 214, 246, 247, and 264 were synthesized in a similar procedure to that described in example 198.
Examples 248, 249 were synthesized in a similar procedure to that described in example 198, with NH 4 OH was used as modifier for the final purification step.
Example 200 was synthesized in a similar procedure as described in example 114.
In a similar procedure to that described in example 131 step a, followed by steps B to C in example 152, followed by UPCC (Daicel CHIRALPAK AD _3,3 x 150mm, co 2 Chiral separation with MeOH (0.1% DEA) =50/50) followed by synthesis of examples 202 and 203 (stereochemistry arbitrarily specified) from (3-bromophenyl) methanol and 2, 4-dichlorophenol in a similar procedure to that described in step D of example 152.
Examples 204 and 205 (R) -2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) phenyl) (methoxy) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (204) and (S) -2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) phenyl) (methoxy) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (205)
Step A.4- ((3- ((2, 4-dichlorophenoxy) methyl) phenyl) (methoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (204 a)
To a mixture of NaH (86 mg,2.1mmol,60% dispersion in mineral oil) in THF (15 mL) was added a solution of 204a (prepared by following a procedure similar to 130 b) (500 mg,1.1 mmol) in THF (20 mL). The reaction was stirred at 0deg.C for 30min. Then add CH 3 I (759 mg,5.3 mmol). The reaction was allowed to warm to room temperature and was quenched under N 2 Stirring was carried out for 48h. After completion, the reaction was completed with H 2 O (20 mL) was quenched and extracted with EtOAc (20 mL. Times.3). The combined organic layers were treated with H 2 O (10 mL), brine (10 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (204 b) as a yellow oil (400 mg, 74%). m/z (ESI, positive ion) =502.2 [ m+na ] ] + 。
Step B. (R) -4- ((3- ((2, 4-dichlorophenoxy) methyl) phenyl) (methoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (204 b-P1) and (R) -4- ((3- ((2, 4-dichlorophenoxy) methyl) phenyl) (methoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (204 b-P2)
By UPCC (Daicel CHIRALPAK IA 4.6.6 x 250mm, co 2 Chiral separation of 204b was performed with MeOH (0.1% DEA) =80:20) to obtain the title products (204 b-P1 and 204 b-P2). 204b-P1:130mg, rt=1.186 min, white solid; 204b-P2:140mg, rt=1.441 min, white solid. Stereochemistry is arbitrarily specified.
Step C. (R) -2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) phenyl) (methoxy) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (204) and (S) -2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) phenyl) (methoxy) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (205)
The title compound 204 was synthesized from 204B-P1 in a similar procedure as described in steps B to D of example 152. m/z (ESI, positive ion) =662.3 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.89-8.97(m,2H),8.23(s,1H),8.05(dd,J＝8.5,1.5Hz,1H),7.83(d,J＝8.3Hz,1H),7.37-7.46(m,3H) 7.20-7.29 (m, 2H), 7.12 (d, j=8.7 hz, 1H), 6.99 (br s, 1H), 5.82 (s, 2H), 5.21 (s, 2H), 4.45-4.65 (m, 2H), 4.30 (q, j=7.3 hz, 2H), 4.02 (br d, j=7.0 hz, 1H), 3.50-3.74 (m, 2H), 3.20 (s, 3H), 2.78-3.05 (m, 2H), 2.10 (br s, 1H), 1.88 (br s, 1H), 1.45-1.67 (m, 6H). m/z (ESI, positive ion) = 662.3.
The title compound 205 was synthesized from 204B-P2 in a similar procedure as described in steps B through D of example 152. m/z (ESI, positive ion) =662.3 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.12(s,1H),7.97(dd,J＝8.5,1.1Hz,1H),7.74(s,1H),7.64(d,J＝8.7Hz,1H),7.41(d,J＝2.2Hz,1H),7.18-7.29(m,2H),7.08(d,J＝8.7Hz,1H),6.82-6.88(m,2H),6.85(dd,J＝8.2Hz,1H),6.52(s,1H),5.76(s,2H),5.14(s,2H),4.31-4.39(m,1H),4.09(q,J＝7.4Hz,2H),4.83(s,2H),3.30(s,3H),2.66-2.78(m,2H),2.35(br t,J＝8.9Hz,2H),1.81-1.93(m,2H),1.52-1.77(m,2H),1.22-1.38(m,4H)。
EXAMPLE 206 (S) -2- ((4- (3- ((2-cyano-4-fluorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (206)
Step A.4- (3- (methoxycarbonyl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester (206 a)
At 0℃under N 2 Next, methyl 3-hydroxybenzoate (4.88 g,32.1 mmol), tert-butyl (4-hydroxypiperidin-1-yl) formate (6.5 g,32.1 mmol), PPh 3 (12.63 g,48.1 mmol) to a mixture of THF (30 mL) was added DEAD (8.39 g,48.1 mmol). The mixture was stirred at 20 ℃ for 18h and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (206 a) as a white solid with some impurities (4.3 g). m/z (ESI, positive ion) =358.1 [ m+na ]] + 。
Step B.4- (3- (hydroxymethyl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester (206 b)
A solution of 206a (4.3 g,12.8 mmol) in THF (40 mL) was cooled to 0deg.C. Lithium aluminum hydride (15.4 mL,15.3mmol,1N in THF) was added and the reaction stirred at 0deg.C for 1.5h. At 0 ℃, na is used for the reaction 2 SO 4 .10H 2 O (15 g) quench. After stirring at the same temperature for 20min, the mixture was filtered and concentrated in vacuo to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=3:1) to afford the title product (206 b) (3.2 g, 77%) as a colorless oil. m/z (ESI, positive ion) =330.1 [ m+na ]] + 。
Step C.4- (3- ((2-cyano-4-fluorophenoxy) methyl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester (206 c)
To a solution of 206b (50 mg,0.16mmol,1.0 eq.) in DMF (1.5 mL) was added NaH (10 mg,0.24mmol,60% dispersion in mineral oil) at 0deg.C and stirred at the same temperature for 30min. A solution of 2, 5-difluorobenzonitrile (23 mg,0.17 mmol) in DMF (0.5 mL) was added. After stirring at 20 ℃ for 2h, the mixture was poured into ice water (8 mL) and extracted with EtOAc (8 ml×2). The combined organic layers were treated with H 2 O (3 mL), brine (3 mL), washed over Na 2 SO 4 Dried, filtered and concentrated in vacuo to give the title product (206 c) as a white solid with some impurities (65 mg). m/z (ESI, positive ion) =449.1 [ m+na ]] + 。
Step D.5-fluoro-2- ((3- (piperidin-4-yloxy) benzyl) oxy) benzonitrile (206 d)
To a solution of 206c (65 mg,0.13 mmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at 18 ℃ for 1.5h and concentrated to give the crude title product (206 d) (45 mg) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =327.1 [ M+H ] ] + 。
Step E. (S) -2- ((4- (3- ((2-cyano-4-fluorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (206 e)
206d (45 mg,0.14 mmol), K at 20 ℃ 2 CO 3 (56 mg,0.41 mmol) in CH 3 The mixture in CN (4 mL) was stirred for 20min. KI (3 mg,0.01 mmol) and 1h (40 mg,0.14 mmol) were added and the reaction was stirred for an additional 1.5h at 18 ℃. The reaction was then diluted with EtOAc (15 mL) and concentrated with H 2 O (5 mL) and brine (5 mL). The organic layer was purified by Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the title product (206 e) (20 mg, 20%) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =585.2 [ m+h ]] + 。
Step F. (S) -2- ((4- (3- ((2-cyano-4-fluorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (206)
206e (20 mg,0.03 mmol) in CH 3 OH/H 2 To a solution in O (3 mL, 1:1) was added LiOH (10 mg,0.3 mmol). The reaction was stirred at 30 ℃ for 18h, adjusted to ph=7 with 1NHCl, and taken up with DCM/CH 3 OH (10:1) (5 mL. Times.2) extraction. The organic layer was concentrated in vacuo to give a crude residue which was purified by preparative TLC (silica gel, DCM/CH 3 Oh=10:1) to afford the title product (206) (7.2 mg, 35.1%) as a white solid. m/z (ESI, positive ions) )＝571.2[M+H] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.33(d,J＝0.9Hz,1H),7.97(dd,J＝8.5,1.5Hz,1H),7.67(d,J＝8.3Hz,1H),7.46(dd,J＝8.1,3.3Hz,1H),7.37(ddd,J＝9.3,8.0,3.3Hz,1H),7.21-7.31(m,2H),7.09(s,1H),7.01(d,J＝7.4Hz,1H),6.90(dd,J＝8.1,2.0Hz,1H),5.20-5.29(m,3H),4.86-4.93(m,1H),4.72(dd,J＝15.7,2.6Hz,1H),4.65(td,J＝7.6,6.1Hz,1H),4.46(dt,J＝9.2,5.9Hz,2H),3.92-4.09(m,2H),2.75-2.93(m,3H),2.47-2.58(m,3H),1.98-2.09(m,2H),1.81(ddd,J＝12.5,8.4,4.4Hz,2H)。
Example 317 was synthesized in a similar procedure to that described in example 206, using THF as the solvent in the final step.
Examples 207, 221 were synthesized in a procedure similar to that described in the synthesis of 157a, followed by procedures similar to those described in steps C-D of example 152.
Example 208.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (isoxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (208)
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Step A.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (isoxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid tert-butyl ester (208 a)
To a mixture of tert-butyl 2- (chloromethyl) -3- (1, 2-oxazol-5-ylmethyl) -1, 3-benzodiazole-5-carboxylate (30 mg,0.086mmol, synthesized in a similar procedure to 57 f), 157a (33 mg,0.095 mmol) and potassium carbonate (36 mg, 0.319 mmol) in DMF (1 mL) was added potassium iodide (29 mg,0.173 mmol). The reaction was stirred at 20℃for 3h. After completion, the reaction was completed with H 2 O (5 mL) was diluted and extracted with EtOAc (10 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=3:1) to afford the product as a solidThe title product (208 a) was a white solid (35 mg, 58%). m/z (ESI, positive ion) =663.2 [ m+h ] ] + 。
Step B.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (isoxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (208)
A solution of 208a (20 mg,0.03 mmol) in 4N HCl in dioxane (1 mL) was stirred for 2h at 18 ℃. After completion, the reaction was cooled in an ice bath. 1N NaOH was added to the mixture to adjust to ph=5. The reaction mixture was then extracted with EtOAc (5 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=2:1) to afford the title product (208) as a white solid (9.4 mg, 51%). m/z (ESI, positive ion) =607.2 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δ8.35(d,J＝1.80Hz,1H),8.20(s,1H),7.99(d,J＝8.44Hz,1H),7.67(d,J＝8.44Hz,1H),7.41(d,J＝2.52Hz,1H),7.18-7.28(m,2H),7.07(d,J＝8.88Hz,1H),6.96-7.03(m,2H),6.86(dd,J＝8.12,2.1Hz,1H),6.30(d,J＝1.72Hz,1H),5.95(s,2H),5.13(s,2H),4.36(s,1H),3.94(s,2H),2.76(s,2H),2.41(t,J＝8.64Hz,2H),1.88(s,2H),1.65(d,J＝8.9Hz,2H)
Examples 257, 280 were synthesized from 145d in a similar procedure to that described in example 208. For example 280, tert-butyl 1- ((1- (tert-butoxycarbonyl) azetidin-3-yl) methyl) -2- (chloromethyl) -1H-benzo [ d ] imidazole-6-carboxylate was used in the last step.
Example 215 was synthesized in a similar procedure as described in example 145.
Example 216.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (216)
Step A.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid tert-butyl ester (216 a)
To 157a (10 mg,0.028 mmol) and 2- (chloromethyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ]]To a solution of tert-butyl imidazole-6-carboxylate (9.9 mg,0.028 mmol) in DMF (1 mL) was added Et 3 N (57.5 mg,0.57 mmol). The resulting mixture was stirred at room temperature overnight. The crude mixture was purified directly by reverse phase HPLC (gradient elution, CH 3 CN/H 2 O, containing 0.1% TFA as modifier, 20-100%) to afford the title product (216 a) (17 mg, 90%) as a white solid. m/z (ESI, positive ion) =663.3 [ m+h ]] + 。
Step B.2- ((4- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (216)
216a (17 mg,0.026 mmol) was dissolved in a solution containing TFA: triisopropylsilane: H 2 O (3.7 mL:0.1mL:0.2 mL)/DCM (4 mL). The reaction was stirred at room temperature for 1h. After completion, the reaction was concentrated in vacuo and redissolved in DMSO (1 mL), followed by reverse phase HPLC purification (gradient elution, CH) 3 CN/H 2 O, containing 0.1% TFA as modifier, 0-90%) to afford the title product (216) as a white solid (13.4 mg, 72.5%). 1 H NMR (600 MHz,) δppm 8.40 (d, j=1.10 hz, 1H), 8.16 (s, 1H), 8.03 (dd, j=8.62, 1.65hz, 1H), 7.79 (d, j=8.44 hz, 1H), 7.42 (d, j=2.57 hz, 1H), 7.31-7.39 (m, 2H), 7.24 (dd, j=8.80, 2.57hz, 1H), 7.15 (s, 1H), 7.07-7.13 (m, 2H), 7.01 (dd, j=8.25, 2.38hz, 1H), 5.76 (s, 2H), 5.17 (s, 2H), 4.93 (s, 2H), 4.80 (br s, 1H), 3.72 (br s, 2H), 3.67 (br s, 2H), 2.32 (m, 2H), 2.24 (m, 2H). m/z (ESI, positive ion) =607.2 [ m+h ] ] + 。
Examples 217 and 232 were synthesized in a similar procedure to that described in example 216.
EXAMPLE 220 (S) -2- ((4- ((2- ((2-chloro-4-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (220)
Step A.4- ((2- (((methylsulfonyl) oxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (220 a)
Ms is added to a solution of 145b (50 mg,0.16 mmol) in DCM (3 mL) at 0deg.C 2 O (157 mg,0.48 mmol) and Et 3 N (80 mg,0.8 mmol). The mixture was stirred at 5℃for 1h. After completion, the mixture was taken up with H 2 O (2 mL) was quenched and extracted with EtOAc (5 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to provide the crude title product (220 a) (80 mg), which was used in the next step without further purification.
Step B.4- ((2- ((2-chloro-4-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (220 b)
To a solution of crude 220a (80 mg,0.21 mmol) in DMF (5 mL) was added 2-chloro-4-fluorophenol (30 mg,0.21 mmol) and Cs at 20deg.C 2 CO 3 (105 mg,0.32 mmol). The mixture was heated at 50℃for 5h. After completion, the reaction was passed through H 2 O (10 mL) was quenched and extracted with EtOAc (5 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated to provide a crude residue, which was purified by silica gel column chromatography (petroleum etherEtoac=1:1) to afford the title product 220b (80 mg, 87%). m/z (ESI, positive ion) =437.1 [ m+h ]] + 。
Step C.2- ((2-chloro-4-fluorophenoxy) methyl) -4- (piperidin-4-yloxy) pyridine (220 c)
To a solution of 220b (80 mg,0.18 mmol) in DCM (3 mL) was added TFA (0.6 mL) at 0deg.C. The resulting mixture was stirred at 20℃for 1h. After completion, the reaction was concentrated to afford the crude title product (220 c) (100 mg), which was used in the next step without further purification. m/z (ESI, positive ion) =337.1 [ m+h ]] + 。
Step d. (S) -2- ((4- ((2- ((2-chloro-4-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (220 d)
At 0deg.C, 220c (50 mg,0.15 mmol) in CH 3 To a solution in CN (3 mL) was added 1h (44 mg,0.15 mmol) and K 2 CO 3 (124 mg,0.9 mmol). The resulting mixture was stirred at 20℃for 4h. After completion, the reaction was concentrated and purified by preparative TLC (EtOAc: meoh=10:1) to afford the title product (220 d) (40 mg, 38%). m/z (ESI, positive ion) =595.2 [ m+h ]] + 。
Step E. (S) -2- ((4- ((2- ((2-chloro-4-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (220)
220d (15 mg,0.03 mmol) in MeOH/THF/H 2 To a solution in O (1:1:1, 3 mL) was added LiOH (7.3 mg,0.3 mmol). At 20 DEG CThe resulting mixture was stirred for 3h. After completion, the mixture was quenched with 1N aqueous HCl (0.5 mL) to adjust to ph=6, extracted with EtOAc (5 ml×3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to provide a crude product which was purified by reverse phase HPLC (CH 3 CN/H 2 O, with 0.05% TFA as modifier) to afford the title product (220) (7.4 mg, 48%). m/z (ESI, positive ion) =581.2 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.56(d,J＝6.54Hz,1H),8.36(d,J＝0.87Hz,1H)8.05(dd,J＝8.50,1.53Hz,1H),7.80(d,J＝8.72Hz,1H),7.53(d,J＝2.18Hz,1H),7.35(dd,J＝6.32,2.40Hz,1H),7.29(dd,J＝7.85,3.05Hz,1H),7.21(dd,J＝9.16,4.80Hz,1H),7.08(ddd,J＝9.05,7.96,3.05Hz,1H),5.32(s,2H),5.18-5.26(m,1H),5.07(br s,1H),4.78-4.83(m,3H),4.63-4.72(m,2H),4.45(dt,J＝9.37,5.78Hz,1H),3.46-3.70(m,4H),2.76-2.87(m,1H),2.45-2.56(m,1H),2.14-2.42(m,4H)。
Examples 308, 352, 356, 357, 358, 359 were synthesized from 220a in a similar procedure as described in example 220. Examples 309, 318 were synthesized from 206b in a similar procedure as described in example 220. Examples 316, 321, 322, 333, 354 were synthesized in a similar procedure as described in example 220. For all these compounds synthesized according to example 220, DMF may be used as solvent in the penultimate step and THF as solvent in the final step. The final purification step may optionally be performed without the use of a modifier in the reverse phase purification.
Examples 378, 379 were synthesized in a similar procedure to that described in example 220, except that DIPEA/DMF was used in the penultimate step instead of K 2 CO 3 。NH 4 OH was used as modifier for the final purification step.
Example 288 was synthesized from 206b in a similar procedure as described in example 220. The Boc group was removed using a 4N HCl dioxane solution instead of TFA (step C). Example 294 was synthesized in a similar procedure as described in example 288. In the penultimate step 57f of the mesylate analogue derived from 145e was used.
Example 290 was then synthesized from methyl 6-hydroxypicolinate and tert-butyl (2 s,4 s) -4-hydroxy-2-methylpiperidine-1-carboxylate as described in example 271 steps a-B, followed by example 220 steps a-E. Example 291 was synthesized in a similar procedure as described in example 290.
Example 224 was synthesized from 157a in a similar procedure as described in example 155, steps E and F.
Example 227 is a byproduct of the last hydrolysis of example 168.
Example 230.2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (230)
Step A.2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (230 b)
A solution of 230a (prepared in a similar procedure to 145d, 19.0mg,0.056 mmol), 57f (25.2 mg,0.056 mmol) and DIPEA (0.02 mL,1.13 mmol) in DMF (0.3 mL) was stirred overnight at room temperature. After completion, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL. Times.2), brine (3 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-20% MeOH/DCM) to provide the title product (230 b) as a pale yellow oil (7.6 mg, 21%). m/z (ESI, positive ion) =633.3 [ m+h ]] + 。
Step B.2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (230)
230b (7.6 mg,0.012 mmol) and LiOH (2.5 mg,0.060 mmol) were combined in THF, meOH, H at 30 ℃ 2 The solution in o=2:1:1 (0.4 mL) was stirred overnight. After completion, the reaction mixture was diluted to 1mL with water and purified by reverse phase HPLC (gradient elution, 20-50% CH) 3 CN/H 2 O, with 0.1% TFA as modifier) to afford the title product (230) (8.7 mg, 99%) as a white solid. m/z (ESI, positive ion) =619.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 9.11(d,J＝1.1Hz,1H),8.63(d,J＝7.0Hz,1H),8.26(s,1H),8.09(dd,J＝8.4,1.5Hz,1H),7.85(d,J＝8.8Hz,1H),7.60(d,J＝2.6Hz,1H),7.48(dd,J＝6.8,2.8Hz,1H),7.32(dd,J＝11.0,2.2Hz,1H),7.23-7.27(m,2H),7.11(d,J＝1.1Hz,1H),5.93(s,2H),5.42(s,2H),5.06(br s,1H),4.50(br s,2H),4.39(q,J＝7.2Hz,2H),3.30-3.37(m,2H),3.15-3.25(m,2H),2.22-2.30(m,2H),2.06(br s,2H),1.59(t,J＝7.3Hz,3H)。
Examples 259, 267 were synthesized in a similar procedure as described in example 230.
Example 250 was synthesized in a similar procedure to that described in example 230, with the final reverse phase HPLC purification using 0.05% NH 4 OH is used as a modifier.
Examples 336, 344, 345, 362, 365 were synthesized in a similar procedure as described in example 250. Example 346 is a by-product isolated in the last synthesis step of example 345. Example 364 was synthesized from 274c in a similar procedure as described in example 250.
Example 277 was synthesized in a similar procedure as described in example 230, with the final step product purified by normal phase silica gel column chromatography.
Examples 302, 335, 337 and 363 were synthesized in a similar procedure as described in example 277.
Example 231 was synthesized as described in example 155, steps E and F from 4- (3- ((4-chloro-2-fluorophenoxy) methyl) phenoxy) piperidine (following a similar procedure to 145 d) and 57F.
Examples 242 and 243 were synthesized in a similar procedure to that described in example 231.
Example 239.2- ((4- ((2- ((4-chloro-2-isocyanatophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxazol-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (239)
Step A.2- ((4- ((2- ((4-chloro-2-isocyanatophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxazol-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid tert-butyl ester (239 b)
239a (prepared in analogy to 145d, 13.0mg,0.038 mmol), 2- (chloromethyl) -1- (oxazol-2-ylmethyl) -1H-benzo [ d ] are reacted at room temperature]A solution of imidazole-6-carboxylic acid tert-butyl ester (13.2 mg,0.038 mmol) and DIPEA (132.0. Mu.L, 0.76 mmol) in DMF (0.4 mL) was stirred for 2h. After completion, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL. Times.2), brine (3 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 80-100% EtOAc/hexanes, then 0-20% MeOH/DCM) to afford the title product (239 b) as a colorless oil (20.9 mg, 84%). m/z (ESI, positive ion) =655.1 [ m+h ]] + 。
Step B.2- ((4- ((2- ((4-chloro-2-isocyanatophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxazol-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (239)
A solution of 239b (20.9 mg,0.032 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred overnight at room temperature. After completion, the reaction solvent was removed under reduced pressure and the resulting residue was diluted with water to 1mL,and by reversed phase HPLC (gradient elution, 20-60% CH) 3 CN/H 2 O, with 0.1% TFA as modifier) to afford the title product (239) (22.7 mg, 100%) as a white solid. m/z (ESI, positive ion) =599.3 [ m+h ] ] + 。 1 H NMR(600MHz,CD 3 OD)δppm 8.57(d,J＝8.2Hz,1H),8.35(d,J＝1.1Hz,1H),8.05(dd,J＝8.6,1.7Hz,1H),7.96(d,J＝1.1Hz,1H),7.80(d,J＝8.1Hz,1H),7.78(d,J＝2.6Hz,1H),7.70(dd,J＝8.8,2.6Hz,1H),7.61(d,J＝2.6Hz,1H),7.31-7.34(m,2H),7.19(d,J＝1.1Hz,1H),5.86(s,2H),5.42(s,2H),5.06(br s,1H),4.75(s,2H),3.55(br s,2H),3.37-3.48(m,2H),2.28-2.39(m,2H),2.12-2.24(m,2H)。
Examples 240, 241, 258, 265, 266 were synthesized in a similar procedure as described in example 239. Examples 268, 269, 270 were synthesized from the corresponding analogs of 198c in a similar procedure as described in example 239.
Examples 251, 252, 253 were synthesized in a similar procedure to that described in examples 198, steps a to C, followed by a similar procedure to that described in examples 219, steps a to B.
Example 254 was synthesized from methyl 3-hydroxybenzoate and tert-butyl (2 s,4 s) -4-hydroxy-2-methylpiperidine-1-carboxylate in a procedure similar to that described in examples 145, steps a to D followed by a procedure similar to that described in example 155, steps E and F.
Example 255 was synthesized from 157a in a similar procedure as described in example 152, steps C and D.
Example 256 was synthesized from tert-butyl ester analogs 186B and 57f in a similar procedure to that described in example 208, steps a and B.
Examples 260 and 263 (R) -2- ((4- ((3- ((4-chloro-2-cyanophenoxy) methyl) phenyl) fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (260) and (S) -2- ((4- ((3- ((4-chloro-2-cyanophenoxy) methyl) phenyl) fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (263)
Step A.4- (hydroxy (3- (methoxycarbonyl) phenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester (260 a)
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A solution of methyl 3-iodobenzoate (3.5 g,13.4 mmol) and isopropyl magnesium chloride (2M in THF) (7.35 mL,14.7 mmol) in anhydrous THF (30 mL) was stirred at-65℃for 0.5h. Tert-butyl (4-formylpiperidin-1-yl) carboxylate (3.16 g,14.7 mmol) was then added to the mixture. After stirring for 1h at 17℃the reaction was saturated with NH 4 The Cl solution (100 mL) was quenched and extracted with ethyl acetate (100 mL. Times.3). The organic layer was purified by Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=7:3) to afford the title product (260 a) as a colorless oil (4.2 g, 85%). m/z (ESI, positive ion) =372.2 [ m+na ]] + 。
Step B.4- (fluoro (3- (methoxycarbonyl) phenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester (260 b)
To a solution of 260a (4.2 g,12mmol,1.0 eq.) in THF (45 mL) was added Deoxo-Fluor (3.18 g,14.4 mmol) at 0deg.C. At 0℃under N 2 The mixture was stirred for 2h. After completion, saturated aqueous sodium bicarbonate was added to the mixture in an ice bath to adjust to ph=7. Then the reaction is carried out using H 2 O (100 mL) was diluted and extracted with EtOAc (100 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=8:2) to afford the title product (260 b) as a colorless oil (2.8 g, 62%). m/z (ESI, positive ion) =374.2 [ m+na ]] + 。
Step C.4- (fluoro (3- (hydroxymethyl) phenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester (260 c)
260b (2.7 g,7.7 mmol) and LiAlH at 0deg.C 4 A solution of (440 mg,11.5 mmol) in THF (30 mL) was stirred for 1h. After completion, the reaction was quenched with sodium sulfate decahydrate and the precipitate was rinsed with THF (50 ml×3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=7:3) to afford the title product (260 c) as a colorless oil (2.1 g, 79%). m/z (ESI, positive ion) =346.1 [ m+na ]]。
Step D.4- ((3- ((4-chloro-2-cyanophenoxy) methyl) phenyl) fluoromethyl) piperidine-1-carboxylic acid tert-butyl ester (260 d)
260c (2.17 g,6.7 mmol), 5-chloro-2-hydroxybenzonitrile (1.03 g,6.7 mmol), PPh 3 A solution of (2.64 g,10.0 mmol) and DEAD (1.75 g,10.0 mmol) in THF (20 mL) was stirred at 0deg.C for 1h and 25℃for 12h. After completion, the reaction was completed with H 2 O (50 mL) was diluted and extracted with EtOAc (50 mL. Times.3). The organic layer was treated with anhydrous Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=9:1) to afford the title product (260 d) as a colorless oil (1.5 g, 46%). m/z (ESI, positive ion) =481.2 [ m+na ] ] + 。
Step E. (R) -4- ((3- ((4-chloro-2-cyanophenoxy) methyl) phenyl) fluoromethyl) piperidine-1-carboxylic acid tert-butyl ester (260 d-P1) and (S) -4- ((3- ((4-chloro-2-cyanophenoxy) methyl) phenyl) fluoromethyl) piperidine-1-carboxylic acid tert-butyl ester (260 d-P2)
By UPCC (Daicel CHIRALPAK OJ-3X 150mm, CO 2 /MeOH(0.1％ DEA) Chiral separation of 260d to afford 260d-P1 (130 mg, rt= 2.911 m) and 260d-P2 (140 mg, rt= 3.321 m) as colorless oils to afford the title products (260 d-P1 and 260 d-P2). The stereochemistry of 260d-P1 and 260d-P2 is arbitrarily specified.
Step F. (R) -2- ((4- ((3- ((4-chloro-2-cyanophenoxy) methyl) phenyl) fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (260) and (S) -2- ((4- ((3- ((4-chloro-2-cyanophenoxy) methyl) phenyl) fluoromethyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (263)
The title compound (260) was synthesized from 260D-P1 in a similar procedure as described in steps B through D of example 152. 1:1THF:H 2 The O-mixed solvent is used in the final step. m/z (ESI, positive ion) =641.2 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.98(d,J＝1.0Hz,1H),8.23(d,J＝0.7Hz,1H),8.05(dd,J＝8.6,1.7Hz,1H),7.82(d,J＝8.3Hz,1H),7.69(d,J＝2.7Hz,1H),7.62(dd,J＝9.1,2.7Hz,1H),7.42-7.54(m,3H),7.31-7.37(m,1H),7.28(d,J＝9.1Hz,1H),7.00(d,J＝1.2Hz,1H),5.83(s,2H),5.36(dd,J＝48.0,8.0Hz,1H),5.28-5.31(m,2H),4.48(br s,2H),4.32(q,J＝7.3Hz,2H),3.45-3.63(m,2H),2.73-2.92(m,2H),2.02-2.20(m,2H),1.97(br d,J＝15.4Hz,1H),1.44-1.72(m,5H)。
The title compound (263) was synthesized from 260D-P2 in a similar procedure as described in steps B to D of example 152. 1:1THF:H 2 The O-mixed solvent is used in the final step. m/z (ESI, positive ion) =641.3 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δ＝8.23(d,J＝0.73Hz,1H),8.05(dd,J＝8.4,1.6Hz,1H),7.83(d,J＝8.6Hz,1H),7.69(d,J＝2.7Hz,1H),7.62(dd,J＝9.1,2.7Hz,1H),7.51(s,1H),7.43-7.49(m,3H),7.22-7.38(m,1H),7.28(d,J＝9.1Hz,1H),7.01(s,1H),5.83(s,2H),5.37(dd,J＝48.0,8.0Hz,1H),5.28(s,2H),4.53(br s,2H),4.33(q,J＝7.3Hz,2H),3.50-3.68(m,2H),2.79-2.99(m,2H),2.05-2.22(m,1H),1.99(br d,J＝13.5Hz,1H),1.45-1.73(m,6H)。
Example 261.2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (261)
Step A.4- ((4-chloropyrimidin-2-yl) methoxy) -3-fluorobenzonitrile (261 a)
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 taken up in Cs at room temperature 2 CO 3 (324 mg,1 mmol) treatment. The reaction mixture was stirred for 2h, then quenched with water (50 mL) and extracted with EtOAc (20 mL. Times.3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (261 a) as a white solid (93 mg, 71%). m/z (ESI, positive ion) =264.1 [ m+h ]] + 。
Step B.4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (261 b)
The reaction vial was charged with 261a (18.7 mg,0.071 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (17.1 mg,0.085 mmol), cs 2 CO 3 (46.2 mg,0.14 mmol) and degassed with Ar, then anhydrous toluene (4 mL) was added under an Ar balloon. The same preparation applies to Pd-containing 2 (dba) 3 Separate vials of solutions (2.9 mg, 0.04 mmol) and BINAP (4.4 mg,0.0071 mmol) in anhydrous toluene (2 mL), heated to 110℃for 5min, then injected using a syringeWhich is transferred to a first reaction vial. The resulting reaction mixture was heated at 110 ℃ overnight. After completion, the reaction solvent was removed in vacuo and the residue was taken up in EtOAc/H 2 O was diluted and extracted with EtOAc. The organic layer was purified by Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography to provide the title product (261 b) (25 mg, 82%). m/z (ESI, positive ion) =429.3 [ M+H ]] + 。
Step C.3-fluoro-4- ((4- (piperidin-4-ylmethyl) pyrimidin-2-yl) methoxy) benzonitrile (261 c)
261b (149 mg,0.35 mmol) was dissolved in TFA (2 mL) in DCM (5 mL). After stirring for 10min, the reaction was concentrated in vacuo. The resulting residue was redissolved in DMSO (1 mL) and purified by reverse phase HPLC (gradient elution, 0-60% CH) 3 CN/H 2 O, containing 0.1% TFA as modifier) to afford the title product (261 c) as a white solid (117 mg, 76%). m/z (ESI, positive ion) =329.3 [ m+h ]] + 。
Step D.2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (261 d)
To a solution of 261c (TFA salt, 7.3mg,0.017 mmol) and 57f (6.6 mg,0.02 mmol) in DMF (1 mL) was added Et 3 N (33.4 mg,0.33 mmol). The resulting mixture was stirred at room temperature overnight, followed by reverse phase HPLC (gradient elution, 0-75% CH) 3 CN/H 2 O, containing 0.1% TFA as modifier) to afford the title product (261 d) as a white solid (9.2 mg, 75%). m/z (ESI, positive ion) =625.3 [ M+H ]] + 。
Step E.2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (261)
261d (9.2 mg,0.012 mmol) was dissolved in CH 3 CN (0.5 mL) and treated with 2NNaOH (0.5 mL). The mixture was stirred at room temperature for 24h, followed by reverse phase HPLC (gradient elution, 0-75% CH) 3 CN/H 2 O, containing 0.1% TFA as modifier) to afford the title product (261) as a white solid (7.8 mg, 86%). m/z (ESI, positive ion) =611.4 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 9.08(s,1H),8.50(br d,J＝5.87Hz,1H),8.24(br s,1H),8.07(dd,J＝8.80,1.47Hz,1H),7.85(br d,J＝8.44,1H),7.56-7.61(m,1H),7.45-7.48(m,1H),7.25(br t,J＝8.44Hz,1H),7.07(s,1H),6.82(m,1H),5.87(s,2H),5.40(s,2H),4.65-4.74(m,2H),4.57-4.64(m,1H),4.35(q,J＝7.34Hz,2H),3.47-3.58(m,2H),3.33-3.45(m,2H),2.10-2.22(m,2H),1.94-2.10(m,2H),1.57(t,J＝7.34Hz,3H)。
EXAMPLE 262 (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (262)
Step a. (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (262 a)
To a solution of 261c (7.3 mg,0.017 mmol) and 1h (5.8 mg,0.02 mmol) in DMF (1 mL) was added Et 3 N (33.4 mg,0.33 mmol). The resulting mixture was stirred at room temperature overnight, then passed through reverse phaseHPLC (gradient elution, 0-75% CH 3 CN/H 2 O, containing 0.1% TFA as modifier) to afford the title product (262 a) as a white solid (11.9 mg, with impurities). m/z (ESI, positive ion) =587.4 [ m+h ]] + 。
Step B. (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (262)
262a (12 mg,0.017 mmol) was dissolved in CH 3 CN (0.5 mL) and treated with 2NNaOH (0.5 mL). The mixture was stirred at room temperature for 24h, then directly by reverse phase HPLC (gradient elution, 0-75% CH) 3 CN/H 2 O, containing 0.05% NH 4 OH as a modifier) to afford the title product (262) (5.5 mg, 55%) as a white solid. m/z (ESI, positive ion) =573.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm8.43(d,J＝5.87Hz,1H),8.31(d,J＝1.10Hz,1H),7.97(dd,J＝8.44,1.47Hz,1H),7.67(d,J＝8.44Hz,1H),7.59(dd,J＝11.00,1.83Hz,1H),7.43-7.50(m,1H),7.22(t,J＝8.44Hz,1H),6.75(d,J＝5.87Hz,1H),5.39(s,2H),5.25(qd,J＝7.07,2.89Hz,1H),4.96-5.03(m,1H),4.85-4.90(m,1H),4.70(br dd,J＝15.41,2.93Hz,1H),4.64(td,J＝7.89,5.87Hz,1H),4.46(dt,J＝9.08,5.91Hz,1H),4.01(br d,J＝13.57Hz,1H),3.90(br d,J＝13.57Hz,1H),2.77-2.84(m,2H),2.71-2.77(m,1H),2.49-2.55(m,1H),2.30-2.38(m,2H),1.87-1.94(m,2H),1.68-1.77(m,2H)。
Example 374 was synthesized from 4-chloro-2- (chloromethyl) -5-fluoropyrimidine in analogy to the procedure described in example 262.
Examples 296, 315, 328, 331, 339, 343 were synthesized in a similar procedure to that described in example 262.
Example 271.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-3-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (271)
Step A.3- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) oxy) picolinic acid methyl ester (271 a)
At 0℃under N 2 Next, methyl 3-hydroxypyridine-2-carboxylate (1.5 g,9.8 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.97 g,9.8 mmol), PPh 3 A solution of (3.86 g,14.7 mmol) and DEAD (2.56 g,14.7 mmol) in dry THF (15 mL) was stirred for 1h. The resulting mixture was stirred at 17℃for 11h. After completion, the reaction was completed with H 2 O (100 mL) was diluted and extracted with EtOAc (100 mL. Times.3). The organic layer was purified by Na 2 SO 4 Dried, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=7:3) to afford PPh containing some of the PPh as a colorless oil 3 Crude product of O (271 a) (5.1 g). m/z (ESI, positive ion) =337.1 [ m+h ]] + 。
Step B.4- ((2- (hydroxymethyl) pyridin-3-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (271 b)
Crude 271a (5.1 g) and LiBH were combined at 0deg.C 4 A solution of (330 mg,1.5 mmol) in THF/MeOH (50 mL/10 mL) was stirred for 1h. After completion, the reaction was quenched with sodium sulfate decahydrate and filtered. The filter cake was further rinsed with THF (100 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by reverse phase HPLC (27% CH) 3 CN/H 2 O, with 0.05% TFA as modifier) to afford the title product (271 b) as a colorless oil (1.3 g, 26.3%). m/z (ESI, positive ion) =309.2 [ m+h ] ] + 。
Step C.4- ((2, 4-dichlorophenoxy) methyl) pyridin-3-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (271 c)
At 0℃under N 2 Next, 271b (303 mg,1.02 mmol), 2, 4-dichlorophenol (167 mg,1.02 mmol), PPh 3 A solution of (403 mg,1.54 mmol) and DEAD (268 mg,1.54 mmol) in dry THF (6 mL) was stirred for 1h. The resulting mixture was then stirred overnight at 17 ℃. After completion, the reaction solution was taken up with H 2 O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=7:3) to afford the title product (271 c) as a colorless oil (180 mg, 38%). m/z (ESI, positive ion) =453.1 [ m+h ]] + 。
Step D.2- ((4- ((2, 4-dichlorophenoxy) methyl) pyridin-3-yl) oxy) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (271)
The title compound 271 was synthesized from 271c in a similar procedure as described in steps B to D of example 152. 1:1THF:H 2 The O-mixed solvent is used in the final step. m/z (ESI, positive ion) =635.1 [ m+h] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.23(d,J＝1.7Hz,1H),8.05(dd,J＝8.6,1.5Hz,1H),7.83(d,J＝8.6Hz,1H),7.79(d,J＝7.8Hz,1H),7.56(dd,J＝8.6,4.9Hz,1H),7.42(d,J＝2.2Hz,1H),7.22-7.30(m,2H),7.04(d,J＝1.2Hz,1H),5.86(s,2H),5.37(s,2H),4.73(s,2H),4.35(q,J＝7.3Hz,2H),3.50-3.70(m,5H),2.28-2.40(m,2H),2.12-2.27(m,2H),1.57(t,J＝7.3Hz,3H)。
Example 286 was synthesized in a similar procedure to that described in example 271.
Example 272 was synthesized from methyl 2-hydroxybenzoate in a procedure similar to that described in example 271, step a, followed by procedures similar to those described in example 60, steps D and E, followed by procedures similar to those described in example 106, steps D through F.
Example 284 was synthesized in a similar procedure as described in example 272.
Example 274.2- (((2S, 4S) -4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) -2-methylpiperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (274)
Step A. (2S, 4R) -2-methyl-4- ((methylsulfonyl) oxy) piperidine-1-carboxylic acid tert-butyl ester (274 a)
To a mixture of (2S, 4R) -4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (400 mg,1.86 mmol), DIPEA (960 mg,7.43 mmol) in DCM (10 mL) was added a solution of methanesulfonic anhydride (809 mg,4.64 mmol) in DCM (2.5 mL). After stirring at 0deg.C for 2H, the reaction was diluted with EtOAc (100 mL) and taken up with H 2 O (40 mL. Times.2) was washed. The organic layer was purified by Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the title product (274 a) (550 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =316.1 [ m+na ]] + 。
Step B.4- (((2S, 4S) -1- (tert-Butoxycarbonyl) -2-methylpiperidin-4-yl) oxy) picolinic acid methyl ester (274 b)
274a (460 mg,1.55 mmol), 4-hydroxypyridine-2-carboxylic acid methyl ester (238 mg,1.55 mmol), cs were reacted at 90℃ 2 CO 3 (608 mg,1.86 mmol) in DMF (4 mL) was stirred for 3h. The mixture was poured into water (20 mL) and extracted with EtOAc (20 ml×3). Using H for the organic layer 2 O (10 mL), brine (10 mL), washed with Na 2 SO 4 Dried, filtered and concentrated in vacuo to give a crude residue which was purified by preparative TLC (EtOAc/petroleum ether=2:1) to afford the title product (274 b) (317 mg, 52.4%) as a colorless oil. m/z (ESI, positive ion) =351.1 [ M+H ]] + 。
Step C. (2S, 4S) -4- ((2- (hydroxymethyl) pyridin-4-yl) oxy) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (274 c)
To 274b (300 mg,0.86 mmol) in THF (4 mL) at 0deg.C was added LiAlH 4 (1 mL,1.03 mmol). The mixture was stirred at 0deg.C for 1h and taken up with Na 2 SO 4 .10H 2 And O quenching. After stirring at 20 ℃ for 30min, the reaction was filtered and concentrated in vacuo to afford the title product (274 c) (229 mg, 75%) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =323.1 [ m+h ]] + 。
Step D.2- (((2S, 4S) -4- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) -2-methylpiperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (274)
The title product (274) was synthesized from 274c in a similar procedure as described in steps a through E of example 220. DMF was used as solvent in the penultimate step. m/z (ESI, positive ion) =649.1 [ m+h ] ] + 。 1 H NMR(400MHz,MeOD)δppm 1 H NMR(400MHz,CD 3 OD)9.10(d,J＝1.47Hz,1H)8.57(d,J＝6.60Hz,1H)8.22(d,J＝0.73Hz,1H),8.08(dd,J＝8.56,1.47Hz,1H),7.83(d,J＝8.31Hz,1H),7.53(d,J＝2.45Hz,2H),7.32-7.41(m,2H),7.20(d,J＝8.80Hz,1H),7.08(d,J＝1.22Hz,1H),5.95(br d,J＝3.42Hz,2H),5.37(s,2H),4.76(br d,J＝15.16Hz,1H),4.41(q,J＝7.34Hz,2H),4.17-4.08(m,1H),3.23 -3.31(m,2H),3.23-3.13(m,1H),2.90-2.78(m,1H),2.17-2.41(m,2H),1.66-1.82(m,2H),1.62(t,J＝7.34Hz,3H),1.40(d,J＝6.11Hz,3H)。
Example 283 was synthesized in a similar procedure as described in example 274. Example 295 was synthesized from (2 s,4 s) -4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester in analogy to the procedure described in example 274. LiBH 4 Is the reducing agent of step C. In the final step, these compounds were all purified using silica gel column or preparative TLC.
Example 366 was synthesized in a similar procedure to that described in example 274, with the final purification using reverse phase HPLC (NH 4 OH as modifier).
Example 275 was synthesized in a similar procedure as described in example 145.
Example 276.2- ((4- ((2- ((4-chloro-2-cyanophenoxy) methyl) pyridin-4-yl) oxy) -2, 2-dimethylpiperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (276)
Step A.4- ((2- (bromomethyl) pyridin-4-yl) oxy) -2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (276 b)
276a (prepared in a similar procedure to 145a, 70.7mg,0.21 mmol), PPh 3 CBr was added to a solution of (82.7 mg,0.32 mmol) in DCM (2.1 mL) 4 (105 mg,0.32 mmol). The reaction was stirred at room temperature for 35min. After completion, the reaction was concentrated in vacuo and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 5-40% acetone/hexanes) to afford the title product (276 b) (57.7 mg, 69%) as a pale yellow oil. m/z (ESI, positive ion) =399.3 [ m+h ] ] + 。
Step B.4- ((2- ((4-chloro-2-cyanophenoxy) methyl) pyridin-4-yl) oxy) -2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (276 c)
To a solution of 276b (57.7 mg,0.14 mmol) and 5-chloro-2-hydroxybenzonitrile (44.4 mg,0.29 mmol) in DMF (0.72 mL) was added Cs 2 CO 3 (118 mg,0.36 mmol). It was stirred at room temperature for 1h. After completion, the reaction was quenched by water (5 mL). The aqueous layer was extracted with EtOAc (5 mL. Times.3). The combined organic layers were washed with water (5 mL), brine (5 mL. Times.3), and dried over Na 2 SO 4 Dried, filtered, concentrated and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 20-100% EtOAc/hexanes) to afford the title product (276 c) as a white solid (53.8 mg, 79%). m/z (ESI, positive ion) =472.4 [ m+h ]] + 。
Step C.5-chloro-2- ((4- ((2, 2-dimethylpiperidin-4-yl) oxy) pyridin-2-yl) methoxy) benzonitrile (276 d)
A solution of 276c (53.8 mg,0.114 mmol) in DCM (1.14 mL) and TFA (0.57 mL) was stirred at room temperature for 30min. After completion, the reaction solvent was removed under reduced pressure and the resulting residue was diluted with EtOAc (3 mL). The organic layer was saturated with NaHCO 3 (5 mL), brine (3 mL), washed over Na 2 SO 4 Dried, filtered and concentrated to afford the title product (276 d) (20 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =372.3 [ m+h ] ] + 。
Step D.2- ((4- ((2- ((4-chloro-2-cyanophenoxy) methyl) pyridin-4-yl) oxy) -2, 2-dimethylpiperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (276 e)
276d (20.0 mg,0.054 mmol), 57f (46.2 mg,0.10 mmol) and Et at 80 ℃ 3 A solution of N (75. Mu.L, 0.54 mmol) in DMF (0.3 mL) was stirred. After completion, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL. Times.2), brine (3 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-10% MeOH/DCM) to provide the title product (276 e) as a white solid (9.2 mg, 26%). m/z (ESI, positive ion) =668.4 [ m+h ]] + 。
Step E.2- ((4- ((2- ((4-chloro-2-cyanophenoxy) methyl) pyridin-4-yl) oxy) -2, 2-dimethylpiperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (276)
276e (9.2 mg,0.014 mmol) and LiOH (1.7 mg,0.041 mmol) were combined in THF: meOH: H at 30 ℃ 2 The solution in o=2:1:1 (0.4 mL) was stirred overnight. After completion, the reaction mixture was diluted to 1mL with water and purified by reverse phase HPLC (gradient elution, 15-40% CH) 3 CN/H 2 O, with 0.1% TFA as modifier) to afford the title product (276) (5.8 mg, 55%) as a white solid. 1 H NMR(600MHz,CD 3 OD) delta ppm 9.07 (s, 1H), 8.49 (d, j=6.2 hz, 1H), 8.17 (s, 1H), 8.07 (d, j=8.4 hz, 1H), 7.82 (d, j=8.4 hz, 1H), 7.76 (d, j=2.6 hz, 1H), 7.69 (dd, j=9.2, 2.6hz, 1H), 7.49 (d, j=2.2 hz, 1H), 7.31 (d, j=9.2 hz, 1H), 7.18 (dd, j=6.4, 2.4hz, 1H), 7.04 (s, 1H), 5.87-5.98 (m, 2H), 5.37 (s, 2H), 4.96-5.03 (m, 1H), 4.61 (d, j=15.4 hz, 1H), 4.40 (q, j=7.2.2 hz, 1H), 7.17.18 (dd, 1H), 7.7.18 (dd, 1.7.7, 3 m-2H), 7.24 (3.7, 2H), 7.7.8 (m, 1H), 7.7-5.98 (m, 2H), 4.37 (3.7, 3H), 3.7 (m, 3.7-7, 1H), 3.7 (2H), 3.7 (2.7, 3.7H), 1H). m/z (ESI, positive ion) =654.5 [ m+h] + 。
In a similar manner to that described in example 106, step A, followed by steps B through 128Similar procedure as described in C (use of LiBH in step C 4 ) Examples 278 and 279 were then synthesized from methyl 5- ((diethoxyphosphoryl) methyl) oxazole-2-carboxylate and tert-butyl (S) -2-methyl-4-oxopiperidine-1-carboxylate in a similar procedure to that described in examples 220, steps a to E. Chiral separation was performed after step B of example 220.
EXAMPLE 285 (S) -2- ((4- ((6- ((4-cyano-2-fluorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (285)
Step A.4- ((methylsulfonyl) oxy) piperidine-1-carboxylic acid tert-butyl ester (285 a)
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (8 g,0.0396 mol), methanesulfonic anhydride (17.25 g,0.099 mol) in DCM (100 mL) was added DIPEA (20.47 g,0.1584 mol). The reaction was stirred at 23℃for 2h. After completion, the reaction was completed with H 2 O (30 mL) was diluted and extracted with EtOAc (60 mL. Times.3). The organic layer was dried, filtered and concentrated to afford the crude title product (285 a) (10 g) as a colorless oil. m/z (ESI, positive ion) =302.1 [ m+na ]] + 。
Step B.6- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) oxy) picolinic acid methyl ester (285 b)
To a solution of 285a (5.03 g,17.9 mmol), methyl 6-hydroxypicolinate (2.5 g,16.3 mmol) in DMF (50 mL) was added Cs 2 CO 3 (15.93 g,48.9 mmol). The reaction was stirred at 90℃for 10h. After completion, the reaction was completed with H 2 O (15 mL) was diluted and extracted with EtOAc (30 mL. Times.3). Will be combinedThe organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=6:1) to afford the title product (285 b) as a white solid (2.1 g, 36%). m/z (ESI, positive ion) =337.2 [ m+h ]] + 。
Step C.4- ((6- (hydroxymethyl) pyridin-2-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (285 c)
The flask was filled with 285b (2.1 g,6.2 mmol) and LiAlH was added 4 (1M in THF, 10mL,10 mmol). The reaction was stirred at 0℃for 2h. After completion, the reaction was completed with H 2 O (15 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=2:1) to afford the title product (285 c) as a white solid (1.0 g, 52%). m/z (ESI, positive ion) =309.2 [ m+h ]] + 。
Step D.4- ((6- ((4-cyano-2-fluorophenoxy) methyl) pyridin-2-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (285 d)
285c (100 mg,0.32 mmol), 3-fluoro-4-hydroxybenzonitrile (45 mg,0.32 mmol), PPh at 0deg.C 3 (128 mg,0.49 mmol)) in dry DCM (1.6 mL) in CH 2 Cl 2 N- ({ [ (4-chlorophenyl) methoxy) in (2.5 mL)]Carbonyl } imino) [ (4-chlorophenyl) methoxy group]Formamide (DCAD) (178 mg,0.49 mmol). The reaction was allowed to warm to room temperature, and a white precipitate formed. After 1.5h, the reaction mixture was filtered and the filtrate was concentrated to provide a crude residue, which was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc/hexanes) to provide the title product (285 d) (140 mg, 100%). m/z (ESI, positive ion) =450.3 [ m+na ]] + 。
Step E. (S) -2- ((4- ((6- ((4-cyano-2-fluorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (285)
The title product (285) was synthesized in a similar procedure as described in example 198, steps C to E. m/z (ESI, positive ion) =572.4 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 8.31(s,1H),7.97(br dd,J＝8.44,1.10Hz,1H),7.63-7.71(m,2H),7.57(br dd,J＝10.82,2.02Hz,1H),7.50(br d,J＝8.44Hz,1H),7.33(br t,J＝8.44Hz,1H),7.05(d,J＝7.34Hz,1H),6.69(d,J＝8.07Hz,1H),5.23-5.30(m,3H),5.02-5.07(m,1H)4.93-4.85(m,1H),4.72(br dd,J＝15.41,2.57Hz,1H),4.65(br dd,J＝13.76,7.89Hz,1H),4.47(dt,J＝9.08,5.91Hz,1H),3.90-4.07(m,2H),2.77-2.90(m,3H),2.40-2.57(m,3H),1.97-2.04(m,2H),1.73-1.85(m,2H)。
Example 297 (S) -2- ((4- ((2- ((4- (difluoromethyl) -2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (297)
Step A.4- (difluoromethyl) -2-fluorophenol (297 a)
To 3-fluoro-4-hydroxybenzaldehyde (3 g,21.4 mmol) in anhydrous CH at 0deg.C 2 Cl 2 Deoxo-Fluor (15.8 g,32.1mmol,45% in THF) was added dropwise to the solution in (107 mL). The reaction was warmed to room temperature and stirred for 24h. After completion, the reaction was cooled to 0 ℃, and saturated NaHCO was used dropwise 3 Quench and extract with EtOAc. The combined organic layers were washed with water, brine, and dried over Na 2 SO 4 Drying, filtering, concentrating and purifying by silica gel column chromatography (gradient elution, 0-30% EtOAc ∈ -Hexane) to afford the title product (297 a) (1.88 g, 54%) as a colorless oil. A stock solution of 297a in toluene (18.8 mL,100 mg/mL) was prepared and stored in a refrigerator for further use. m/z (ESI, negative ion) =161.1 [ M-H ]] - 。
Step b. (S) -2- ((4- ((2- ((4- (difluoromethyl) -2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (297)
The title product (297) was prepared from 297a in a similar procedure as described in example 277. m/z (ESI, positive ion) =597.3 [ m+h ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δppm 8.37(d,J＝5.7Hz,1H),8.26(d,J＝1.3Hz,1H),7.79(dd,＝8.4,1.5Hz,1H),7.64(d,J＝8.4Hz,1H),7.48(d,J＝11.7Hz,1H),7.34-7.38(m,2H),7.07(d,J＝2.6Hz,1H),6.97(dd,J＝5.9,2.6Hz,1H),6.96(t,J＝40.0Hz,1H),5.24(s,2H),5.08(qd,J＝7.2,2.8Hz,1H),4.78(dd,J＝15.3,7.2Hz,1H),4.63(dd,J＝15.2,2.8Hz,1H),4.54-4.60(m,1H),4.46-4.52(m,1H),4.37(dt,J＝9.0,5.9Hz,1H),3.94(d,J＝13.8Hz,1H),3.79(d,J＝13.6Hz,1H),2.74-2.81(m,1H),2.66-2.74(m,2H),2.34-2.45(m,3H),1.91-1.98(m,2H),1.58-1.68(m,2H)。
EXAMPLE 299 (S) -2- ((4- ((2- ((4-chloro-2- (fluoromethyl) phenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (299)
Step A.4- ((2- ((4-chloro-2- (methoxycarbonyl) phenoxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (299 a)
220a (1.0 g,2.6 mmol), methyl 5-chloro-2-hydroxybenzoate (490 mg,2.6 mmol) and K were added at 50deg.C 2 CO 3 A solution of (2.54 g,7.8 mmol) in DMF (10 mL) was stirred for 5h. After completion, the reaction was completed with H 2 O (30 mL) was diluted and extracted with EtOAc (30 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=7:3) to afford the title product (299 a) as a yellow oil (1.0 g, 77%). m/z (ESI, positive ion) =477.1 [ m+h ]] + 。
Step B.4- ((2- ((4-chloro-2- (hydroxymethyl) phenoxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (299 b)
299a (1.0 g,2.1 mmol) and LiAlH at 0deg.C 4 A solution of (240 mg,6.3 mmol) in THF (12 mL) was stirred for 1h. After completion, the reaction was quenched with sodium sulfate decahydrate, filtered and the filter cake was rinsed with DCM (50 ml×3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: ea=1:1) to afford the title product (299 b) as a yellow solid (719mg, 71%). m/z (ESI, positive ion) =449.1 [ m+h ]] + 。
Step C.4- ((2- ((4-chloro-2- (fluoromethyl) phenoxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (299 c)
DAST (144 mg,0.891 mmol) was added to a mixture of 299b (200 mg,0.445 mmol) in DCM (2 mL) at 0deg.C. At 20℃under N 2 The mixture was stirred for 12h. After completion, the reaction was quenched with EtOAc (10 mL) and H 2 O (5 mL) dilution. The organic phase was separated and concentrated. The crude residue was purified by preparative TLC plate (EtOAc: petroleum ether=1:5) to give the title product as an oil (299c) (90 mg, 53.8%). m/z (ESI, positive ion) =451.2 [ M+H ]] + 。
Step D.2- ((4-chloro-2- (fluoromethyl) phenoxy) methyl) -4- (piperidin-4-yloxy) pyridine (299 d)
To a mixture of 299c (120 mg,0.266 mmol) in dioxane (1 mL) was added a solution of 4N HCl in dioxane (0.33 mL,1.33 mmol) at 0 ℃. At 20℃under N 2 The mixture was stirred for 1h. After completion, the mixture was concentrated to give the crude title product (299 d) (90 mg) as a colorless oil. m/z (ESI, positive ion) =351.2 [ M+H ] ] + 。
Step e. (S) -2- ((4- ((2- ((4-chloro-2- (fluoromethyl) phenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (299)
The title product (299) was synthesized from 299d in a similar procedure as described in example 72, steps F and G. m/z (ESI, positive ion) =595.2 [ m+h ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δppm 8.35(d,J＝5.9Hz,1H),8.16(s,1H),7.78(br d,J＝8.3Hz,1H),7.53(br d,J＝8.3Hz,1H),7.47(br s,1H),7.41(br dd,J＝8.8,2.0Hz,1H),7.13(br d,J＝8.8Hz,1H),7.06(br d,J＝2.0Hz,1H),6.94(br dd,J＝5.4,2.5Hz,1H),5.50(d,J＝48.0Hz,2H),5.18(s,2H),5.03-5.12(m,1H),4.73(br dd,J＝15.2,6.9Hz,1H),4.44-4.65(m,3H),4.36(dt,J＝8.8,5.9Hz,1H),3.73-3.97(m,2H),2.63-2.83(m,3H),2.30-2.47(m,3H),1.87-2.03(m,2H),1.55-1.69(m,2H)。
Examples 287 and 292 were synthesized from 299b in a similar procedure as described in steps D to E of example 299. 57f of the mesylate analogue derived from 145e was used in the penultimate step of 287.
Example 300.2- ((4- (3- ((4-cyano-2-fluorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -4-fluoro-1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (300)
Step A.3-fluoro-5- (((1- (fluoromethyl) cyclopropyl) methyl) amino) -4-nitrobenzoic acid methyl ester (300 a)
To methyl 3, 5-difluoro-4-nitrobenzoate (500 mg,2.3 mmol) and [1- (fluoromethyl) cyclopropyl ] at room temperature]To a solution of methylamine trifluoroacetic acid (500 mg,2.3 mmol) in anhydrous DMF (7.7 mL) was added DIPEA (1.0 mL,5.8 mmol). After stirring for 0.5h, the reaction was diluted with EtOAc (20 mL) and washed with brine (10 ml×2). The organic layer was purified by Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 0-40% etoac/hexanes) to afford the title product (300 a) (481mg, 70%) as an orange solid. m/z (ESI, positive ion) =301.4 [ m+h ] ] + 。
Step B.4-amino-3-fluoro-5- (((1- (fluoromethyl) cyclopropyl) methyl) amino) benzoic acid methyl ester (300 b)
10% Pd/C (33 mg,0.031 mmol) was added to 300a (186 mg,0.62 mmol) in EtOH (6.2 mL) at room temperature. The mixture was purged with hydrogen for 10min, followed by H 2 Stirring under a balloon for 1h. The reaction was filtered through a pad of celite, rinsed with EtOAc, and concentrated to provide the crude title product (300 a) (167 mg). m/z (ESI, positive ion) =271.4 [ M+H ]] + 。
Step C.2- (chloromethyl) -4-fluoro-1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (300 c)
To crude 300b (167 mg,0.62 mmol) and 2-chloro-1, 1-trimethoxyethane (0.25 mL,287mg,1.86 mmol) in dry CH at room temperature 3 To a solution in CN (3.1 mL) was added PTSA (6 mg,0.03 mmol) and heated to 60 ℃. After stirring for 30min, the mixture was concentrated and purified by silica gel column chromatography (gradient elution, 0-80% EtOAc/hexanes) to afford the title product (300 c) as a light brown oil (194 mg,95%, 2 steps). m/z (ESI, positive ion) =329.3 [ m+h ]] + 。
Step D.4- (3- ((4-cyano-2-fluorophenoxy) methyl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester (300 d)
At 0deg.C, 206b (100 mg,0.33 mmol) in anhydrous CH 2 Cl 2 PPh was added to the solution in (1.6 mL) 3 (3.29 g,12.5 mmol), 3-fluoro-4-hydroxybenzonitrile (1.36 g,8.35 mmol) followed by the dropwise addition of DCAD (2.53 g,12.5 mmol) in dry CH 2 Cl 2 (1.6 mL). The resulting mixture was warmed to room temperature, stirred for 1h, filtered and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc/hexanes) to afford the title product (300 d) (130 mg) with some triphenylphosphine oxide impurities (130 mg). m/z (ESI, positive ion) =449.3 [ m+na ]] + 。
Step E.3-fluoro-4- ((3- (piperidin-4-yloxy) benzyl) oxy) benzonitrile (300 e)
To 300d (28 mg,0.066 mmol) in dry CH at room temperature 2 Cl 2 To a solution of (0.66 mL) was added TFA (0.25 mL,3.3 mmol). After stirring for 1h, the mixture was concentrated and azeotroped with (2 ml×2) to afford the crude title product (300 e) (21 mg) without going throughFurther purification was used in the next step. m/z (ESI, positive ion) =327.3 [ M+H ]] + 。
Step F.2- ((4- (3- ((4-cyano-2-fluorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -4-fluoro-1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (300 f)
To a solution of crude 300e (21 mg,0.066 mmol) in dichloroethane (0.66 mL) was added 1h (8 mg,0.059 mmol) and DIPEA (0.034 mL,0.20 mmol) at room temperature. The reaction was heated to 60 ℃. After 20h, the reaction was cooled to room temperature, concentrated and purified by silica gel column chromatography (gradient elution, 0-60% EtOAc/hexanes) to afford the title product (300 f) as a light brown oil (24 mg,59%, over 2 steps). m/z (ESI, positive ion) =619.3 [ m+h ] ] + 。
Step G.2- ((4- (3- ((4-cyano-2-fluorophenoxy) methyl) phenoxy) piperidin-1-yl) methyl) -4-fluoro-1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (300)
At room temperature, the flask was filled to dissolve in THF/H 2 300f (24 mg,0.039 mmol) in O (1:1, 0.8 mL). LiOH.H 2 O (8 mg,0.19 mmol) and a few drops of MeOH were added to the mixture and heated to 40 ℃. After 2.5h, the reaction was cooled and acidified with acetic acid to ph=5. The solution was diluted with EtOAc (3 mL) and washed with brine (2 mL). The organic layer was purified by Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 0-5% MeOH/DCM) to afford the title product (300) as a colorless film, which was further lyophilized to afford a white solid (11.6 mg, 49%). m/z (ESI, positive ion) =605.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 8.16(d,J＝0.73Hz,1H),7.64(d,J＝11.00Hz,1H),7.55(dd,J＝10.82,2.02Hz,1H),7.50(dd, j=8.44, 1.47hz, 1H), 7.29 (td, j=8.16, 1.65hz, 2H), 6.99-7.06 (m, 2H), 6.92 (dd, j=8.25, 2.38hz, 1H), 5.23 (s, 2H), 4.70 (s, 2H), 4.46 (brdd, j=7.15, 3.85hz, 1H), 4.08-4.22 (m, 2H), 3.99 (s, 2H), 2.81-2.87 (m, 2H), 2.47-2.54 (m, 2H), 1.98-2.07 (m, 2H), 1.77-1.84 (m, 2H), 0.89 (q, j=5.26 hz, 2H), 0.77-0.82 (m, 2H). m/z (ESI, positive ion) =605.3 [ m+h ]] + 。
Examples 301, 303, 310 were synthesized in a similar procedure to that described in example 300, except that the Boc group deprotection was performed in step E using HCl in dioxane.
EXAMPLE 304 (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (304)
Step a. (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (304 b)
A solution of 304a (TFA salt, prepared in a similar procedure to 261c, 24.0mg,0.051 mmol), 1h (18.1 mg,0.062 mmol) and DIPEA (170. Mu.L, 1.03 mmol) in DMF (0.5 mL) was stirred overnight at room temperature. After completion, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water (3 mL. Times.2), brine (3 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 80-100% EtOAc/hexanes, then 0-20% MeOH/DCM) to afford the title product (304 b) as a pale yellow oil (11.9 mg, 38%). m/z (ESI, positive ion) =612.3 [ m+h ]] + 。
Step B. (S) -2- ((4- ((2, 4-dichlorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (304)
304b (11.9 mg,0.019 mmol) and LiOH (4.1 mg,0.097 mmol) were combined in THF: meOH: H at 30 ℃ 2 The solution in o=2:1:1 (0.4 mL) was stirred overnight. After completion, the reaction mixture was diluted to 1mL with water and purified by reverse phase HPLC (gradient elution, 20-45% CH) 3 CN/H 2 O, with 0.05% NH 4 OH as a modifier) to afford the title product (304) as a white solid (10.5 mg, 88%). 1 H NMR(600MHz,DMSO-d 6 ) Delta ppm 8.49 (d, j=5.9 hz, 1H), 8.22 (s, 1H), 7.79 (dd, j=8.4, 1.5hz, 1H), 7.60 (d, j=8.4 hz, 1H), 7.57 (d, j=2.6 hz, 1H), 7.28 (dd, j=8.8, 2.6hz, 1H), 7.11 (d, j=8.8 hz, 1H), 6.8 (d, j=5.9 hz, 1H), 5.37 (s, 2H), 5.07 (qd, j=7.2, 3.1hz, 1H), 4.85 (dt, j=8.7, 4.6hz, 1H), 4.75 (br, j=15.2, 2.8hz, 1H), 4.46 (m-6 hz), 4.46 (3.9 hz, 1H), 5.37 (s, 2H), 5.07 (qd, j=7.85 (dt, j=8.7, 4.6hz, 1H), 4.75 (br, j=15.2.2, 1H), 4.61 (m-1H), 4.46 (3.6 hz), 4.6 m-1.6, 1H), 1.6 (3.9 m-1H), 1.7.6 (1H), 1.7.6 hz (1H), 1.6 m (1H). m/z (ESI, positive ion) =598.2 [ m+h ]] + 。
Examples 305, 306, 307, 338, 340, 341, 342, 348, 349 were synthesized in a similar procedure as described in example 304.
Examples 369, 370, 371, 373 were synthesized in a similar procedure to that described in example 304, except that purification was performed in the final step using a silica gel column.
EXAMPLE 313.2- (((2S, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylpiperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (313)
Step A. (2S, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (313 a)
Pd was added to a solution of 261a (50 mg,0.19 mmol) and tert-butyl (2S, 4S) -4-hydroxy-2-methylpiperidine-1-carboxylate (49 mg,0.23 mmol) in dry toluene (1.9 mL) at room temperature 2 (dba) 3 (7.7 mg,0.0095 mmol), BINAP (11.8 mg,0.019 mmol) and Cs 2 CO 3 (124 mg,0.38 mmol). The mixture was purged with argon for 15min and then heated to 90 ℃. After 12H, the reaction was cooled to room temperature and H was added 2 O (2 mL). The reaction was extracted with EtOAc (3 ml×3) and the combined organic layers were taken up over Na 2 SO 4 Drying, filtration, concentration and purification of the crude residue by silica gel column chromatography (gradient elution, 0-50% EtOAc/hexanes) afforded the title product (313 a) (89 mg, quantitative), m/z (ESI, positive ion) =443.3 [ m+h] + 。
Step B.2- (((2S, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylpiperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (313)
The title product (313) was synthesized in a similar procedure as described in example 300, steps E to G. m/z (ESI, positive ion) =587.4 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.42(d,J＝5.87Hz,1H),8.31(d,J＝0.98Hz,1H),7.97(dd,J＝8.56,1.47Hz,1H),7.69(d,J＝8.56Hz,1H),7.60(dd,J＝11.00,1.96Hz,1H),7.47(dt,J＝8.56,1.59Hz,1H),7.22(t,J＝8.56Hz,1H),6.70(d,J＝5.87Hz,1H),5.40(s,2H),5.24-5.32(m,1H),4.91-4.96(m,1H),4.73(dd,J＝15.53,5.75Hz,1H),4.56-4.65(m,3H),4.31(dt,J＝9.29,5.87Hz,1H),3.60(d,J＝13.94Hz,1H),2.70-2.83(m,2H),2.35-2.51(m,2H),2.19(td,J＝12.23,1.96Hz,1H),1.82-2.01(m,2H),1.40-1.65(m,2H),1.20(d,J＝6.11Hz,3H)。
Examples 311, 312, 314, 323, 324, 325, 326, 327, 329, 353, 375, 376, 377 were synthesized in a similar procedure as described in example 313. For examples 311 and 312, HCl in dioxane was used to remove the Boc group.
Example 319 was synthesized from methyl 3-hydroxybenzoate and tert-butyl (2 s,4 r) -4-hydroxy-2-methylpiperidine-1-carboxylate in a similar procedure to that described in example 206, steps a and B, followed by a similar procedure to that described in example 300, steps D to G.
Example 320 was synthesized in a similar procedure as described in example 319.
EXAMPLE 330 (S) -2- ((4- ((6- ((4-cyano-2-fluorophenoxy) methyl) -3-fluoropyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (330)
Step A.6- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) oxy) -5-fluoropyridine methyl formate (330 a)
Pd was added to a solution of methyl 6-bromo-5-fluoropyridine-2-carboxylate (100 mg,0.43 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (103 mg,0.51 mmol) in anhydrous toluene (4.3 mL) at room temperature 2 (dba) 3 (17 mg,0.021 mmol), BINAP (27 mg,0.043 mmol) and Cs 2 CO 3 (278 mg,0.86 mmol). The reaction was purged with argon for 15min and then heated to 90 ℃. After 12H, the reaction was cooled to room temperature and H was added 2 O (2 mL). The reaction mixture was extracted with EtOAc (3 ml×3) and the combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and the crude residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc/hexanes) to afford the title product (330 a) (105 mg, 69%) as a colorless oil. m/z (ESI, positive ion) =377.3 [ m+na ] ] + 。
Step B.4- ((3-fluoro-6- (hydroxymethyl) pyridin-2-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (330 b)
To a solution of 330a (103 mg,0.29 mmol) in anhydrous THF (2.9 mL) at 0deg.C was added LiAlH 4 (0.44 mL,0.44mmol,1M in THF). After 0.5h, etOAc (3 mL) was added dropwise and the reaction was diluted with a half-saturated Rochelle salt (Rochelle salt) solution (2 mL). The reaction mixture was extracted with EtOAc (5 ml×3) and the combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and the crude residue was purified by silica gel column chromatography (gradient elution, 0-60% EtOAc/hexanes) to afford the title product (330 b) as a colorless oil (78 mg, 82%). m/z (ESI, positive ion) =349.4 [ m+na ]] + 。
Step c. (S) -2- ((4- ((6- ((4-cyano-2-fluorophenoxy) methyl) -3-fluoropyridin-2-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (330)
The title product (330) was synthesized in a similar procedure as described in example 300, steps D to G. m/z (ESI, positive ion) =590.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 8.33(d,J＝1.10Hz,1H),7.97(dd,J＝8.62,1.65Hz,1H),7.67(d,J＝8.44Hz,1H),7.57(dd,J＝10.82,2.02Hz,1H),7.45-7.53(m,2H),7.34(t,J＝8.44Hz,1H),7.07(dd,J＝8.07,2.93Hz,1H),5.26(qd,J＝7.21,2.57Hz,1H),5.23(s,2H),5.14(dt,J＝7.79,3.99Hz,1H),4.88(dd,J＝15.41,7.34Hz,1H),4.72(dd,J＝15.41,2.57Hz,1H),4.65(td,J＝7.89,5.87Hz,1H),4.47(dt,J＝9.17,6.05Hz,1H),3.92-4.08(m,2H),2.78-2.91(m,3H)2.44-2.57(m,3H),2.00-2.07(m,2H),1.79-1.90(m,2H)。
Example 347 was synthesized in a similar procedure as described in example 330.
Example 355.2- (((2S, 4S) -4- ((2- ((2-cyano-4-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylpiperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (355)
Step A. (2S, 4S) -4- ((2-chloropyrimidin-4-yl) oxy) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (355 a)
To a solution of 2, 4-dichloropyrimidine (5.20 g,34.90 mmol) and (2S, 4S) -4-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (7.51 g,34.90 mmol) in DMF (50 mL) was added Cs 2 CO 3 (17.06 g,52.4 mmol). The reaction was stirred at 80℃for 3h. After completion, the reaction was completed with H 2 O (200 mL) was diluted and extracted with EtOAc (200 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried and concentrated to provide a crude residue which was purified by silica gel column chromatography (gradient elution, 2.5 to 5% EtOAc/petroleum ether) to provide the title product (355 a) as a white solid (5.65 g, 48%). m/z (ESI, positive ion) =328.1 [ m+h ]] + 。
Step B.4- (((2S, 4S) -1- (tert-Butoxycarbonyl) -2-methylpiperidin-4-yl) oxy) pyrimidine-2-carboxylic acid methyl ester (355 b)
355a (7.20 g,21.96 mmol), pd (dppf) Cl 2 (803.57mg,1.10mmol)、Et 3 N (3.06 mL,21.96 mmol) in MeOH (70 mL) and DMSO (35 mL) was performed with N 2 Degassing and purging 3 times. The reaction was heated at 60℃under CO (50 Psi) atmosphere for 16h. After completion, the reaction was concentrated with H 2 O (200 mL) was diluted and extracted with EtOAc (200 mL. Times.3). For combining organic layersBrine (100 mL. Times.3), washed with Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 2-20% EtOAc/petroleum ether) to afford the title product (355 b) as a white solid (4.0 g, 52%). m/z (ESI, positive ion) =352.2 [ M+H ] ] + 。
Step C. (2S, 4S) -4- ((2- (hydroxymethyl) pyrimidin-4-yl) oxy) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (355 c)
355b (4.50 g,12.81 mmol), caCl 2 (1.42 g,12.81 mmol) in EtOH (90 mL) with N 2 Degassing and purging 3 times, followed by addition of NaBH at 0deg.C 4 (484.45 mg,12.81 mmol). At 20℃under N 2 It was stirred for 1h under an atmosphere. After completion, the reaction mixture was cooled to 0 ℃, followed by the addition of MeOH (50 mL), followed by concentration. The residue obtained is treated with H 2 O (100 mL) was diluted and the aqueous layer was extracted with EtOAc (100 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 5-100% EtOAc/hexanes) to afford the title product (355 c) (2.7 g,65% yield), m/z (ESI, positive ion) =324.1 [ m+h] + 。
Step D. (2S, 4S) -2-methyl-4- ((2- (((methylsulfonyl) oxy) methyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (355 d)
Et is added to 3 N (174. Mu.L, 1.24 mmol) and MsCl (57.4. Mu.L, 0.74 mmol) were added to an ice-cold solution of 355c (200.0 mg,0.062 mmol) in dichloromethane (3.1 mL). The reaction was stirred at 0℃for 1h. After completion, the reaction was quenched with saturated NaHCO 3 The aqueous solution (10 mL) was quenched and extracted with EtOAc (10 mL. Times.3). The combined organic layers were washed with brine (10 mL), and dried over Na 2 SO 4 Drying and filteringAnd concentrated to give the crude title product (355 d) (248.0 mg) as a pale yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =402.3 [ m+h ]] + 。
Step E. (2S, 4S) -4- ((2- ((2-cyano-4-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (355 e)
To a solution of 355d (248.0 mg,0.62 mmol) and 5-fluoro-2-hydroxybenzonitrile (88.9 mg,0.65 mmol) in DMF (3.1 mL) was added K 2 CO 3 (171.0 mg,1.24 mmol). The reaction was stirred at room temperature for 2h. After completion, the reaction was quenched by the addition of water (5 mL) and extracted with EtOAc (10 ml×3). The combined organic layers were washed with water (10 mL), brine (10 mL. Times.3), and dried over Na 2 SO 4 Dried, filtered, concentrated and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc/hexanes) to afford the title product (355 e) as yellow (164.0 mg, 60%). m/z (ESI, positive ion) =443.4 [ m+h] + 。
Step F.5-fluoro-2- ((4- (((2S, 4S) -2-methylpiperidin-4-yl) oxy) pyrimidin-2-yl) methoxy) benzonitrile (355 f)
A solution of 355e (164.0 mg,0.37 mmol) in DCM (6 mL) and TFA (3 mL) was stirred at room temperature for 10min. After completion, the reaction solvent was removed under reduced pressure and the resulting residue was diluted with EtOAc (10 mL). The organic layer was saturated with NaHCO 3 (5 mL), brine (3 mL), washed over Na 2 SO 4 Dried, filtered and concentrated to afford the title product (355 f) (127 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =343.4 [ M+H ]] +
Step G.2- (((2S, 4S) -4- ((2- ((2-cyano-4-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylpiperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (355 g)
A solution of 355d (127.0 mg,0.37 mmol), 1h (186.0 mg,0.63 mmol) and DIPEA (323. Mu.L, 1.85 mmol) in DMF (1.2 mL) was stirred overnight at 70 ℃. After completion, the reaction mixture was diluted with EtOAc (20 mL). The organic layer was washed with water (10 mL. Times.2), brine (10 mL. Times.3), and dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-20% acetone/DCM) to provide the title product (355 g) as a colorless oil (160.0 mg, 72%). m/z (ESI, positive ion) =601.3 [ m+h ]] + 。
Step H.2- (((2S, 4S) -4- ((2- ((2-cyano-4-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylpiperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (355)
355g (160.0 mg,0.27 mmol) and LiOH (112.0 mg,2.66 mmol) were combined in THF, meOH, H at 30 ℃ 2 The solution in o=2:1:1 (12 mL) was stirred for 2h. After completion, the reaction mixture was diluted with water (20 mL) and neutralized with glacial acetic acid (0.16 mL) until ph=7. The reaction was then extracted with 30% IPA/chloroform (30 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 0-10% MeOH/DCM) to afford the title product (355) as a colorless oil (122.0 mg, 76%). m/z (ESI, positive ion) =587.2 [ m+h ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δppm 8.48(d,J＝5.8Hz,1H),8.24(s,1H),7.80(dd,J＝8.3,1.5Hz,1H),7.76(dd,J＝8.0,3.3Hz,1H),7.65(d,J＝8.3,Hz,1H),7.48(ddd,J＝9.4,8.3,3.1Hz,1H),7.22(dd,J＝9.5,4.0Hz,1H),6.77(d,J＝5.8Hz,1H),5.75(s,2H),5.46(s,2H),5.08-5.18(m,1H),4.65-4.85(m,2H),4.36-4.51(m,2H),4.20-4.29(m,1H),3.55(br d,J＝14.1Hz,1H),2.58-2.77(m,2H),2.29-2.44(m,2H),2.05-2.22(m,1H),1.73-1.90(m,1H),1.36-1.52(m,1H),1.20-1.34(m,1H),1.09(d,J＝6.3Hz,3H)。
EXAMPLE 367 (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (367)
Step A.4- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) oxy) -5-fluoropyridine methyl formate (367 b)
To a solution of 367a (prepared from 2-bromo-5-fluoropyridine-4-ols similar to 145a, 360mg,0.96 mmol), palladium diacetate (43 mg,0.19 mmol) and DPPP (79 mg,0.19 mmol) in DMSO/MeOH (15 mL) was added Et 3 N (968 mg,9.57 mmol). The reaction mixture was purged with CO and stirred at 80 ℃ for 4h. After completion, the reaction was completed with H 2 O (25 mL) was diluted and extracted with EtOAc (30 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by silica gel column chromatography (DCM: meoh=20:1) to afford the title product (367 b) as a white solid (230 mg, 64%). m/z (ESI, positive ion) =355.2 [ m+h ] ] + 。
Step B.4- ((5-fluoro-2- (hydroxymethyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (367 b)
The flask was charged with 367b (200 mg,0.56 mmol) and THF (10 mL) was added. At 0deg.C under nitrogen gas adding LiAlH 4 (1.1 mL,1M in THF). The reaction was stirred at 0℃for 2h. After completion, the reaction is carried outWith saturated NH 4 Aqueous Cl (15 mL) was quenched and extracted with EtOAc (20 mL. Times.3). The organic layer was dried, filtered and concentrated to afford the crude title product (367 c) (93 mg, 48%) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =327.1 [ M+H ]] + 。
Step C.4- ((5-fluoro-2- (((methylsulfonyl) oxy) methyl) pyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (367 d)
To a solution of 367c (40 mg,0.12 mmol), methanesulfonic anhydride (53 mg,0.31 mmol) in DCM (2 mL) was added DIPEA (47 mg,0.37 mmol). The reaction mixture was stirred at 25℃for 2h. After completion, the reaction solution was taken up with H 2 O (10 mL) was diluted and extracted with EtOAc (10 mL. Times.3). The organic layer was dried, filtered and concentrated to afford the crude title product (367 d) as a yellow oil (43 mg, 82%). m/z (ESI, positive ion) =405.1 [ m+h ]] + 。
Step D.4- ((2- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (367 e)
To a solution of 367d (50 mg,0.12 mmol), 3-fluoro-4-hydroxybenzonitrile (20 mg,0.15 mmol) in DMF (2 mL) was added K 2 CO 3 (51 mg,0.37 mmol). The reaction was stirred at 80℃for 2h. After completion, the reaction was completed with H 2 O (15 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by silica gel column chromatography (DCM: meoh=30:1) to afford the title product (367 e) as a white solid (48 mg, 83%). m/z (ESI, positive ion) =446.1 [ M+H ]] + 。
Step E.3-fluoro-4- ((5-fluoro-4- (piperidin-4-yloxy) pyridin-2-yl) methoxy) benzonitrile (367 f)
A solution of 367e (40 mg,0.09 mmol) in 4N HCl in dioxane (1 mL) was stirred for 2h at 25deg.C. After completion, 1N NaOH was added to the mixture in an ice bath to adjust to ph=8. The reaction mixture was then extracted with EtOAc (15 mL. Times.3). The organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (DCM: meoh=20:1) to afford the title product (367 f) (30 mg, 92%) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =346.1 [ m+h ]] + 。
Step F. (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (367 g)
To a solution of 367f (30 mg,0.09 mmol), 1h (31 mg,0.11 mmol) in DMF (1 mL) was added K 2 CO 3 (36 mg,0.26 mmol). The reaction mixture was stirred at 25℃for 2h. After completion, the reaction solution was taken up with H 2 O (15 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by silica gel column chromatography (DCM: meoh=20:1) to afford the title product (367 g) as a white solid (34 mg, 62%). m/z (ESI, positive ion) =604.3 [ m+h ]] + 。
Step g. (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (367)
To a solution of 367g (30 mg,0.05 mmol) in THF (1.5 mL) was added lithium hydroxide (12 mg,0.5 mmol) in H 2 O (0.5 mL)Is a solution of (a) and (b). The reaction was stirred at 25℃for 2h. After completion, 1N HCl was added to the reaction in an ice bath to adjust to ph=5. The reaction mixture was then extracted with EtOAc (15 mL. Times.3). The organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (EtOAc/petroleum ether, 20-30%) to afford the title product (367) as a white solid (24 mg,78% yield). m/z (ESI, positive ion) =590.3 [ m+h ] ] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.27-8.37(m,2H),7.96(d,J＝8.56Hz,1H),7.66(d,J＝8.31Hz,1H),7.57(dd,J＝10.88,1.83Hz,1H),7.52(br d,J＝8.56Hz,1H),7.38(d,J＝6.85Hz,1H)7.33(t,J＝8.44Hz,1H),5.18-5.34(m,3H),4.65-4.75(m,3H),4.46(dt,J＝9.05,5.87Hz,1H)3.89-4.09(m,2H),3.68-3.78(m,1H),2.72-2.91(m,3H),2.24-2.58(m,3H),1.98-2.13(m,2H),1.79-1.94(m,2H)。
Example 380 was synthesized in a similar procedure as described in example 367.
Example 368.2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-methoxycyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (368)
Step A.2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-methoxycyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (368 b)
Ice-cold solution of 368a (intermediate in the synthesis of 345, 200mg,0.34 mmol) in DMF (1 mL) was taken up in N 2 Deaeration and purging 3 times, and NaH (26.89 mg,0.67mmol,60% mineral oil dispersion) was added. After stirring at 0deg.C for 30min, meI (25.1 μL,0.40 mmol) was added. The reaction was warmed to room temperature and taken up in N 2 Stirring for 3.5h under an atmosphere. After completion, the reaction was saturated with NH 4 Aqueous Cl (20 mL) was quenched and quenched with EtOAc (30 mL. Times.3) extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering, concentrating and purifying by reverse phase HPLC (gradient elution, 35-65% CH) 3 CN/H 2 O, with 0.05% NH4HCO3 as modifier) to afford the title product (368 b) as a white solid (80.0 mg, 39%). m/z (ESI, positive ion) =609.2.
Step B.2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1-methoxycyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (368)
To 368b (25 mg,0.041 mmol) in THF (0.6 mL), meOH (0.3 mL) and H 2 LiOH.H was added to a solution in O (0.3 mL) 2 O (5.17 mg,0.12 mmol). The reaction was stirred at 20℃for 16h. After completion, the reaction solvent was removed under reduced pressure. The resulting residue was diluted with water (2.0 mL) and then neutralized with saturated aqueous citric acid until ph=7. A white precipitate formed. It was filtered and dried to provide the title product (368) as a white solid (13.5 mg,55% yield). m/z (ESI, positive ion) = 595.2. 1 H NMR(400MHz,DMSO-d 6 )δppm 8.36(d,J＝5.5Hz,1H),8.27(s,1H),7.80(d,J＝8.5Hz,1H),7.65(d,J＝8.5Hz,1H),7.46(dd,J＝11.0,2.5Hz,1H),7.17-7.30(m,2H),7.05(d,J＝2.0Hz,1H),6.97(dd,J＝5.6,2.3Hz,1H),5.18(s,2H),4.73(s,2H),4.59(br s,1H),3.92(br s,2H),3.21(s,3H),2.69-2.84(m,2H),2.57-2.65(m,2H),1.91-2.04(m,2H),1.66(br d,J＝9.5Hz,2H),0.83(br d,J＝10.5Hz,4H)。
EXAMPLE 372 (S) -2- ((4- ((6- ((4-cyano-2-fluorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (372)
Step A.4- ((6-bromopyridin-2-yl) methoxy) -3-fluorobenzonitrile (372 a)
To (6-bromopyridin-2-yl) methanol (1.53 g,8.14 mmol), 3-fluoro-4-hydroxybenzonitrile (1 g,7.32 mmol) and PPh 3 To a solution of (3.2 g,12.2 mmol) in THF (33 mL) was added DIAD (2.4 mL,12.2 mmol) dropwise. The resulting mixture was stirred at room temperature for 2h. After completion, the reaction was concentrated and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc/hexanes) to afford the impure product, which was wet-triturated with MeOH. The product precipitated out as a white solid. After stirring for an additional 10min at 0 ℃, the mixture was filtered and rinsed with MeOH. The solid was dried on a high vacuum pump to provide the title product (372 a) as a white solid (1.59 g, 63.6%). m/z (ESI, positive ion) =307.1 [ m+h ] ] + 。
Step B.4- ((6- ((4-cyano-2-fluorophenoxy) methyl) pyridin-2-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester 4- ((6- ((4-cyano-2-fluorophenoxy) methyl) pyridin-2-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (372 b)
The flask was charged with 372a (1.59 g,5.2 mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.25 g,6.2 mmol), pd 2 (dba) 3 (209 mg,0.26 mmol), BINAP (322 mg,0.52 mmol) and Cs 2 CO 3 (3.37 g,10.4 mmol) and toluene (52 mL) were added. The resulting mixture was degassed with Ar for 5min, then heated at 110℃under Ar overnight. After completion, the solvent was removed in vacuo and the residue was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 0-40% EtOAc/hexanes) to afford the title product (372 b) (1.65 g, 75%). m/z (ESI, positive ion) =450.3 [ m+na ]] + 。
Step C. (S) -2- ((4- ((6- ((4-cyano-2-fluorophenoxy) methyl) pyridin-2-yl) oxy) piperidin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (372)
The title product (372) was synthesized from 372b in a similar procedure as described in example 300 steps E to G. m/z (ESI, positive ion) =573.3. 1 H NMR(400MHz,DMSO-d 6 )δppm 13.06(br s,1H),8.14(d,J＝8.3Hz,1H),7.99(d,J＝8.3Hz,1H),7.88(dd,J＝11.3,2.0Hz,1H),7.73(dd,J＝8.3,7.3Hz,1H),7.64-7.69(m,1H),7.45(t,J＝8.7Hz,1H),7.06(d,J＝7.3Hz,1H),6.74(d,J＝8.0Hz,1H),5.76(s,1H),5.31(s,2H),5.12-5.20(m,1H),4.88-4.96(m,1H),4.84(dd,J＝14.7,6.4Hz,1H),4.66-4.76(m,1H),4.49(ddd,J＝8.4,7.2,5.8Hz,1H),4.37(dt,J＝9.0,6.1Hz,1H),3.88-4.02(m,2H),2.63-2.82(m,3H),2.26-2.38(m,2H),1.86-1.96(m,2H),1.56-1.70(m,2H)。
Example 381 (S) -2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (381)
Step A.4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (381 a
A solution of 360a (27.3 mg,0.1 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (22 mg, 110. Mu. Mol) and DIPEA (34.8. Mu.L, 0.2 mmol) in DMF (0.5 mL) was heated to 40℃for 24h. After completion, the reaction mixture was taken up with H 2 O (5 mL) was diluted and stirred for 30min. The aqueous layer was decanted and the residue was taken up with H 2 O (1 mL) was washed and dried to afford the title product (381 a) (8 mg), which was used directly in the next without further purificationIn the step. m/z (ESI, positive ion) =437.4 [ m+h ]] + 。
Step B.2- ((4-chloro-2-fluorophenoxy) methyl) -N- (piperidin-4-yl) pyrimidin-4-amine (381 b)
A solution of 381a (8 mg, 18.3. Mu. Mol) and trifluoroacetic acid (0.5 mL) in DCM (1 mL) was stirred for 2h at 21 ℃. After completion, the reaction was concentrated and co-evaporated with DCE (3×2 mL) to afford the title product (381 b) (8 mg), which was used directly in the next step without further purification. m/z (ESI, positive ion) =337.3 [ m+h ]] + 。
Step C. (S) -2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (381 c)
A solution of crude 381b (8 mg), 1h (7 mg, 23.8. Mu. Mol) and DIPEA (41.4. Mu.L, 238. Mu. Mol) in DMF (0.5 mL) was stirred for 24h at 21 ℃. After completion, the reaction mixture was taken up with H 2 O (10 mL) was diluted, stirred for 30min and the aqueous layer was decanted. The residue was dried to afford the title product (381 c) (14 mg), which was used directly in the next step without further purification. m/z (ESI, positive ion) =595.3 [ m+h ]] + 。
Step d. (S) -2- ((4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (381)
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A mixture of 381c (14 mg, 23.5. Mu. Mol) and LiOH (1M) (118. Mu.L, 118. Mu. Mol) in THF (235. Mu.L) and MeOH (235. Mu.L) was stirred for 4h at 21 ℃. After completion, the reaction was mixedFor things H 2 O (2 mL) was diluted and directly purified by reverse phase HPLC (Gemini 5. Mu. m C18)250X 21.2mm AXIA filled) (gradient elution, 10-40% CH 3 CN/H 2 O, with 0.05% NH 4 OH as a modifier) to afford the title product (381) (7.1 mg, 52%) as a colorless solid. m/z (ESI, positive ion) =581.3 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm:8.19(s,1H),7.90-8.03(m,2H),7.59(d,J＝8.44Hz,1H),7.19-7.23(m,1H),7.02-7.08(m,2H),6.36(br s,1H),5.28(qd,J＝7.03,2.87Hz,1H),5.11(s,2H),4.91-4.93(m,1H),4.84-4.87(m,1H),4.68-4.74(m,1H),4.61-4.68(m,1H),4.48(dt,J＝9.17,5.99Hz,1H),4.00(d,J＝13.69Hz,1H),3.85-3.97(m,1H),2.88-2.95(m,1H),2.74-2.86(m,2H),2.48-2.60(m,1H),2.15-2.31(m,2H),1.85(br s,2H),1.52(br d,J＝12.84Hz,2H)。
Example 382 was synthesized in a similar procedure as described in example 381.
In a similar procedure to that described in example 355, steps A to E, followed by a cyclopropanation step (Pd (OAc) similar to that described in example 136, step A 2 、PPh 3 、K 3 PO 4 ) Synthesis example 475 was then initiated from 4-bromo-2-fluorophenol in a similar manner to that described in steps F to H of example 480, with LiOH being used in the final step.
Examples 476, 508, 509 and 510 were synthesized in a similar procedure as described in example 475.
Example 477 was synthesized in a similar procedure to that described in example 300, step D, followed by a similar procedure to that described in examples 355, steps F through H.
Example 478 was synthesized in a similar procedure as described in example 367.
Example 479 was synthesized from 367f in a similar procedure to that described in example 355.
Example 480.2- ((4- ((2- (1- (4-cyano-2-fluorophenoxy) ethyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (480)
Step A.4- ((2- (1-ethoxyvinyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (480 b)
To a solution of 480a (synthesized in a similar procedure to 355 a) (1 g,3.2 mmol) and tributyl (1-ethoxyvinyl) stannane (1.39 g,3.8 mmol) in NMP (10 mL) was added Pd (PPh) 3 ) 2 Cl 2 (0.22 g,0.3 mmol). At 110℃under N 2 After heating down for 6H, the mixture was filtered and poured onto H 2 O (50 mL) and extracted with EtOAc (35 mL. Times.3). The combined organic layers were treated with H 2 O (25 mL) washed with Na 2 SO 4 Dried, filtered and concentrated in vacuo. The resulting crude residue was purified by preparative TLC (EtOAc: petroleum ether=1:10) to afford the impure title product (480 b) (0.53 g) as a colorless oil. m/z (ESI, positive ion) =350.1 [ m+na ]] + 。
Step B.4- ((2-acetylpyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (480 c)
To a mixture of 480b (530 mg,1.51 mmol) in acetone (10 mL) was added 1N HCl (6 mL,6.05 mmol) at 25 ℃. After stirring at 25℃for 18H, the acetone is removed under reduced pressure and the residue is taken up in THF/H 2 The mixed solution of O (5 mL/5 mL) was diluted. Na is mixed with 2 CO 3 (1.6 g,15.1 mmol) was added to the residue. The resulting mixture was stirred at 25 ℃ for 1h and extracted with EtOAc (10 ml×2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated in vacuo, which was purified by preparative TLC (EtOAc: petroleum ether=1:4) to afford the title product (480 c) (240 mg, 44%) as a colorless oil. m/z (ESI, positive ion) =322.1 [ m+h ]] + 。
Step C.4- ((2- (1-hydroxyethyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (480 d)
480c (260 mg,0.806 mmol) at 0deg.C in CH 3 NaBH was added to the mixture in OH (8 mL) 4 (61 mg,1.6 mmol). After stirring at 0deg.C for 1h, the mixture was poured into water (20 mL) and extracted with EtOAc (35 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the crude title product (480 d, rac) (210 mg, 72%) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =324.3 [ m+h ]] + 。
Step D.4- ((2- (1- ((methylsulfonyl) oxy) ethyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (480 e)
To a solution of 480d (216 mg,0.0928 mmol) and DIPEA (345 mg,2.67 mmol) in DCM (6 mL) was added methanesulfonic anhydride (2918 mg,1.67 mmol) at 0 ℃. After stirring at 0deg.C for 1H, the reaction was diluted with DCM (20 mL) and taken up with H 2 O (10 mL. Times.2) was washed. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the crude title product (480 e) (250 mg) as a colorless oil, which was used in the next step without further purification. m/z (ESI, positive ion) =402.2 [ m+h ]] + 。
Step E.4- ((2- (1- (4-cyano-2-fluorophenoxy) ethyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (480 f)
480e (250 mg,0.56 mmol), 3-fluoro-4-hydroxybenzonitrile (77 mg,0.56 mmol) and K were combined at 80 ℃ 2 CO 3 (232 mg,1.68 mmol) in DMF (5 mL) was heated for 2h. The mixture was poured into water (30 mL)) And extracted with EtOAc (25 ml×2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated to give a crude residue, which was purified by preparative TLC (EtOAc: petroleum ether=2:1) to afford the title product (480 f) as a colorless oil with about 90% purity (180 mg, 65%). m/z (ESI, positive ion) =443.1 [ m+h] + 。
Step F.3-fluoro-4- (1- (4- (piperidin-4-yloxy) pyrimidin-2-yl) ethoxy) benzonitrile (480 g)
To a solution of 480f (180 mg,0.41 mmol) in DCM (3 mL) was added TFA (1 mL). After stirring for 1h at 25 ℃, the reaction was concentrated to afford the crude title product (480 g) (130 mg) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =343.1 [ M+H ]] + 。
Step G.2- ((4- ((2- (1- (4-cyano-2-fluorophenoxy) ethyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (480H)
480g (143 mg,0.42 mmol), 1h (123 mg,0.42 mmol) and K were combined at 25 ℃ 2 CO 3 (173 mg,1.25 mmol) in DMF (5 mL) was stirred for 4h. The mixture was poured into water (35 mL) and extracted with EtOAc (25 ml×2). The combined organic layers were treated with H 2 O (20 mL) washing, na 2 SO 4 Dried, filtered and concentrated in vacuo to give a crude residue which was purified by preparative TLC (EtOAc: petroleum ether=2:1) to afford the title product (480 h) as a yellow oil (180 mg, 64.6%). m/z (ESI, positive ion) =601.3 [ m+h ] ] + 。
Step H.2- ((4- ((2- (1- (4-cyano-2-fluorophenoxy) ethyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (480)
480H (20 mg,0.033 mmol) in THF/H 2 NaOH (27 mg,0.66 mmol) was added to the mixture in O (1 mL/1 mL). After stirring at 25 ℃ for 18h, the reaction was adjusted to ph=7-8 with 1NHCl and with DCM/CH 3 OH (10/1) (15 mL. Times.2) extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by preparative TLC (DCM: CH) 3 Oh=10:1) to afford the title product (480) (5.1 mg,24%, diastereomer mixture) as a white solid. 1 H NMR(400MHz,CD 3 OD) δppm8.42 (d, j=5.75 hz, 1H), 8.30 (s, 1H), 7.97 (br d, j=8.50 hz, 1H), 7.66 (d, j=8.50 hz, 1H), 7.53-7.58 (m, 1H), 7.36 (br t, j=7.38 hz, 1H), 7.01 (t, j=8.38 hz, 1H), 6.72 (d, j=6.00 hz, 1H), 5.58 (q, j=6.50 hz, 1H), 5.22-5.38 (m, 2H), 5.03-5.11 (m, 1H), 4.56-4.77 (m, 2H), 4.42-4.51 (m, 1H), 4.02 (brdd, j=13.88, 4.38hz, 1H), 3.91 (brdd, j=13.76, 1 hz), 5.22-5.38 (m, 2H), 5.03-5.11 (m, 1H), 4.56-4.77 (m, 2H), 4.42-4.51 (m, 1H), 4.02 (m, 1H), 3.9-1.1H), 1.9-1H (m, 1.3.3.9-1H). m/z (ESI, positive ion) =587.2 [ m+h ]] + 。
Example 481 was synthesized from tert-butyl 4-hydroxypiperidine-1-carboxylate in a procedure similar to that described in steps a to E of example 355 followed by a procedure similar to that described in steps C to E of example 360.
Example 482 was synthesized in a similar procedure as described in example 481, except that TFA was used to remove the Boc protecting group.
Example 483 (R) -2- ((4- ((2- ((2-chloro-4-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1- (isoxazole-3-carbonyl) azetidin-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (483)
Step a. (R) -1- (azetidin-2-ylmethyl) -2- ((4- ((2- ((2-chloro-4-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (483 b)
To a mixture of 483a (synthesized in a similar procedure to that described in example 355) (64 mg,0.094 mmol) in DCM (2 mL) was added TFA (0.5 mL). After stirring at 25 ℃ for 2h, the reaction was concentrated to afford the crude title product (483 b), which was used in the next step without further purification. m/z (ESI, positive ion) =581.2 [ m+h ]] + 。
Step b. (R) -2- ((4- ((2- ((2-chloro-4-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- ((1- (isoxazole-3-carbonyl) azetidin-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (483)
To a solution of 1, 2-oxazole-3-carboxylic acid (15 mg,0.133 mmol) and DIPEA (86 mg, 0.264 mmol) in DCM (2.5 mL) was added HATU (55 mg,0.146 mmol) at 25 ℃. After stirring for 30min, a solution of 483b (54 mg,0.093 mmol) in DCM (0.5 mL) was added to the above mixture. After stirring for a further 30min, the reaction was concentrated and purified by reverse phase HPLC (37% CH 3 CN/H 2 O, with 0.5% NH 4 OH as a modifier) to afford the title product (483) (4.7 mg, 5.0%) as a white solid. m/z (ESI, positive ion) =676.2 [ m+h ]] + 。
Example 484 was synthesized from 261c in a similar procedure as described in example 360, steps D and E, with the addition of NaI in step D.
Example 485 was synthesized from 2- (bromomethyl) -4-chloropyrimidine in a similar procedure to that described in steps a through C of example 216, followed by a similar procedure to that described in steps a and B of example 304.
EXAMPLE 486 (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [4,5-b ] pyridine-6-carboxylic acid (486)
(S) -5-bromo-2-nitro-N- (oxetan-2-ylmethyl) pyridin-3-amine (486 a)
To 5-bromo-3-fluoro-2-nitropyridine (750 mg,3.39 mmol) and K 2 CO 3 (935 mg,6.78 mmol) to a mixture of DMF (10 mL) was added 1e (1.48 g,16.97 mmol). After stirring for 16h at 25 ℃, the reaction was diluted with EtOAc (50 mL) and washed with brine (50 ml×2). The combined organic layers were dried and evaporated to dryness to afford the crude title product (486 a) (950 mg) as a yellow solid. m/z (ESI, positive ion) =288.0 [ m+h ]] + 。
Step b. (S) -5-bromo-N 3 - (oxetan-2-ylmethyl) pyridine-2, 3-diamine (486 b)
To a solution of 486a (220 mg,0.76 mmol) in acetic acid (5 ml) was added Fe (128 mg,2.3 mmol). After stirring at 25 ℃ for 2h, the reaction was filtered and the filtrate was diluted with EtOAc (30 mL) and washed with brine (30 ml×3). The combined organic layers were dried and evaporated to dryness to afford the crude title product (486 b) (185 mg) as a brown solid. m/z (ESI, positive ion) =258.0 [ m+h ]] + 。
(S) -6-bromo-2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [4,5-b ] pyridine (486 c)
Direction 486b(70 mg,0.27 mmol) and 2-chloro-1, 1-trimethoxyethane (125.7 mg,0.81 mmol) in CH 3 To a solution of CN (3 ml) was added TsOH (17.2 mg,0.02 mmol). At 60℃under N 2 After stirring for 16h, the reaction was diluted with EtOAc (20 mL) and washed with brine (20 ml×2). The combined organic layers were dried and evaporated to dryness to afford the crude title product (486 c) (70 mg) as a yellow solid. m/z (ESI, positive ion) =316.0 [ m+h ]] + 。
Step d. (S) -4- ((4- ((1- ((6-bromo-1- (oxetan-2-ylmethyl) -1H-imidazo [4,5-b ] pyridin-2-yl) methyl) piperidin-4-yl) oxy) pyrimidin-2-yl) methoxy) -3-fluorobenzonitrile (486 d)
To 261c (40 mg,0.12 mmol) and K 2 CO 3 (49.7 mg,0.36 mmol) in CH 3 To a solution of CN (5 ml) was added 486c (38.5 mg,0.122 mmol). After stirring for 16h at 25 ℃, the reaction was diluted with EtOAc (20 mL) and washed with brine (20 ml×2). The combined organic layers were dried and evaporated to dryness, and the resulting residue was purified by preparative TLC (5% MeOH/DCM) to give the title product (486 d) as a yellow solid (70 mg, 85%). m/z (ESI, positive ion) =608.1 [ m+h ]] + 。
Step E. (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [4,5-b ] pyridine-6-carboxylic acid methyl ester (486 e)
To 486d (100 mg,0.16 mmol) and Et 3 To a solution of N (49.7 mg,0.49 mmol) in 50% DMSO/MeOH (5 ml) was added Pd (dppf) Cl 2 (12 mg,0.016 mmol). The reaction was stirred at 75℃under CO (1 atm) for 16h. The reaction was then diluted with EtOAc (50 mL) and washed with brine (50 ml×3). The combined organic layers were dried, evaporated to dryness and the resulting crude residue was purified by preparative TLC(5% MeOH/DCM) to afford the title product (486 e) as a yellow solid (50 mg, 47%). m/z (ESI, positive ion) =588.2 [ m+h ]] + 。
Step F. (S) -2- ((4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [4,5-b ] pyridine-6-carboxylic acid (486)
To 486e (50 mg,0.085 mmol) in 50% THF/H 2 To a solution in O (2 mL) was added LiOH (4 mg,0.17 mmol). After stirring at 20 ℃ for 2h, the reaction was adjusted to ph=6 and purified by reverse phase HPLC (CH 3 CN/H 2 O) to afford the title product as a white solid (2.8 mg, 5.6%). 1 H NMR(400MHz,CD 3 OD) delta ppm 9.06 (d, j=1.71 hz, 1H), 8.68 (d, j=1.71 hz, 1H), 8.44 (d, j=5.87 hz, 1H), 7.56-7.65 (m, 1H), 7.47 (br d, j=8.56 hz, 1H), 7.23 (t, j=8.56 hz, 1H), 6.76 (d, j=5.87 hz, 1H), 5.39 (s, 2H), 5.15-5.32 (m, 1H), 5.02 (br d, j=4.16 hz, 1H), 4.84-4.86 (m, 1H), 4.59-4.80 (m, 2H), 4.48 (dt, j=9.11, 5.96hz, 1H), 4.08 (br d, j=14.18 hz, 1H), 3.97 (br d, j=13.87 hz, 1H), 5.02 (br d, 2H), 5.84-5.32 (m, 1H), 4.84-4.80 (m, 1H), 4.84-4.84 (m, 1H), 3.82 (m, 1H). m/z (ESI, positive ion) =574.1 [ M+H ]] + 。
Examples 512 and 513 were synthesized in a procedure similar to that described in steps a through F of example 355 followed by a procedure similar to that described in example 486, with KI added at step D of 486 synthesis.
Examples 487 and 488 were synthesized from 261a following a procedure similar to that described in example 313.
Example 489 was synthesized from 355d following a procedure similar to that described in steps E and F of example 355 followed by a procedure similar to that described in steps F and G of example 367.
Example 490.2- (((2R, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2- (fluoromethyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (490)
Step A. (2R, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (490 b)
To a solution of 490a (synthesized in a similar procedure to 261b, 144mg,0.30 mmol) in dry EtOH (3.0 mL) at 0deg.C was added NaBH 4 (32 mg,0.89 mmol) and CaCl 2 (99 mg,0.89 mmol). The reaction was warmed to room temperature, stirred for 12h and quenched dropwise with 1N HCl (1 mL) at 0deg.C. The reaction was extracted with EtOAc (5 ml×3) and the combined organic layers were taken up over Na 2 SO 4 Drying, filtering, concentrating and purifying by silica gel column chromatography (gradient elution, 0-5% MeOH/CH) 2 Cl 2 ) To afford the title product (490 b) (24 mg, 18%). m/z (ESI, positive ion) =459.3 [ m+h ]] + 。
Step B.2- (((2R, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2- (hydroxymethyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (490 c)
The title product (490 c) was synthesized from 490b in a similar procedure as described in steps F and G of example 355.
Step C.methyl 2- (((2R, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2- (fluoromethyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate (490 d)
At 0deg.C, 490c (23 mg,0.037 mmol) in dry CH 2 Cl 2 Deoxo-Fluor (22 mg,0.045mmol,45% in THF) was added dropwise to the solution in (0.37 mL). The reaction was allowed to warm to room temperature and stirred for 1h. Additional Deoxo-Fluor (22 mg,0.045mmol,45% in THF) was added. After completion, the reaction was cooled to 0 ℃ and saturated NaHCO was added dropwise 3 Quenching. The reaction was extracted with EtOAc and washed with water and brine. The organic layer was purified by Na 2 SO 4 Drying, filtering, concentrating and purifying by silica gel column chromatography (gradient elution, 0-5% MeOH/CH) 2 Cl 2 ) To afford the title product (490 d) (8 mg, 35%) as a colorless oil. m/z (ESI, positive ion) =619.3 [ m+h ]] + 。
Step D.2- (((2R, 4S) -4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2- (fluoromethyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (490)
To 490d (8 mg,0.013 mmol) in THF/H 2 LiOH.H was added to a solution in O (1/1, 0.3 mL) 2 O (3 mg,0.065 mmol) and a few drops of MeOH. . After heating at 40 ℃ for 4h, the reaction was acidified with acetic acid to adjust to ph=5. The reaction mixture was diluted with EtOAc (3 mL) and washed with brine (2 mL). The organic layer was then taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 0-5% MeOH/DCM) to afford the title product (490) (3 mg, 38%) as a colorless film. NMR shows a pair of rotary isomers. 1H NMR (400 MHz, CD) 3 OD)δppm 8.43(dd,J＝5.87,1.71Hz,1H),8.34-8.30(m,1H),8.01-7.93(m,1H),7.71-7.65(m,1H),7.64-7.50(m,1H),7.49-7.40(m,1H),7.27-7.11(m,1H),6.77-6.71(m,1H),5.48(s,1H),5.42-5.34(m,1H),5.30-5.19(m,1H)5.18-4.97(m,1H),5.30-4.91(m,1H),4.96-4.89(m,1H),4.81-4.30(m,5H),4.21-4.06(m,1H),3.14-2.44(m,5H),2.31-1.52(m,4H)。m/z(ESI, positive ion) =605.4 [ m+h] + 。
Example 491 was synthesized from 3, 5-dichloropyridazine in a similar procedure as described in example 355, with NaH as base in the first step, and the reaction was carried out at 0 to 20 ℃ for 2h.
Examples 492 and 493, 494 and 495 were synthesized in a similar procedure to that described in example 355.
Example 496 was synthesized from 220a in a similar procedure to that described in example 367, step D, followed by a procedure similar to that described in examples 355, steps F to H.
Example 497 was synthesized from 274C in a similar procedure as described in steps C through G of example 367.
Example 498 (S) -2- ((4- ((2- ((4-cyano-2, 5-difluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (498)
Step A.2, 5-difluoro-4-hydroxybenzonitrile (498 a)
To a solution of 4-bromo-2, 5-difluorophenol (300 mg,1.4 mmol) in DMF (10 mL) was added CuCN (514 mg,5.7 mmol). After heating at 100deg.C for 12H, the reaction was cooled, using H 2 O (30 mL) was quenched and extracted with EtOAc (50 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Drying, filtering, concentrating and purifying by reverse phase HPLC (gradient elution, 0-70% CH) 3 CN/H 2 O) to afford the title product (498 a) as a white solid (200 mg, 85%). m/z (ESI, negative ion) =154.1 [ M-H ]] - 。
Step B.4- ((2- (((methylsulfonyl) oxy) methyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (498 c)
To a solution of 498b (synthesized in a similar procedure to 355c, 400mg,1.2 mmol) in DCM (10 mL) was added DIPEA (1000 mg,7.7 mmol). After stirring at 0℃for 3min, methanesulfonic anhydride (675 mg,3.8 mmol) was added and the resulting mixture was stirred at 20℃for 2h. Will react with H 2 O (8 mL) was quenched and extracted with EtOAc (5 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to afford the crude title product (498 c), which was used in the next step without further purification. m/z (ESI, positive ion) =388.2 [ m+h ]] + 。
Step C.4- ((2- ((4-cyano-2, 5-difluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidine-1-carboxylic acid tert-butyl ester (498 d)
To a solution of 498c (100 mg,0.25 mmol) in DMF (10 mL) was added 498a (44 mg,0.28 mmol) and K 2 CO 3 (178 mg,1.29 mmol). After heating at 80℃for 5H, reaction H was used 2 O (40 mL) was quenched and extracted with EtOAc (15 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Drying, filtering, concentrating and purifying by reverse phase HPLC (gradient elution, 0-80% CH) 3 CN/H 2 O) to afford the title product (498 d) (100 mg, 82%) as a pale yellow solid. m/z (ESI, positive ion) =447.2 [ m+h ]] + 。
Step d. (S) -2- ((4- ((2- ((4-cyano-2, 5-difluorophenoxy) methyl) pyrimidin-4-yl) oxy) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (498)
The title compound (498) was synthesized from 498D in a similar procedure to that described in steps C to E of example 220, wherein step D was heated to 90 ℃ for 1 duration2h。 1 H NMR(400MHz,CD 3 OD) delta ppm 8.44 (d, j=5.87 hz, 1H), 8.21 (s, 1H), 7.95 (dd, j=8.31, 1.47hz, 1H), 7.64 (dd, j=10.51, 6.11hz, 1H), 7.60 (d, j=8.56 hz, 1H), 7.25 (dd, j=11.00, 6.85hz, 1H), 6.77 (d, j=5.87 hz, 1H), 5.40 (s, 2H), 5.26 (qd, j=7.13, 2.81hz, 1H), 5.02 (br d, j=4.16 hz, 1H), 4.83-4.87 (m, 1H), 4.60-4.73 (m, 2H), 4.46 (dt, j=9.17, 5.93, 1H), 3.96-4.02 (m, 1H), 3.85.85 (m, 2H), 3.85-7.13, 2.81hz, 1H), 5.83-4.82 (m, 2H), 3.82-3.85 (m, 1H), 2.82 (m, 2H), 4.80-7.7.7 (m, 1H). m/z (ESI, positive ion) =589.1 [ m+h ] ] + 。
Example 500 was synthesized in a similar procedure to that described in example 498, with KI added at the penultimate step, and the reaction was performed at room temperature.
Example 499 was synthesized in a similar procedure as described in example 220.
Examples 501, 503 were synthesized in a similar procedure as described in example 363.
Example 502 was synthesized from 498D in a similar procedure to that described in example 206, steps D through F, with THF as the solvent for the last step.
Example 504 was synthesized from 498c in a similar procedure to that described in example 498 step D, followed by a procedure similar to that described in example 355 step F and example 304 steps a and B. Isopropyl alcohol was used as solvent in the final step to replace MeOH.
Example 505 was synthesized in a similar procedure as described in example 504.
Example 506, example 507 were synthesized from 261a in a similar procedure to that described in example 313. DMF is used as the solvent for the penultimate step, and THF/H 2 O/isopropanol (2:1:1) was used as solvent for the last step.
Example 511 was synthesized in a similar procedure as described in example 382.
Example 514 was synthesized in a similar procedure to that described in examples 261 steps a through C, followed by a procedure similar to that described in examples 367 steps F and G, with KI added at the penultimate step.
Example 515 was synthesized in a similar procedure to that described in steps a through F of example 355, followed by procedures similar to those described in steps F and G of example 367, with KI added at the penultimate step.
Biological example 1
GLP-1R cAMP assay
cAMP accumulation was measured in Chinese Hamster Ovary (CHO) cells stably overexpressing the human GLP-1 receptor using the HitHunter cAMP assay kit (HitHunter cAMP Assay for Small Molecules Kit) (Eurofins) for small molecules. Briefly, cells were grown in a hamming F12 Nutrient Mix (Ham's F Nutrient Mix) with 10% FBS and lifted with PBS-based enzyme-free cell dissociation buffer (thermo fisher). Cells were pelleted and resuspended in hank's buffered saline solution with 10mM HEPES and 625 μm 3-isobutyl-1-methylxanthine. anti-cAMP antibody reagent was then added to the cells at a 1:2 ratio, and 5 μl of the mixture was seeded into 384 well small volume white assay plates at 10,000 cells/well. Cells were then treated with 50nL of compound in triplicate for 30min in a 20 point dose response format using an ECHO 550 acoustic dispenser (Labcyte). The cells are then lysed and the detection reagents are added according to the manufacturer's protocol. After overnight incubation, luminescence was measured using a Perkin Elmer Envision plate reader. Dose response curves were analyzed using GraphPad Prism 9.0.
The results are reported in table 1 below. In the tables, EC 50 The value is++ less than or equal to 50nM<++≤500nM<+. Molecular weights were calculated by standard techniques and mass spectral results were reported according to the examples above.
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Intravenous glucose tolerance test (IVGTT) in cynomolgus monkeys
Aged (< 8 years) cynomolgus monkeys (cynomolgus macaques (Macaca fascicularis); n=4-5/test article) were fasted overnight and anesthetized with ketamine (ketamine) followed by intravenous glucose tolerance test (IVGTT). Test articles were formulated at 6mg/mL in vehicle (5% polyethylene glycol 400:95% (12% (w/v) solution of sulfobutyl ether- β -cyclodextrin in deionized water) (v/v)) and administered into peripheral veins by intravenous bolus injection 1-6 minutes prior to IVGTT. IVGTT was initiated by administering an Intravenous (IV) glucose bolus (0.5 g/kg, in the form of a 50% dextrose solution). Blood samples were collected from peripheral veins 0, 1, 3, 5, 10, 20, 40 and 60 minutes after completion of intravenous glucose bolus injection. Blood samples were collected directly into potassium ethylenediamine tetraacetate tubes and plasma was separated by centrifugation at 2,500g for 10 minutes within 30 minutes after collection. Plasma insulin concentrations (mu U/mL) from all time points were analyzed using a Cobas e411 immunoassay. The area under insulin curve (AUC) was calculated using GraphPad Prism software (v 9). As shown in fig. 1, an increase in insulin secretion was observed, consistent with a substantial increase in insulin AUC after administration of compounds 145, 171, 313, 326, 335, 355, and 338, respectively.
Equivalent scheme
The disclosure set forth above may encompass a number of different embodiments having independent utility. Although each of these embodiments has been disclosed, the specific embodiments thereof as disclosed and illustrated herein should not be considered in a limiting sense as numerous variations are possible. The subject matter of the embodiments includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions and/or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Alternative embodiments as well as other combinations and subcombinations of features, functions, elements, and/or properties may be claimed in this or a related application in which priority is claimed. Such claims, whether they are directed to different embodiments or directed to the same embodiments, and whether broader, narrower, equal, or different in scope to the original claims, also are regarded as included within the subject matter of the present disclosure.
One or more features from any embodiment described herein or in the accompanying drawings may be combined with one or more features of any other embodiment described herein or in the accompanying drawings without departing from the scope of the disclosure.
All publications, patents, and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this disclosure that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (56)

1. A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, -NMe 2 or-CF 3 ；
Ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted bicyclic ring;
ring C is a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkenyl, each containing at least one N, attached to L as depicted 3 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
W is N, CR 14 Or C; when W is CR 14 When adjacent dotted lines indicate single bonds; when W is C, adjacent dashed lines indicate a double bond or L 2 is-C (H) =;
L 1 selected from the group consisting of: bond, -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -, -NH-, -N (Me) -and process for preparing the same
L 3 is-CH 2 -or-C (O) -;
L 4 is absent, or L 4 And L is equal to 1 And rings A and B together form a fused tricyclic ring, and L 5 Is absent;
L 5 is absent, or L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring, and L 4 Is absent;
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 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, 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, hydroxy, alkyl, haloalkyl, methyl, CH 2 F or CH 2 OH；
Wherein when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-orOr L 3 is-C (O) -, or both.
2. A compound of formula Ia or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, -NMe 2 or-CF 3 ；
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 One, or both of zero are N, and the remainder are CH or CR 6 ；
W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; when W is C, an adjacent dotted line indicates a double bond or L 2 is-C (H) =;
L 1 selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-OC(H,Me)-、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-CF 2 -、-SO 2 -, -O-, NH-, -N (Me) -and
L 3 is-CH 2 -or-C (O) -;
L 4 is absent, or L 4 And L is equal to 1 And rings A and B together form a fused tricyclic ring, and L 5 Is absent;
L 5 is absent, or L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring, and L 4 Is absent;
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 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, 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;
wherein when L 1 is-CH 2 O-，L 4 Is absent and L 5 When not present, then L 2 is-C (O) -CH 2 -、-C(H)＝、-SO 2 -, -O-orOr L 3 is-C (O) -, or both.
3. The compound of claim 1 according to formula IIa or IIb, or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；
B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein in formula IIb, B 4 Is absent;
D 1 、D 2 and D 3 One, or both of zero are N, and the remainder are CH or CR 6 The method comprises the steps of carrying out a first treatment on the surface of the Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 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; and is also provided with
o is 1, 2, 3 or 4.
4. The compound of claim 1, according to formula IIc, IId, IIg or IIh, or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein A is 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；
B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 Wherein in formula IIb, B 4 Is absent;
D 1 、D 2 and D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 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;
R 14 is hydrogen, cyano, halo, hydroxy, methyl, CH 2 F or CH 2 OH; and is also provided with
o is 1, 2, 3 or 4.
5. The compound of claim 1, according to any one of the following formulas, or a pharmaceutically acceptable salt or stereoisomer thereof:
/>
wherein each R is 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
R 4 Is alkyl, substituted alkyl, unsubstitutedSubstituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene;
R 5 Selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、/>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, hydroxy, methyl, CH 2 F or CH 2 OH
n is an integer from 0 to 5; m is an integer from 0 to 4; o is an integer from 0 to 4; and r is an integer from 0 to 3.
6. A compound of formula XXX or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; when W is C, an adjacent dashed line indicates a double bond;
A 1 、A 2 、A 3 、A 4 and A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；
B 1 、B 2 、B 3 And B 4 One, or both of zero are N, and the remainder are CH or CR 2 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
L 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -, NH-, -N (Me) -and process for preparing the same
L 3 is-CH 2 -or-C (O) -;
each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 2 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
Each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
R 4 Is unsubstituted alkyl, substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heterocycloalkyl alkylene, or substituted heterocycloalkyl alkylene;
R 5 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、 And tetrazolyl;
each R 6 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, hydroxy, alkoxy, 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; and is also provided with
o is an integer from 0 to 4.
7. A compound of formula XXXI, or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein W is N, CH or C; when W is CH, adjacent dotted lines indicate a single bond; a is that 1 、A 2 、A 3 、A 4 And A 5 One, or both of zero are N, and the remainder are CH or CR 1 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
Each R 1 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkoxy and R 11 R 12 NCO-；
L 1 Selected from the group consisting of: -O-, -CH 2 -、-NH-、-N(Me)-、-N(Et)-、-OCH 2 -、-CH 2 O-、-NHCH 2 -、-N(Me)CH 2 -and-SO 2 NH-；
L 2 Selected from the group consisting of: bond, -C (O) -, -CH 2 -、-C(H)＝、-SO 2 -、-O-、-CF 2 -, -CHF-, -CH (OH) -, NH-, -N (Me) -and process for preparing the same
L 3 is-C 2 -or-C (O) -;
each R 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, 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 selected from the group consisting of: -COOH, -COCF 3 、-C(OH)CF 3 、-CONHCN、-CONHOH、CONHOMe、-CONHSO 2 N(Me) 2 、-PO 3 H 2 、-PO(Me)(OH)、-SO 3 H、-SO 2 NH 2 、-SO 2 NHMe、-B(OH) 2 、
And tetrazolyl;
each R 6 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; and is also provided with
o is 1, 2, 3 or 4.
8. The compound of any one of the preceding claims, wherein each R 2 And R is 3 Is H or F.
9. The compound of any one of the preceding claims, wherein m is 0 and o is 0.
10. The compound of any one of the preceding claims, wherein W is N or CH.
11. The compound of any one of the preceding claims, wherein W is C.
12. The compound of any one of the preceding claims, wherein W is CH.
13. The compound of any one of the preceding claims, wherein W is N.
14. The compound of any one of the preceding claims, wherein R 4 Selected from the group consisting of: azetidin-3-yl-methyl, (3R) -azetidin-3-yl-methyl, (3S) -azetidin-3-yl-methyl, (S) -but-4-yl-1, 3-diol, but-1-yl-one, 1- (cyanomethyl) -cyclopropan-1-yl-methyl, (1-ethyl-1H-imidazol-5-yl) -methyl, 1- (fluoromethyl) -cyclopropan-1-yl-methyl, 1-hydroxy-cyclopropan-1-yl-methyl, isoxazol-5-yl-methyl, (1-methyl-1H-imidazol-5-yl) -methyl, 1-methoxy-cyclopropan-1-yl-methyl, methoxyethane-2-yl, 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl, { [1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }, { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }, { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }, oxetan-2-yl-methyl, (2S) -oxetan-2-yl-methyl, oxolan-3-yl-methyl, (3R) -oxolan-3-yl-methyl, 1, 3-oxazol-2-yl-methyl and 2-oxabicyclo [2.1.1 ]Hex-1-yl-methyl.
15. The compound of any one of the preceding claims, wherein R 4 Selected from the group consisting of: (1-ethyl-1H-imidazol-5-yl) -methyl, oxetan-2-yl-methyl, (2S) -oxetan-2-yl-methyl, (3R) -oxolan-3-yl-methyl and 1, 3-oxazol-2-yl-methyl.
16. The compound of any one of the preceding claims, wherein R 4 Selected from the group consisting of: azetidin-3-yl-methyl, (3R) -azetidin-3-yl-methyl, (3S) -azetidin-3-yl-methyl, (S) -but-4-yl-1, 3-diol, but-1-yl-one, 1- (cyanomethyl) -cyclopropan-1-yl-methyl, 1- (fluoromethyl) -cyclopropan-1-yl-methyl, 1-hydroxy-cyclopropan-1-yl-methyl, isoxazol-5-yl-methyl, (1-methyl-1H-imidazol-5-yl) -methyl, 1-methoxy-cyclopropyl-1-yl-methyl, methoxyethane-2-yl, 1- (2-methoxyethyl) -cyclopropan-1-yl-methyl, { [1- (1, 2-oxazol-3-carbonyl) azetidin-2-yl]Methyl }, { [ (2R) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl }, { [ (2S) -1- (1, 2-oxazole-3-carbonyl) azetidin-2-yl]Methyl } and 2-oxabicyclo [2.1.1]Hex-1-yl-methyl.
17. The compound of any one of claims 1-15, wherein R 4 Selected from the group consisting of oxetan-2-yl-methyl and (1-ethyl-1H-imidazol-5-yl) -methyl.
18. The compound of any one of claims 1-15, wherein R 4 Is oxetan-2-yl-methyl.
19. The compound of any one of claims 1-15, wherein R 4 Is (2S) -oxetan-2-yl-methyl.
20. The compound of any one of claims 1-15, wherein R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl.
21. The compound of any one of claims 1-15, wherein R 4 Selected from the group consisting of oxacyclopentane-3-yl-methyl and 1, 3-oxazol-2-yl-methyl.
22. The compound of any one of claims 1-15, wherein R 4 Is (3R) -oxolane-3-yl-methyl.
23. The compound of any one of claims 1-15, wherein R 4 Is 1, 3-oxazol-2-yl-methyl.
24. The compound of any one of the preceding claims according to formula XXX, wherein R 4 Is H.
25. The compound of any one of the preceding claims, wherein R 5 is-COOH or-COOMe.
26. The compound of any one of the preceding claims, wherein R 5 is-COOH.
27. The compound of any one of claims 1-24, wherein R 5 Is tetrazolyl.
28. The compound of any one of claims 1-24, wherein R 5 Is 1H-1,2,3, 4-tetrazol-5-yl.
29. The compound of any one of the preceding claims, wherein L 2 is-CH 2 -, -C (O) -or-SO 2 -。
30. The compound of any one of claims 1-28, wherein L 2 is-ch=or-O-.
31. The method of any one of claims 1-28A compound wherein L 2 is-CF 2 -, -CHF-or-CHOH-.
32. The compound of any one of claims 1-29, wherein L 2 is-CH 2 -。
33. The compound of any one of claims 1-28, wherein L 2 Is NH-or-N (Me) -.
34. The compound of any one of the preceding claims, according to formula XXX, wherein L 2 Is a key.
35. The compound of any one of the preceding claims, wherein L 3 is-CH 2 -。
36. The compound of any one of claims 1-35, wherein L 3 is-C (O) -.
37. The compound of any one of the preceding claims, according to formula XXX, wherein L 1 is-CH 2 O-or-OCH 2 -。
38. The compound of any one of claims 1-29 and 37, wherein L 1 is-CH 2 O-; and L is 2 is-CH 2 -or-CO-.
39. The compound of any one of claims 1-29 and 36-38, wherein L 1 is-CH 2 O-; and L is 3 is-C (O) -.
40. The compound of any one of claims 1-36, wherein L 1 is-O-.
41. The compound of any one of claims 1-39, wherein L 1 is-CH 2 O-。
42. The compound of any one of claims 1-36, wherein L 1 is-NH-.
43. The compound of any one of claims 1-36, wherein L 1 is-N (Me) -.
44. The compound of any one of claims 1-36, wherein L 1 is-N (Et) -.
45. The compound of any one of claims 1-37, wherein L 1 is-OCH 2 -。
46. The compound of any one of claims 1-36, wherein L 1 is-OC (H, me) -.
47. The compound of any one of claims 1-39 and 41, wherein L 1 is-CH 2 O-。
48. The compound of any one of claims 1-36, wherein L 1 is-NHCH 2 -。
49. The compound of any one of claims 1-36, wherein L 1 is-N (Me) CH 2 -。
50. The compound of any one of claims 1-36, wherein L 1 is-SO 2 NH-。
51. The compound of any one of the preceding claims, selected from the following, or a pharmaceutically acceptable salt or solvate thereof:
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52. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
53. A method of treating a metabolic disease or disorder, the method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 52.
54. A compound according to any one of claims 1 to 51 or a pharmaceutical composition according to claim 52 for use in therapy.
55. A compound according to any one of claims 1 to 51 or a pharmaceutical composition according to claim 52 for use in the treatment of a metabolic disease or disorder.
56. Use of a compound according to any one of claims 1 to 51 or a pharmaceutical composition according to claim 52 in the manufacture of a medicament for the treatment of a metabolic disease or disorder.
CN202280024605.7A 2021-01-28 2022-01-27 GPCR receptor agonists, pharmaceutical compositions comprising same, and methods of use thereof Pending CN117043154A (en)

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US63/183,612 2021-05-03
US202163274893P 2021-11-02 2021-11-02
US63/274,893 2021-11-02
PCT/US2022/014156 WO2022165076A1 (en) 2021-01-28 2022-01-27 Gpcr receptor agonists, pharmaceutical compositions comprising the same, and methods for their use

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