CN117545748A - Benzimidazolyl GLP-1GPCR receptor agonists, pharmaceutical compositions comprising the same, and methods of use thereof - Google Patents

Benzimidazolyl GLP-1GPCR receptor agonists, pharmaceutical compositions comprising the same, and methods of use thereof Download PDF

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CN117545748A
CN117545748A CN202280040978.3A CN202280040978A CN117545748A CN 117545748 A CN117545748 A CN 117545748A CN 202280040978 A CN202280040978 A CN 202280040978A CN 117545748 A CN117545748 A CN 117545748A
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alkyl
substituted
methyl
compound
group
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杜晓慧
R·富奇尼
X·冉
叶建宏
周翔
S·M·萨基亚
X·王
H·卡瓦依
C·李
S·加雷
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Camote Medical Co ltd
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Camote Medical Co ltd
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Priority claimed from PCT/US2022/027535 external-priority patent/WO2022235717A1/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

Benzimidazolyl GLP-1GPCR receptor agonists, pharmaceutical compositions comprising the same, and methods of use thereof
Cross Reference to Related Applications
This application is PCT International application, claims the benefit of U.S. provisional application Ser. No. 63/282,686, filed on even 24, 11, 2021, and U.S. provisional application Ser. No. 63/183,612, filed on even 3, 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 onDiabetes,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.epidemic mol. Glob. Health10 (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 formulae (I) - (LVIII) 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 formulae (I) - (LVI) 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 a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted bicyclic ring;
ring C is substituted or unsubstituted C 4 -C 6 Heterocycloalkyl or substituted or unsubstituted C 5 Heterocycloalkenyl or substituted or unsubstituted phenyl, wherein heterocycloalkyl and heterocycloalkenyl each comprise 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 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 -and OCH 2 -；
L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-;
L 3 is-CH 2 -
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 alkylSubstituted 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 or methyl;
wherein when the C ring is C 6 When the heterocycloalkyl group is, the B ring is pyrazole or
In one aspect, there is provided a compound of formula (Ia):
wherein a is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring C is further unsubstituted or further substituted, and/or bridged;
D 1 、D 2 and D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
W is 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 -and-OCH 2 -；
L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-;
L 3 is-CH 2 -；
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; and is also provided with
R 13 Is hydrogen or alkyl.
In one aspect, there is provided a compound of formula (Ib):
wherein a is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring C is further unsubstituted or further substituted, and/or fused;
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 -and-OCH 2 -；
L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-;
L 3 is-CH 2 -；
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; and is also provided with
R 13 Is hydrogen or alkyl.
In one aspect, there is provided a compound of formula (Ic), or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein a is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring C is further unsubstituted or further substituted, and/or fused;
C 1 、C 2 、C 3 and C 4 One, or both of zero are N, and the remainder are CH or CR 6 ；
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 -and-OCH 2 -；
L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-;
L 3 is-CH 2 -；
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; and is also provided with
R 13 Is hydrogen or alkyl.
In one aspect, there is provided a compound selected from compounds 529, 530, 533, 534, 535 and 551, or pharmaceutically acceptable salts, tautomers, stereoisomers and/or mixtures of stereoisomers thereof:
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), (Ib) or (Ic) 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), (Ib), or (Ic), 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.
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" refers to alkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl alkylene. 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-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 aralkylene" refers to an aralkylene group as defined herein, wherein the aralkylene group is substituted as defined herein for aryl groups. "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.
The term "cycloalkylene" as used herein 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, 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.
"heterocycloalkenyl" as used herein refers to a monocyclic or bicyclic (e.g., 5-to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more ring atoms are heteroatoms (e.g., N, O or S). Monocyclic and bicyclic heterocycloaliphatic are numbered according to standard chemical nomenclature.
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, 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 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 formula (I), (Ia-Ic), (IIe), (IIf), (IIi-IIo), (XIX) - (XXIV), (XXVIII), (XXIX), (XXXII-XXXVIII) and (XLVIII-LVI)
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 a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; ring B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; ring C is further unsubstituted or further substituted, and/or bridged; d (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 -and-OCH 2 -；L 2 Selected from the group consisting ofThe group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -；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, or substituted heteroarylalkylene; 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 of formula (I), when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-, or L 3 is-CH 2 -, or both. In certain embodiments, when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-. In certain embodiments, when L 1 is-OCH 2 -when, 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-OCH 2 -when, 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-OCH 2 When 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. 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. In certain embodiments, ring C is selected from the group consisting of substituted piperidines, azetidines, pyrrolidines, phenyl, and pyridines. In certain embodiments, ring B is selected from phenyl, furan, pyridine, pyrimidine, thiophene, oxazole, and benzofuran. In certain embodiments, a is phenyl and ring C is azetidine. In certain embodiments, a is phenyl and ring C is pyrrolidine. In certain embodiments, a is phenyl, ring C is azetidine, and ring B is phenyl. In certain embodiments, a is phenyl, ring C is azetidine, and ring B is furan. In certain embodiments, a is phenyl, ring C is pyrrolidine, and ring B is phenyl. In certain embodiments, a is phenyl, ring C is pyrrolidine, and ring B is furan. In certain embodiments, a is phenyl, ring C is phenyl, and ring B is pyrimidine. In certain embodiments, a is phenyl, ring C is pyridine, and ring B is pyrimidine.
In certain embodiments, there is provided a compound of formula (Ia), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
Wherein A is substituted or unsubstitutedOr a substituted or unsubstituted heteroaryl group; 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 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -；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, or substituted heteroarylalkylene; 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 、
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 of formula (Ia), when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-, or L 3 is-OCH 2 Or both. In certain embodiments, when L 1 is-OCH 2 ，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-. In certain embodiments, when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 3 is-CH 2 -. In certain embodiments, when L 1 is-OCH 2 -when, 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-OCH 2 -when, L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring.
In certain embodiments, there is provided a compound of formula (Ib):
wherein a is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; ring B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; ring C is further unsubstituted or further substituted, and/or fused; 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 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-；L 3 is-CH 2 -；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, or substituted heteroarylalkylene; 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 、
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 of formula (Ib), when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-, or L 3 is-OCH 2 Or both. In certain embodiments, when L 1 is-OCH 2 ，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-. In certain embodiments, when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 3 is-CH 2 -. In certain embodiments, when L 1 is-OCH 2 -when, 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-OCH 2 -when, L 5 And L is equal to 2 And rings B and C together form a fused tricyclic ring.
In certain embodiments, there is provided a compound of formula (Ic), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein a is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; ring B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; ring C is further unsubstituted or further substituted, and/or fused; c (C) 1 、C 2 、C 3 And C 4 One, or both of zero are N, and the remainder are CH or CR 6 ；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 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -；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 heteroalkylAryl alkylene or substituted heteroaryl 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 、
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 of formula (Ic), when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-, or L 3 is-OCH 2 Or both. In certain embodiments, when L 1 is-OCH 2 ，L 4 Is absent and L 5 When not present, then L 2 is-CH 2 -, -C (H) =or-O-. In certain embodiments, when L 1 is-OCH 2 -，L 4 Is absent and L 5 When not present, then L 3 is-CH 2 -. In certain embodiments, when L 1 is-OCH 2 -when, 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-OCH 2 -when, 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. 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, the compound of formula (I) is according to formula (IIe), 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 IIe, 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, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, or substituted heteroarylalkylene; 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; o is 1, 2, 3 or 4; p is 0 or 1; and q is 0 or 1.
In certain embodiments, the compound of formula (I) is according to formula (IIf), 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 IIf, 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, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkyleneA heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroarylalkylene, or a substituted heteroarylalkylene; 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; o is 1, 2, 3 or 4; p is 0 or 1; and q is 0 or 1.
In certain embodiments, the compound of formula (I) is according to formula (IIi), 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 IIi, 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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene or 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; o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0.
In certain embodiments, the compound of formula (I) is according to formula (IIj), 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 IIj, 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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene or 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; o is an integer from 0 to 4.
In certain embodiments, the compound of formula (I) is according to formula (IIk), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
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 IIk, 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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene or 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; o is an integer from 0 to 4.
In certain embodiments, the compound of formula (I) is according to formula (il), 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 IIl, 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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene or 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; o is an integer from 0 to 4.
In certain embodiments, the compound of formula (I) is according to formula (IIm), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
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 IIm, 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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene or 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; o is an integer from 0 to 4. In certain embodiments, each R 3 Independently selected from the group consisting of: F. alkyl, substituted alkyl, CH 2 F and CN.
In certain embodiments, the compound of formula (I) is according to formula (IIn), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
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 IIn, 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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylAn aminoalkylene or substituted heteroarylalkylene, an unsubstituted heterocycloalkylalkylene or a 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; o is an integer from 0 to 4. In certain embodiments, each R 3 Independently selected from the group consisting of: F. alkyl, substituted alkyl, CH 2 F and CN.
In certain embodiments, the compound of formula (I) is according to formula (IIm), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
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 IIo, B 4 Is absent; c (C) 1 、C 2 、C 3 And C 4 One, or both of zero are N, and the remainder are CH or CR 6 ；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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene or 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; o is an integer from 0 to 4. In certain embodiments, each R 3 Independently selected from the group consisting of: F. alkyl, substituted alkyl, CH 2 F and CN.
In certain embodiments, there is provided a compound of formula (XIX) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein L is 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 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; o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of formula (XIX) is selected from compounds 172, 173, 184, 185, 201, and 209 in table 1.
In certain embodiments, there is provided a compound of formula (XX):
wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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, or substituted heteroarylalkylene; 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; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of formula (XX) is selected from compounds 119, 134, 192, 194-19 in Table 1 7. 210, 212, 222, 223, 228, 229, 233, 234, 237, 238, 350, 383, 387-389, 400, 401, 405, 406, 411, 412, 414, 415, 417-420, 426, 439, 443, and 446-448.
In certain embodiments, there is provided a compound of formula (XXI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 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; o is an integer from 0 to 4. In certain embodiments, the compound of formula (XXI) is selected from compounds 127, 281, and 282 in table 1.
In certain embodiments, there is provided a compound of formula (XXII), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 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; o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of formula (XXII) is selected from compounds 147, 167, 191, 213, 225, and 474 in table 1.
In certain embodiments, there is provided a compound of formula (XXIV), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 heterocycloalkylalkylene, or substituted heterocycloalkylalkylene; r is R 5 Selected from the group consisting ofThe group: -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; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 1 and q is 1. In certain embodiments, the compound of formula (XXIV) is selected from compounds 175-177, 180, 181, 193, 211, 218, 219, 226, 236, 244, 245, 273, 289, 293, 298, 392, 399, 402-404, 431, 433 and 440 in table 1.
In certain embodiments, there is provided a compound of formula (XXVIII), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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, substitutedAlkyl, 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; o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, the compound of formula (XXVIII) is compound 235 in table 1.
In certain embodiments, there is provided a compound of formula (XXIX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is 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 orL 2 is-C (H) =; l (L) 1 Selected from the group consisting of: bond, -O-, -CH 2 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0.In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 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 (XXIX) is selected from compounds 360 and 395 in table 1.
In certain embodiments, there is provided a compound of formula (XXXII) 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 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 (XXXII) is selected from compounds 384, 385, 407-410, 422, 423, 429, 436, 437, 438, and 456 and 458 of table 1.
In certain embodiments, there is provided a compound of formula (XXXIII), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; each R 1 Independently selected from the group consisting ofGroup: 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 from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 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 (XXXIII) is selected from compounds 390, 391, 393, 394, 397, and 398 in table 1.
In certain embodiments, there is provided a compound of formula (XXXIV) 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 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 (XXXIV) is compound 396 in table 1.
In certain embodiments, there is provided a compound of formula (XXXV) 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 of which isR 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, each R 3 Independently selected from the group consisting of: F. alkyl, substituted alkyl, CH 2 F and CN. In certain embodiments, the compound of formula (XXXV) is selected from compounds 462 and 466 in table 1. />
In certain embodiments, there is provided a compound of formula (XXXVI) 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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, each R 3 Independently selected from the group consisting of: F. alkyl, substituted alkyl, CH 2 F and CN. In certain embodiments, the compound of formula (XXXVI) is selected from compounds 460, 465, and 468 in table 1.
In certain embodiments, there is provided a compound of formula (XXXVII) 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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, each R 3 Independently selected from the group consisting of: F. alkyl, substituted alkyl, CH 2 F and CN. In certain embodiments, the compound of formula (XXXVII) is selected from compounds 386, 461, 463, and 464 in table 1.
In certain embodiments, there is provided a compound of formula (XXXVIII), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; each R 1 Independently selected from the group consisting ofIs set of (3): 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 from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 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 (XXXVIII) is compound 435 in table 1.
In certain embodiments, there is provided a compound of formula (XLVIII), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -and-O-; l (L) 3 is-CH 2 -; 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 F and methyl; each R 11 Is hydrogen or alkyl; each R 12 Is hydrogen or alkyl; each R 13 Is hydrogen or alkyl; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is-CH 2 -。R 6 Is F. In certain embodiments, the compound of formula (XLVIII) is selected from compounds 351, 444, 445, 449, and 450 in table 1.
In certain embodiments, there is provided a compound of formula (XLIX) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
wherein W is 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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 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; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is-CH 2 -. In certain embodiments, R 6 Is F. In certain embodiments, the compound of formula (XLIX) is selected from compounds 361 and 546 in table 1.
In certain embodiments, there is provided a compound of formula (L), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -and-O-; l (L) 3 is-CH 2 -; 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; r is 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; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and qIs 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is-CH 2 -. In certain embodiments, R 6 Is F. In certain embodiments, the compound of formula (L) is a compound selected from compounds 427 and 428 in table 1.
In certain embodiments, there is provided a compound of formula (LI), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-; l (L) 3 is-CH 2 -; 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; r is 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; n is an integer from 0 to 5; m is an integer from 0 to 4; and o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 1 and q is 0. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 0. In certain embodiments, p is 0 and q is 0. In certain embodiments, L 2 is-CH 2 -. In certain embodiments, R 6 Is F. In certain embodiments, the compound of formula (LI) is a compound selected from compounds 459, 471, 537, 538 and 543 in table 1.
In certain embodiments, there is provided a compound of formula (LII) 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -and-O-; l (L) 3 is-CH 2 -; 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 ofThe 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; r is 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, L 2 is-CH 2 -. In certain embodiments, R 6 Is F. In certain embodiments, the compound of formula (LII) is a compound selected from the group consisting of compounds 467, 470, 539, and 540 in table 1.
In certain embodiments, there is provided a compound of formula (LIII) or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof:
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Wherein L is 1 Selected from the group consisting of: -O-, -CH 2 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -and-O-; l (L) 3 is-CH 2 -; each R 1 Independently selected from the group consisting ofThe group: 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; r is 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, L 2 is-CH 2 -. In certain embodiments, R 6 Is F. In certain embodiments, the compound of formula (LIII) is compound 469 in table 1.
In certain embodiments, there is provided a compound of formula (LIV) 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 -and-OCH 2 -；L 3 is-CH 2 -; 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 、
Tetrazolyl; r is 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, R 6 Is F. In certain embodiments, the compound of formula (LIV) is a compound selected from compounds 522-525, 531, and 532 in Table 1.
In certain embodiments, there is provided a compound of formula (LV), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -and-O-; l (L) 3 is-CH 2 -; 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. In certain embodiments, the compound of formula (LV) is a compound in Table 1Object 542.
In certain embodiments, there is provided a compound of formula (LVI), 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 -and-OCH 2 -；L 2 Selected from the group consisting of: bond, -CH 2 -and-O-; l (L) 3 is-CH 2 -; 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. In certain embodiments, the compound of formula (LVI) is compound 544 in table 1.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture 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) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture 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) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein W is N or CH.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein W is C.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein W is CH.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein W is CR 14 。
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 4 Selected from the group consisting of: 1- (cyanomethyl) -cyclopropan-1-yl-methyl, (1-ethyl-1H-imidazol-5-yl) -methyl, 1- (fluoromethyl) -cyclopropan-1-yl-methyl, isoxazol-5-yl-methyl, oxetan-2-yl-methyl, (2S) -oxetan-2-yl-methyl, oxolane-3-yl-methyl, (3R) ballistically-1-yl-methylOxazol-3-yl-methyl, 1, 3-oxazol-2-yl-methyl and tetrahydrofuran-2-yl-methyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, 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.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 4 Selected from the group consisting of: 1- (cyanomethyl) -cyclopropan-1-yl-methyl, 1- (fluoromethyl) -cyclopropan-1-yl-methyl, isoxazol-5-yl-methyl and tetrahydrofuran-2-yl-methyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture 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 (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture 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 (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 4 Is oxetan-2-yl-methyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or stereoisomer thereofMixtures of constructs wherein R 4 Is (2S) -oxetan-2-yl-methyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl.
In certain embodiments, there is provided a compound of formula (LVI) 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 (LVI) 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 (LVI) 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 provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 5 is-COOH or-COOMe.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 5 is-COOH.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein R 5 Is tetrazolyl.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture 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) - (LVI), 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) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 2 Is a bond, -CH 2 -or-C (H) = -O-.
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 2 is-ch=or-O-.
In certain embodiments, there is provided a compound of formula (LVI) 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 any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 3 is-CH 2 -。
In certain embodiments, there is provided a compound of formula (LIX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 1 is-OCH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 1 is-OCH 2 -; and L is 2 is-CH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 1 is-O-.
In certain embodiments, a formula is providedI) A compound of any one of (LVI) or a pharmaceutically acceptable salt, tautomer, stereoisomer and/or mixture of stereoisomers thereof, wherein L 1 is-CH 2 -。
In certain embodiments, there is provided a compound of any one of formulas (I) - (LVI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, and/or mixture of stereoisomers thereof, wherein L 1 is-OCH 2 -。
In certain embodiments of any of formulas (I) - (LVI), L 1 is-O-; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (LVI), L 1 is-O-; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), L 1 is-O-; l (L) 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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-COOH. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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, for example 1H-1,2,3, 4-tetrazol-5-yl. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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 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) - (LVI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
In certain embodiments of any of formulas (I) - (LVI), L 1 is-OCH 2 -; and L is 2 is-CH 2 -. In certain embodiments of any of formulas (I) - (LVI), L 1 is-OCH 2 -; and L is 2 is-C (H) =. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), L 1 is-OCH 2 -；L 2 is-C (H) =; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LIX), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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. Certain implementations in any of formulas (I) - (LVI)In the scheme, 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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 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) - (LVI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LIX), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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 certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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 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) - (LVI), R 4 Is 1- (cyanomethyl)Yl) -cyclopropyl-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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 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) - (LVI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1 toFluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
In certain embodiments of any of formulas (I) - (LVI), L 1 is-O-; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (LVI), L 1 is-O-; l (L) 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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 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) - (LVI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
In certain embodiments of any of formulas (I) - (LVI), L 1 is-OCH 2 -; and L is 2 is-O-. In certain embodiments of any of formulas (I) - (LVI), L 1 is-OCH 2 -；L 2 is-O-; and L is 3 is-CH 2 -. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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 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) - (LVI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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-oxazole-2-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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. I 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) - (LVI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
In certain embodiments of any of formulas (I) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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) - (LVI), 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, e.g., 1H-1,2,3, 4-tetrazol-5-yl in certain embodiments of any of formulas (I) - (LVI), 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 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) - (LVI), R 4 Is 1- (cyanomethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is 1- (fluoromethyl) -cyclopropan-1-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is isoxazol-5-yl-methyl. In certain embodiments of any of formulas (I) - (LVI), R 4 Is tetrahydrofuran-2-yl-methyl.
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 one of formulas (I) - (LVI), 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 one of formulas (I) - (LVI), which compositions are 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 one of formulas (I) - (LVI).
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; the other elements are replaced by isotopes,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' sPharmaceutical 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 PharmaceuticalExcipients, 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 Hepatol 2002;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-licardsymond syndrome (Down's 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), bovine spongiform Disease (creutb), chronic bovine spongiform Disease, etc. 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 certain embodiments, the compounds described herein are according to the compounds of formulas IIj-IIn shown in scheme G1.
Scheme G1
In some embodiments, the compounds described herein are prepared as outlined in schemes 1-3. The synthesis of compounds in 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 S1 can be prepared as shown in scheme 1. S1b can be prepared from S1a by a Mitsunobu reaction or alkylation of phenol with the mesylate of S1 a. TFA-catalyzed cleavage of the Boc protecting group in S1b will provide azetidine S1c. Alkylation of S1c, followed by hydrolysis, will yield S1.
Scheme 2
Scheme 2. Compounds having formulas S2 and S2' can be prepared as shown in scheme 2. Compound S2c can be prepared from halide S2a and pinacol borane S2b by a Suzuki reaction. The casting reaction with S2c or alkylation of phenol with the mesylate of S2c will provide S2d. TFA-catalyzed cleavage of the Boc protecting group in S2d will provide pyrroline S2e. Alkylation of S2e, followed by hydrolysis, will produce S2. Similarly, compound S2' may be prepared by alkylation followed by hydrolysis of pyrrolidine S2f, which may be obtained by selective hydrogenation of the endocyclic double bond in S2e.
Scheme 3
Scheme 3. The compounds having formula S3 can be prepared as shown in scheme 3. The SNAr reaction or metal catalyzed coupling reaction of S3a and S3b will provide S3c. R is R 4 Hydrolysis of the group will produce acid S3d, which will undergo an amidation reaction to produce ester S3e. Acetic acid mediated imidazole formation produces S3f, which upon hydrolysis will provide S3.
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 JCt., 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, "SyntheticOrganic 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 OrganicChemistry:reactions, mechanisms and Structure", 4 th edition, wiley-Interscience, new York,1992; larock "ComprehensiveOrganic 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 ofFunctional 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:10μMProteo/>250X 21.2mm A, solvent: acetonitrile/water, containing modifiers such as 0.1% trifluoroacetic acid, formic acid or acetic acid). In analytical HPLC (Waters acquisition A ty UPLC class H instrument) the compound purity was checked at a flow rate of 0.5mL/min (Acquity BEH C18, 50 x 2.1mm column).
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.
Preparation of common intermediates:
intermediate Ih. (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (Ih)
Step a. (S) -2- ((benzyloxy) methyl) oxetane (Ia)
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). To the filtrate was added water (20 mL) and extracted with petroleum ether (2X 10 mL). The combined organic layers were treated with saturated NH 4 Cl (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title compound (Ia) (2.5 g, 47%) as a yellow oil. The m/z (ESI) of the film,positive ion) =201.1 [ m+na] + 。
Step B. (S) -oxetan-2-ylmethanol (Ib)
To a solution of Ia (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 crude mixture was filtered through celite and the resulting crude mixture (Ib) in THF was advanced to the next step without any further purification. m/z (ESI, positive ion) =111.1 [ m+na ]] + 。
(S) -oxetan-2-ylmethyl methanesulfonate (Ic)
To a solution of Ib (6 g,68 mmol) in THF (100 mL) at 0deg.C were added methanesulfonic anhydride (17.1 g,102 mmol) and 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 (3X 30 mL). 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 Ic (6 g, 53.1%) as a yellow oil. m/z (ESI, positive ion) =167.1 [ m+h ] ] + 。
Step D. (S) -2- (azidomethyl) oxetane (Id)
To a solution of Ic (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, extracted with EtOAc (3X 20 mL) and treated with H 2 O (10 mL) was washed. The organic layer (I)d) Concentrate and advance to the next step without any further purification. m/z (ESI, positive ion) =114.1 [ M+H ]] + 。
Step E. (S) -oxetan-2-ylmethylamine (Ie)
To a solution of Id (900 mg,7.96 mmol) in THF (30 mL) was added Pd/C (10 mg). The reaction mixture was stirred under hydrogen at 20 ℃ for 2h. After completion, the crude reaction mixture was filtered through celite. The filtrate (Ie) was used in the next step without any purification. m/z (ESI, positive ion) =88.2 [ M+H ]] + 。
Step F. (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester (If)
To a solution of Ie (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 (3X 10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: etoac=1:1) to give the title product (If) (1.2 g, 43.9%) as a yellow solid. m/z (ESI, positive ion) =267.1 [ m+h ] ] + 。
Step G. (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester (Ig)
Pd/C (100 mg) was added to a solution of If (800 mg,7.9 mmol) in THF (8 mL). At 20℃at 50psi H 2 The reaction mixture was stirred for 3h. After completion, willThe crude mixture was filtered through celite, and the filtrate was concentrated to give the title compound (Ig) 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 (Ih)
To a solution of Ig (700 mg,2.96 mmol) in MeCN (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 (Ih) as a yellow solid (0.6 g, 68.9%). m/z (ESI, positive ion) =295.1 [ m+h ]] + 。
Intermediate IIf.2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (IIf)
Step A.1-ethyl-1H-imidazole-5-carboxylic acid ethyl ester (IIa)
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. The residue was purified by silica gel column chromatography (petroleum ether: etoac=5:1) to afford the title product (IIa) as a white solid (850 mg, 25%). m/z (ESI, positive ion) =169.1 [ m+h ]] + 。
Step B.1-ethyl-1H-imidazole-5-carboxamide (IIb)
IIa (3.6 g,21.4 mmol) was reacted in a sealed reactor at 80℃in 7N NH 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 give the title product (IIb) as a white solid (1.9 g, 64%). m/z (ESI, positive ion) =140.1 [ m+h ]] + 。
Step C. (1-ethyl-1H-imidazol-5-yl) methylamine (IIc)
To a solution of IIb (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 (IIc) (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 (IId)
A mixture of IIc (1.4 g,11.1 mmol), methyl 3-fluoro-4-nitrobenzoate (2.4 g,12.2 mmol) and TEA (3.3 g,33.3 mmol) in THF (20 mL) was stirred at 25deg.C 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 Drying and passingFiltered and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography (DCM: meoh=10:1) to give the title product (IId) as a white solid (1.6 g, 47%). m/z (ESI, positive ion) =305.2 [ m+h ]] + 。
Step E.4 methyl amino-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzoate (IIe)
At 25℃at H 2 A mixture of IId (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 (IIe) as a brown solid (1.3 g, 90%). 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 (IIf)
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 (IIf) as a white solid (46.6 mg, 39.0%). m/z (ESI, positive ion) =333.1 [ m+h ]] + 。
Intermediate IIIf.2- (2, 5-difluoro-4-hydroxyphenyl) acetic acid tert-butyl ester (IIIf)
Step A.1-allyl-2, 5-difluoro-4-methoxybenzene (IIIa)
At 110℃under N 2 Next, 1-bromo-2, 5-difluoro-4-methoxybenzene (5 g,22.4 mmol), allyltributyltin (8.9 g,26.8 mmol), pd (PPh 3 ) 4 A solution of (2.59 g,2.2 mmol) in DMF (100 mL) was stirred for 18h. The reaction was poured into water (500 mL) and extracted with EtOAc (150 ml×2). The combined organic layers were concentrated and purified by silica gel column chromatography (EtOAc: petroleum ether=1:15) to afford the title product (IIIa) as a colorless oil (2.63 g, 57.6%). 1 H NMR(400MHz,CDCl 3 )δppm 6.89(dd,J＝11.56,7.04Hz,1H),6.67(dd,J＝10.10,7.14Hz,1H),5.83-5.95(m,1H),5.03-5.12(m,2H),3.85(s,3H),3.31(dd,J＝6.50,1.05Hz,2H)。
Step B.2- (2, 5-difluoro-4-methoxyphenyl) acetic acid (IIIb)
At 0deg.C, to IIIa (2.5 g,13.6 mmol), naIO 4 (11.64 g,54.4 mmol) in CCl 4 /CH 3 CN/H 2 Ruthenium (III) chloride (560 mg,2.7 mmol) was added to the mixture in the mixed solution of O (40 mL/40mL/70 mL). The reaction was stirred at 0deg.C for 2h, poured into water (50 mL) and extracted with DCM (50 mL. Times.2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the impure crude title product (IIIb) (2.2 g) as a dark green solid which was used in the next step without further purification. m/z (ESI, positive ion) =203.1 [ m+h ]] + 。
Step C.2- (2, 5-difluoro-4-hydroxyphenyl) acetic acid (IIIc)
BBr was added to a stirred solution of crude IIIb (650 mg,3.2 mmol) in DCM (6 mL) at 0deg.C 3 (1.5 mL). The reaction was stirred at 25 ℃ for 2h, poured into ice water, and extracted with EtOAc (50 ml×3). The combined organic layers were concentrated and purified by reverse phase HPLC (32% ch 3 OH/H 2 O) to afford the title product (IIIc) (447mg, 65%) as a grey solid. m/z (ESI, positive ion) =189.1 [ M+H ]] + 。
Step D.2- (4-acetoxy-2, 5-difluorophenyl) acetic acid (IIId)
To IIIc (50 mg,0.26 mmol) and Ac 2 O (54 mg,0.53 mmol) in DCM (3.0 mL) was added a drop of concentrated H 2 SO 4 . The resulting clear solution was stirred at 25 ℃ for 1.5h, poured into water (5 mL) and extracted with EtOAc (15 ml×2). The combined organic layers were concentrated in vacuo and purified by reverse phase HPLC (37% ch 3 OH/H 2 O) to afford the title product (IIId) as a white solid (37 mg, 54%). m/z (ESI, positive ion) =253.0 [ m+na ]] + 。
Step E.2- (4-acetoxy-2, 5-difluorophenyl) acetic acid tert-butyl ester (IIIe)
IIId (100 mg,0.43 mmol), boc at 50deg.C 2 A solution of O (190 mg,0.87 mmol) and DMAP (11 mg,0.09 mmol) in t-BuOH (5 mL) was stirred for 1h. The reaction was concentrated and purified by silica gel column chromatography (EtOAc/petroleum ether=1:10) to afford the title product (IIIe) as a colorless oil (69 mg, 50%). m/z (ESI, positive ion) =309.0 [ m+na ]] + 。
Step F.2- (2, 5-difluoro-4-hydroxyphenyl) acetic acid tert-butyl ester (IIIf)
IIIe (380 mg,1.33 mmol) and K at 25℃C 2 CO 3 (275 mg,2mmol,1.5 eq.) in CH 3 The mixture in OH (5 mL) was stirred for 0.5h. The reaction was poured into water (25 mL) and extracted with EtOAc (15 mL. Times.3). The combined organic layers were concentrated and purified by reverse phase HPLC (37% ch 3 CN/H 2 O, with 0.5% tfa as modifier) to afford the title product (IIIf) as a white solid (320 mg, 88%). m/z (ESI, positive ion) =267.0 [ m+na ]] + 。 1 H NMR(400MHz,DMSO-d6)δppm 10.27(s,1H),7.12(dd,J＝11.50,7.19Hz,1H),6.74(dd,J＝10.80,7.44Hz,1H),3.47(s,2H),1.39(s,9H)。
Example 119.1- (((S) -oxetan-2-yl) methyl) -2- ((3- (3-phenoxyphenyl) pyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (119)
Step A.1- (((S) -oxetan-2-yl) methyl) -2- ((3- (3-phenoxyphenyl) pyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (119 a)
A solution of 3- (3-phenoxyphenyl) pyrrolidine (20 mg,0.084 mmol), ih (19.7 mg,0.084 mmol) and DIPEA (0.029 mL,0.17 mmol) in DCM (0.84 mL) was heated to 40℃overnight. The crude product was purified directly by silica gel column chromatography (gradient elution, 0-100% etoac/hexanes) to afford the title product (119 a) (32 mg, 77%). m/z (ESI, positive ion) =498.1 [ m+h ]] + 。
Step B.1- (((S) -oxetan-2-yl) methyl) -2- ((3- (3-phenoxyphenyl) pyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (119)
To 119a (30 mg,0.06 mmol) in THF/H 2 To a solution in O (0.6 mL, 2:1) was added LiOH (2.5 mg,0.06 mmol) and stirred for 2h. The reaction was neutralized with 1N HCl and extracted with EtOAc. The organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 0-10% meoh/DCM) to afford the title product (119) as a white solid (17 mg, 58%). m/z (ESI, positive ion) =484.3 [ M+H ]] + 。
EXAMPLE 127 (S) -2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (127)
Step A.4- ((3- (methoxycarbonyl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (127 a)
Methyl 1H-pyrazole-3-carboxylate (1.26 g,10.0 mmol), tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (2.7 g,10.0 mmol) and Cs at 60℃C 2 CO 3 (9.78 g,30.0 mmol) in CH 3 The solution in CN (50 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). Using H for the organic layer 2 O (30 mL), brine (30 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a crude residue which was purified by reverse phase HPLC (CH 3 CN/H 2 O, with 0.1% formic acid as modifier) to afford the title product (127 a) (1.60 g, 49%) as a white solid. m/z (ESI, positive ion) =346.1 [ m+na ]] + 。
Step B.4- ((3- (hydroxymethyl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (127 b)
To a solution of 127a (1.60 g,4.9 mmol) in 20mL dry THF was added DIBAL-H solution (1N in hexane, 14.7mL,14.7 mmol) at 0deg.C. At 15℃under N 2 The reaction was stirred for 2h. After completion, the reaction was taken up in 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 (127 b) (970 mg, 67%) as a colorless oil. m/z (ESI, positive ion) =296.2 [ m+h ]] + 。
Step C.4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (127 c)
At 0deg.C, 127b (310 mg,1.1 mmol), 2, 4-dichlorophenol (187 mg,1.2 mmol) and PPh 3 (303 mg,1.2 mmol) to a solution of DEAD (201 mg,1.2 mmol) in THF (10 mL) was added. At 15℃under N 2 The reaction was stirred for 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 (30 mL), 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=10:1) to afford the title product (127 c) as a colorless oil (81 mg, 17%). m/z (ESI, positive ion) =462.0 [ m+na ]] + 。
Step D.4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidine (127 d)
To a solution of 127c (81 mg,0.18 mmol) in DCM (10 mL) was added 2, 6-lutidine (433 mg,3.7 mmo) at 0deg.Cl) and TMSOTF (400 mg,1.8 mmol). After stirring at 0℃for 1h, NH was used for the reaction 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 in vacuo to afford the crude title product (127 d) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =340.1 [ m+h ] ] + 。
Step E. (S) -2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (127 e)
At 10℃to 127D (crude product from step D, 0.18 mmol) and K 2 CO 3 To a mixture of (75 mg,0.54 mmol) in DMF (5 mL) was added Ih (53 mg,0.18 mmol). After stirring at the same temperature for 16H, reaction H was taken up 2 O (5 mL) was diluted 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 in vacuo to give a crude residue which was purified by silica gel column chromatography (DCM/meoh=50:1) to afford the title product (127 e) as a white solid (61 mg, 57%). m/z (ESI, positive ion) =598.1 [ m+h ]] + 。
Step F. (S) -2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (127)
127e (61 mg,0.1 mmol) in THF (3 ml) and H 2 Lithium hydroxide (24 mg,1.0 mmol) was added to the mixture in O (1 mL) and stirred at 30deg.C for 5h. After completion, 1N HCl was added to the reaction to adjust to ph=7. The solvent was removed under reduced pressure and the residue was taken up by reverse phase HPLC(CH 3 CN/H 2 O, with 0.1% tfa as modifier) to afford the title product (127) (23.2 mg, 39%) as a white solid. m/z (ESI, positive ion) =584.2 [ m+h] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.28-8.41(m,1H),7.97-8.11(m,1H),7.79(d,J＝8.56Hz,1H),7.63(d,J＝2.20Hz,1H),7.38(dd,J＝2.32,1.10Hz,1H),7.13-7.28(m,2H),6.42(d,J＝1.96Hz,1H),5.16-5.26(m,1H),5.14(s,2H),4.79(d,J＝3.42Hz,2H),4.70-4.76(m,1H),4.58-4.70(m,2H),4.39(dt,J＝9.11,5.96Hz,1H),4.14(d,J＝6.85Hz,2H),3.78(br d,J＝10.03Hz,2H),3.14-3.29(m,2H),2.68-2.87(m,1H),2.41-2.56(m,1H),2.15-2.32(m,1H),1.74-1.93(m,2H),1.49-1.68(m,2H)。
Example 134.1- ((1-Ethyl-1H-imidazol-5-yl) methyl) -2- ((3-phenoxypyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (134)
Step A.1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- ((3- (3-phenoxyphenyl) pyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (134 a)
3- (3-phenoxyphenyl) pyrrolidine (4 mg,0.017 mmol), IIf (4.6 mg,0.014 mmol) and Et at room temperature 3 A solution of N (14 mg,0.14 mmol) in DMF (1 mL) was stirred for 20h. 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 compound (134 a) (8.2 mg) as a white solid with some impurities, which was used in the next step without further purification. m/z (ESI, positive ion) =536.4 [ M+H ]] + 。
Step B.1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- ((3- (3-phenoxyphenyl) pyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (134)
A solution of 134a (8.2 mg, crude) in THF (0.5 mL) was treated with 2N NaOH (0.5 mL) and MeOH (4 drops). The resulting mixture was stirred at room temperature for 20h. After completion, the reaction was purified by reverse phase HPLC (gradient elution, 0-60% CH 3 CN/water with 0.1% tfa as modifier) to afford the title product (134) (3.7 mg,41%,2 steps, rac) as a white solid. 1 H NMR(600MHz,CD 3 OD) δppm 8.99 (s, 1H), 8.24 (br d, j=0.73 hz, 1H), 8.04-8.07 (m, 1H), 7.83 (d, j=8.44 hz, 1H), 7.33-7.39 (m, 3H), 7.08-7.15 (m, 3H), 7.03 (br t, j=2.02 hz, 1H), 6.96-7.00 (m, 2H), 6.88-6.92 (m, 1H), 5.81 (s, 2H), 4.31 (q, j=7.34 hz, 2H), 3.92-4.01 (m, 2H), 3.65-3.75 (m, 3H), 2.53-2.60 (m, 2H), 2.21-2.29 (m, 2H), 1.53 (t, j=7.34 hz, 3H) m/z (ESI, positive (n+3H) =3.522+m] + 。
Example 147.2- ((3- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) methyl) azetidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (147)
Step A.5- ((1- (tert-butoxycarbonyl) azetidin-3-ylidene) methyl) oxazole-2-carboxylic acid methyl ester (147 a)
To a solution of 5- ((bromotriphenyl- λ5-phosphanyl) methyl) oxazole-2-carboxylic acid methyl ester (211 mg,0.44 mmol) at 0 ℃ prepared by heating triphenylphosphine together with 5- (bromomethyl) -1, 3-oxazole-2-carboxylic acid methyl ester in toluene at 90 ℃ for 24h and decanting the solvent and drying the solid residue on a high vacuum pump) in anhydrous DMF (2.2 mL) was added NaH (19 mg,0.47mmol,60% in mineral oil. After stirring for 10min A solution of tert-butyl 3-oxo-azetidine-1-carboxylate (50 mg,0.29 mmol) in DMF (1.5 mL) was added dropwise and the reaction allowed to warm to room temperature. After 16h, the reaction was quenched with saturated NH 4 Cl was quenched and extracted with EtOAc (5 mL. Times.2). Using H for the organic layer 2 O (5 mL), brine (5 mL), and Na 2 SO 4 Dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (gradient elution, 0-90% etoac/hexanes) to afford the title product (147 a) (48 mg, 56%). m/z (ESI, positive ion) =239.3 [ M-tBu+H ]] + 。
Step B.5- ((1- (tert-Butoxycarbonyl) azetidin-3-yl) methyl) oxazole-2-carboxylic acid methyl ester (147 b)
10% Pd/C (8 mg,0.008 mmol) was added to 147a (45 mg,0.15 mmol) in EtOH (1.5 mL) at room temperature. The mixture was degassed with hydrogen for 10min, followed by H 2 Stirring under a balloon for 4h. The reaction was filtered through a pad of celite, rinsed with EtOAc and concentrated to provide the title product (147 b) (42 mg), which was used in the next step without further purification. m/z (ESI, positive ion) =241.1 [ M-tBu+H ]] + 。
Step C.3- ((2- (hydroxymethyl) oxazol-5-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (147 c)
To a solution of crude 147b (42 mg) in absolute EtOH (1.4 mL) at 0deg.C was added NaBH 4 (16 mg,0.43 mmol) and CaCl 2 (47 mg,0.43 mmol). The reaction was then stirred at room temperature for 4h, quenched with dropwise addition of 1N HCl (1 mL), and extracted with EtOAc (5 mL. Times.3). Using H for the organic layer 2 O (5 mL), brine (5 mL), washed with Na 2 SO 4 Drying, filtration, concentration and purification of the crude residue by silica gel column chromatography (gradient elution, 0-15% MeOH/DCM) to afford the title compoundProduct (147 c) (32 mg,84%,2 steps). m/z (ESI, positive ion) =291.1 [ m+na ]] + 。
Step D.3- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (147 d)
DIAD (41 mg,0.20 mmol), PPh at 0deg.C 3 (53 mg,0.20 mmol) and 2, 4-dichlorophenol (22 mg,0.14 mmol) were added to 147c (30 mg,0.11 mmol) in dry THF (1.1 mL). The reaction was warmed to room temperature. After 3H, add H 2 O (3 mL) and the reaction was extracted with EtOAc (3 mL. Times.3). The organic layer was washed with brine (3 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, 0-90% etoac/hexanes) to afford the title product (147 d) (12 mg, 21%). m/z (ESI, positive ion) =436.0 [ M+Na ]] + 。
Step E.5- (azetidin-3-ylmethyl) -2- ((2, 4-dichlorophenoxy) methyl) oxazole (147 e
To a solution of 147d (11 mg,0.027 mmol) in DCM (0.6 mL) was added TFA (0.051 mL). After stirring at room temperature for 5h, the reaction was concentrated, redissolved in EtOAc and treated with saturated NaHCO 3 And (5) washing. The aqueous layer was extracted with EtOAc (×2) and the combined organic layers were dried, filtered and concentrated to afford the crude title product (147 e) (8.3 mg), which was used in the next step without further purification.
Step E.2- ((3- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) methyl) azetidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (147)
The title product (147) was synthesized from crude 147e in analogy to the procedure described in steps a and B of example 119. m/z (ESI, positive ion) =595.1 [ m+h ]] + 。 1 H NMR(600MHz,MeOD)δppm 9.07(d,J＝1.10Hz,1H),8.24(d,J＝0.73Hz,1H),8.05(dd,J＝8.44,1.47Hz,1H),7.82(d,J＝8.44Hz,1H),7.40(d,J＝2.20Hz,1H),7.28(dd,J＝8.80,2.57Hz,1H),7.20(d,J＝8.80Hz,1H),7.13(d,J＝1.47Hz,1H),6.98(s,1H),5.78(s,2H),5.22(s,2H),4.91(s,2H),4.47-4.57(m,2H),4.21-4.36(m,4H),3.33-3.37(m,1H),3.17-3.24(m,2H),1.53(t,J＝7.34Hz,3H)。
Examples 167 and 191 were synthesized in a similar procedure to that described in example 147.
Example 225 was synthesized from 147a following a procedure similar to that described in example 127, step B (toluene as solvent), followed by procedures similar to those described in example 147, steps D and E.
Example 173.2- ((4- ((2- (5-chloropyridin-2-yl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (173)
Step A.2- (4-bromo-2-methylbenzo [ d ] [1,3] dioxol-2-yl) -5-chloropyridine (173 a)
A mixture of 5-chloro-2-ethynylpyridine (0.18 g,1.31 mmol), 3-bromobenzene-1, 2-diol (0.25 g,1.31 mmol) and triruthenium dodecacarbonyl (0.017 g,0.026 mmol) in toluene (2.6 mL) was degassed with argon for one minute. The resulting mixture was stirred at 100 ℃ overnight. After completion, the reaction mixture was diluted with EtOAc (5 mL) and filtered through a celite pad. The filtrate was concentrated and purified by silica gel column chromatography (gradient elution, 0-10% etoac/hexanes) to afford the title as a pale yellow oilThe title product (173 a) (0.25 g, 59%). m/z (ESI, positive ion) =326.1 [ m+h ]] + 。
Step B.4- ((2- (5-chloropyridin-2-yl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (173 b)
Pure 1-N-Boc-4-methylenepiperidine (0.17 mL,0.85 mmol) was degassed with argon for one minute followed by the addition of 9-BBN in THF (1.7 mL,0.85 mmol). The reaction was stirred at 70 ℃ for one hour. It was then cooled to room temperature and transferred to 173a (0.25 g,0.76 mmol), pd (dppf) Cl 2 (0.017 g,0.023 mmol) and K 2 CO 3 (0.14 g,1.01 mmol) in DMF (1.76 mL) and water (0.18 mL). The resulting mixture was further degassed with argon for one minute and then stirred overnight at 60 ℃. After completion, the reaction mixture was poured into water (5 mL) and adjusted to ph=11 with 1N NaOH. It was then diluted with EtOAc (10 mL). The organic layer was washed with water (5 mL), 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, 0-30% etoac/hexanes) to afford the title product (173 b) (0.19 g, 56%) as a colorless oil. m/z (ESI, positive ion) =445.4 [ m+h ]] + 。
Step C.5-chloro-2- (2-methyl-4- (piperidin-4-ylmethyl) benzo [ d ] [1,3] dioxol-2-yl) pyridine (173 c)
A solution of 173b (192 mg,0.43 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at room temperature for 10min. The reaction was concentrated to remove volatiles and 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 give the crude title product (173 c) (159 mg) as a yellow oil, which was not further purifiedThe process is used in the next step. m/z (ESI, positive ion) =345.3 [ m+h ]] + 。
Step D.2- ((4- ((2- (5-chloropyridin-2-yl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (173 d)
A solution of 173c (9.8 mg,0.028 mmol), ih (8.8 mg,0.030 mmol) and DIPEA (0.099 mL,0.57 mmol) in DMF (0.5 mL) was stirred overnight at room temperature. 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 to give a crude residue which was purified by silica gel column chromatography (gradient elution, 80-100% etoac/hexanes, then 0-20% meoh/DCM) to afford the title product (173 d) as a colorless oil (6 mg, 35%). m/z (ESI, positive ion) =603.3 [ m+h ]] + 。
Step E.2- ((4- ((2- (5-chloropyridin-2-yl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (173)
173d (6 mg, 0.010mmol) and LiOH (2.1 mg,0.05 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 with water to 1mL and purified by reverse phase HPLC (gradient elution, 30-70% CH 3 CN/H 2 O, with 0.1% tfa as modifier) to afford the title product (173) (6.9 mg, 99%) as a white solid. m/z (ESI, positive ion) =589.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 8.60(br t,J＝2.4Hz,1H),8.33(br d,J＝1.10Hz,1H),8.04(dd,J＝8.4,1.5Hz,1H),7.88(dd,J＝8.44Hz,1H),7.81(d,J＝8.4Hz,1H),7.65-7.68(m,1H),6.81(t,J＝1.0Hz,1H),6.76(d,J＝1.0Hz,1H),6.69(br d,J＝7.7Hz,1H),5.17-5.23(m,1H),4.55-4.80(m,5H),4.34-4.41(m,1H),3.67-3.78(m,2H),3.10-3.25(m,2H),2.75-2.84(m,1H),2.65(br d,J＝6.6Hz,2H),2.48(ddd,J＝16.9,11.4,7.3Hz,1H),2.02(s,3H),1.80-2.01(m,3H),1.46-1.64(m,2H)。
Examples 172, 184 and 185 were synthesized in a similar procedure to that described in example 173.
EXAMPLE 177 (S) -2- ((3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (177)
Step A.4-bromo-2- ((2, 4-dichlorophenoxy) methyl) pyridine (177 a)
DIAD (5.00 g,24.7 mmol), PPh at 0deg.C 3 (6.49 g,24.7 mmol) and 2, 4-dichlorophenol (2.69 g,16.5 mmol) were added to (4-bromopyridin-2-yl) methanol (3.10 g,16.5 mmol) in anhydrous THF (33 mL). After 1H, H is added 2 O (30 mL) and the reaction was extracted with EtOAc (20 mL. Times.3). The organic layer was washed with brine (15 mL) and was washed with Na 2 SO 4 Dried, filtered, and concentrated to give a crude residue, which was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc/hexanes) and further purified by recrystallization from EtOAc and hexanes to afford the title product (177 a) (4.65 g, 85%). m/z (ESI, positive ion) =334.0 [ M+H ]] + 。
Step B.3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methylene) azetidine-1-carboxylic acid tert-butyl ester (177 b)
To 177a (1.2 g,3.60 mmol) in dry CH at room temperature 3 Pd (OAc) was added to a solution of CN (36 mL) 2 (162 mg,0.72 mmol), triorthophenylphosphine (439 mg,1.44 mmol), t-butyl 3-methyleneazetidine-1-carboxylate (732 mg,4.32 mmol) and iPr 2 NEt (1.88 ml,1.40g,10.80 mmol). The mixture was purged with argon for 15min and heated to 110 ℃. After 16h, the reaction was cooled to room temperature and saturated NaHCO was added 3 (30 mL) and extracted with EtOAc (20 mL. Times.3). The organic layer was washed with brine, 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, 0-40% etoac/hexanes) to afford the title product (177 b) as a yellow solid (450 mg, 30%). m/z (ESI, positive ion) =421.4 [ m+h ]] + 。
Step C.3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (177 c)
PtO was performed at room temperature 2 (1.4 mg, 0.006mmol) was added to 177b (50 mg,0.12 mmol) in EtOAc (0.6 mL). The mixture was degassed with hydrogen for 10min, followed by H 2 Stirring under a balloon for 16h. The reaction was filtered through a celite pad, rinsed with EtOAc and concentrated to provide the crude title product (177 c) (55 mg), which was used in the next step without further purification. m/z (ESI, positive ion) =423.3 [ M+H ]] + 。
Step d. (S) -2- ((3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) methyl) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (177)
The title product (177) was synthesized from 177C in a similar procedure as described in steps C to E of example 173. 1 H NMR (600 mhz, meod) δppm 8.53 (d, j=5.14 hz, 1H), 8.30 (d, j=1.10 hz, 1H), 8.00-8.04 (m, 1H), 7.75 (d, j=8.07 hz, 1H), 7.58 (s, 1H), 7.42 (d, j=2.57 hz, 1H), 7.34 (dd, j=5.14, 1.47hz, 1H), 7.27 (dd, j=8.80, 2.57hz, 1H), 7.13 (d, j=8.80 hz, 1H), 5.27 (s, 2H), 5.17 (qd, j=7.09, 2.57hz, 1H), 4.91-5.01 (m, 2H), 4.61-4.68 (m, 2H), 4.52-4.59 (m, 1H), 4.41-4.50 (dd, j=5.14, 1H), 7.13 (d, j=8.80, 2.57hz, 1H), 7.13 (d, j=8.80 hz, 1H), 5.27 (s, 2H), 5.17 (qd, j=7.09, 2.57hz, 1H), 4.91-5.01 (m, 2H), 4.61-4.68 (m, 2H), 4.52-4.59 (m, 1H), 4.41-4.50 (d, 2.37 hz), 4.37 (d, 1H), 4.37, 3.37 hz, 1H), 3.37 (d, 1H). m/z (ESI, positive ion) =567.3 [ m+h ] ] +
Example compounds 175, 176, 180, 181 and 190 were synthesized in a similar procedure to that described in example 177.
Example 226 was synthesized in analogy to the procedure described for example 177, without a hydrogenation step.
EXAMPLE 192 (S) -2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (192)
Step A.3- (tosyloxy) azetidine-1-carboxylic acid tert-butyl ester (192 a)
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.99 g,11.5 mmol) in DMF (5 mL) was stirred at 0deg.C for 10min. 4-Methylbenzenesulfonyl chloride (2.41 g,12.6 mmol) and Et were added at 0deg.C 3 N (11.2 g,34.5 mmol). The resulting mixture was warmed to room temperature and stirred for 16h. After completion, the reaction solution was concentrated to remove the solvent. Adding H 2 O (10 mL) and the reaction was extracted with EtOAc (20 mL. Times.3). The organic layer was dried, filtered and concentrated to afford the title product (192 a) (2.5 g, 63%) as a yellow oil, which was used in the next step without further purification. m/z (ESI, positive ion) =330.2 [ m+h ]] + 。
Step B.3- (3- (methoxycarbonyl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester (192 b)
192a (2.5 g,7.6 mmol), methyl 3-hydroxybenzoate (1.16 g,7.6 mmol) and Cs were combined at 80℃C 2 CO 3 A solution of (7.43 g,22.8 mmol) in DMF (5 mL) was stirred for 3h. 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 give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=10:1) to afford the title product (192 b) as a yellow oil (1.20 g, 49.9%). m/z (ESI, positive ion) =330.1 [ m+na ]] + 。
Step C.3- (3- (hydroxymethyl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester (192 c)
To a solution of 192b (600 mg,1.9 mmol) in THF (5 mL) was added LiAlH 4 (36.92 mg,0.97 mmol). The mixture was stirred at 20℃for 1h. After completion, the reaction was completed with H 2 O (2 mL) was quenched and extracted with EtOAc (5 mL. Times.3). The organic layer was dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=5:1) to afford the title product (192 c) as a white solid (460 mg, 84.3%). m/z (ESI, positive ion) =302.2 [ m+na ]] + 。
Step D.3- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester (192 d)
At 20℃under N 2 Next, 2, 4-dichlorophenol (122 mg,0.75 mmol), 192c (210 mg,0.75mmol)、PPh 3 A solution of (295 mg,1.12 mmol) and DEAD (195 mg,1.12 mmol) in dry THF (5 mL) was stirred for 16h. After completion, the reaction was completed with H 2 O (2 mL) was diluted and extracted with EtOAc (5 mL. Times.3). The organic layer was dried, filtered and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether: etoac=5:1) to afford the title product (192 d) as a white solid (148 mg, 45.5%). m/z (ESI, positive ion) =446.0 [ M+Na ]] + 。
Step E. (S) -2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (192)
The title product (192) was synthesized from 192D in a similar procedure as described in step D of example 177. m/z (ESI, positive ion) =568.3 [ m+h ]] + 。
Example 194 was synthesized in a similar procedure as described in example 192.
Examples 210 and 212 were synthesized in a similar procedure as described in example 192.
EXAMPLE 193 (S) -2- ((3- ((2- ((4-chloro-2-cyanophenoxy) methyl) pyridin-4-yl) oxy) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid
Step A.3- ((methylsulfonyl) oxy) azetidine-1-carboxylic acid tert-butyl ester (193 a)
To a mixture of tert-butyl (3-hydroxyazetidin-1-yl) carboxylate (2.0 g,11.5 mmol), DIPEA (3.8 mL,23 mmol) in DCM (10 mL) at 0deg.C was added methanesulfonic anhydride(3.0 g,17.2 mmol) in DCM (5 mL). The mixture was stirred at 0 ℃ for 1.5h, then 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 (193 a) (2.9 g, 89%) as a colorless oil. 1 H NMR(400MHz,CDCl 3 )δppm 5.20(s,1H),4.27(ddd,J＝10.3,6.7,1.1Hz,2H),4.10(ddd,J＝10.3,4.2,1.2Hz,2H),3.06(s,3H),1.44(d,J＝2.4Hz,9H)。
Step B.4- ((1- (tert-Butoxycarbonyl) azetidin-3-yl) oxy) picolinic acid (193 b)
193a (1.38 g,5.48 mmol), methyl 4-hydroxypyridine-2-carboxylate (0.7 g,4.57 mmol), cs at 80deg.C 2 CO 3 A mixture of (2.23 g,6.86 mmol) and potassium iodide (151 mg,0.91 mmol) in DMF (10 mL) was heated for 12h. The mixture was cooled to 18 ℃ and poured into water (10 mL) and adjusted to ph=7 with concentrated hydrochloric acid. The resulting mixture was purified by reverse phase HPLC (41% CH) 3 CN/H 2 O with 0.5% tfa as modifier) to afford the impure title product (193 b) as a white solid (480 mg). m/z (ESI, positive ion) =295.1 [ m+h ]] + 。
Step C.3- ((2- (hydroxymethyl) pyridin-4-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester (193 c)
To a mixture of 193b (430 mg,1.45 mmol) in THF (10 mL) at 0deg.C was added BH 3 -Me 2 S (4.7 mL,9.5mmol,2N in THF). The reaction was heated at 40℃for 2h and CH was used 3 OH (15 mL) quenching. The resulting mixture was stirred at 70℃for a further 30min. LCMS showed some product still with BH 3 Complexing. The mixture was concentrated in vacuo to give the crude title product (193 c), which was used in the next step without further purification. m/z (ESI, positive ion) =281.3 [ m+h ]] + 。
Step D.3- ((2- ((4-chloro-2-cyanophenoxy) methyl) pyridin-4-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester (193 d)
At 0℃under N 2 Next, crude 193c (430 mg,1.63 mmol), 5-chloro-2-hydroxybenzonitrile (251 mg,1.63 mmol), PPh 3 (557 mg,2.12 mmol) to a mixture of THF (15 mL) was added DEAD (370 mg,1.12 mmol). The reaction was warmed to room temperature and stirred for 18h, poured into water (20 mL) and extracted with EtOAc (15 ml×3). Using H for the organic layer 2 O (10 mL), brine (10 mL), dried and concentrated in vacuo to give a crude residue which was subjected to reverse phase HPLC (69% CH) 3 CN/H 2 O with 0.05% tfa as modifier) to afford the title product (193 d) as a white solid (35 mg). MS (ESI, positive ion) M/z 416.2 (M+1).
Step E. (S) -2- ((3- ((2- ((4-chloro-2-cyanophenoxy) methyl) pyridin-4-yl) oxy) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (193)
The title product (193) was synthesized from 193D in a similar procedure as described in step D of example 177. m/z (ESI, positive ion) =560.3 [ m+h ]] + 。
Examples 211 and 218 were synthesized in a similar procedure to that described in example 193.
Example 197.2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) benzyl) azetidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (197)
Step A.1- ((3-bromophenylmethyl) oxy) -2, 4-dichlorobenzene (197 a)
2, 4-dichlorophenol (410 mg,2.5 mmol), 1-bromo-3- (bromomethyl) benzene (629 mg,2.5 mmol) and K at room temperature 2 CO 3 A mixture of (695 mg,5.0 mmol) in DMF (8 mL) was stirred for 0.5h. After completion, the reaction was quenched with water (25 mL) and extracted with ethyl acetate (15 ml×3). The combined organic phases were washed with brine (40 mL), dried over 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 (197 a) (692 mg, 41%). m/z (ESI, positive ion) =334.2 [ M+H ]] + 。
Step B.3- (3- ((2, 4-dichlorophenoxy) methyl) benzylidene) azetidine-1-carboxylic acid tert-butyl ester. (197b)
Pd was added at 85 DEG C 2 (dba) 3 (169 mg,0.2 mmol) and BINAP (260 mg,0.4 mmol) in CH 3 A solution in CN (3 mL) was heated for 5min and then transferred to 197a (692 mg,2.1 mmol), 3-methyleneazetidine-1-carboxylic acid tert-butyl ester (3838 mg,2.3 mmol) and Cs 2 CO 3 (1.36 g,4.2 mmol) in CH 3 In a mixture in CN (18 mL). The mixture was degassed with argon and stirred under argon at 85 ℃ 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 (197 b) as a dark brown oil (265 mg, 30%). m/z (ESI, positive ion) =442.2 [ m+na ]] + 。
Step C.3- (3- ((2, 4-dichlorophenoxy) methyl) benzyl) azetidine-1-carboxylic acid tert-butyl ester (197 c)
PtO is to 2 (7.6 mg,0.3 mmol) was suspended in a solution of 197b (20 mg,0.05 mmol) in ethyl acetate (2 mL). The mixture was degassed with hydrogen and stirred under a balloon of hydrogen at room temperature for 1h. After completion, the reaction was filtered and the filtrate was concentrated and purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (197 c) (11 mg, 56%) as a colorless oil. m/z (ESI, positive ion) =444.2 [ m+na ]] + 。
Step D.3- (3- ((2, 4-dichlorophenoxy) methyl) benzyl) azetidine (197 d)
A solution of 197c (11 mg,0.03 mmol) in DCM (2 mL) was treated with TFA (1 mL) at room temperature for 10min. After completion, the solvent was removed in vacuo and the resulting crude product 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 (197 d) as a white solid (9.1 mg, 80%). m/z (ESI, positive ion) =322.2 [ m+h ]] + 。
Step E.2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) benzyl) azetidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (197 e)
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A solution of 197d (9.1 mg,0.02 mmol), 57f (7.6 mg,0.023 mmol) and triethylamine (42 mg,0.42 mmol) in DMF (1 mL) was stirred at room temperature for 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 (197 e) (8.2 mg, 54%). m/z (ESI, positive ion) =618.3 [ m+h ]] + 。
Step F.2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) benzyl) azetidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (197)
197e (8.2 mg,0.01 mmol) 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, 0-75% CH 3 CN/water with 0.1% formic acid as modifier) to afford the title product (197) as a white solid (5.3 mg, 66%). 1 H NMR(600MHz,CD 3 OD) delta ppm 8.16 (br d, j=0.73 hz, 1H), 7.98 (dd, j=8.44, 1.47hz, 1H), 7.79-7.83 (m, 1H), 7.71 (d, j=8.44 hz, 1H), 7.34 (d, j=2.57 hz, 1H), 7.25-7.33 (m, 3H), 7.20 (dd, j=8.80, 2.57hz, 1H), 7.12-7.15 (m, 1H), 7.07 (d, j=8.80 hz, 1H), 6.69-6.72 (m, 1H), 5.68 (s, 2H), 5.15 (s, 2H), 4.12 (s, 2H), 4.05 (q, j=7.34 hz, 2H), 3.65 (br t, j=7.34 hz, 2H), 3.32-3.38 (m, 1H), 7.89-2.80 hz, 1H), 6.69-6.72 (m, 1H), 5.68 (s, 2H), 5.15 (s, 2H). m/z (ESI, positive ion) =604.3 [ m+h ]] + 。
Example compounds 195 and 196 were synthesized in a similar procedure to that described in example 197.
Example 201.2- ((4- ((2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (201)
Step A.4-chloro-1- (1, 1-dimethoxyethyl) -2-fluorobenzene (201 a)
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To a solution of 1- (4-chloro-2-fluorophenyl) ethanone (25 g,0.145 mol) and trimethoxymethane (46 g,0.435 mol) in MeOH (150 mL) was added TsOH (249 mg, 1.4)5 mmol). The mixture was stirred at 45℃for 2h. It was then diluted with EtOAc (500 mL) and washed with brine (500 mL. Times.3). The organic layer was taken up with Na 2 SO 4 Dried, filtered and concentrated to give the crude title product (201 a) (30 g) as a colorless oil.
Step B.4-bromo-2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxol (201 b)
To a solution of 201a (28 g,0.128 mol) and 3-bromobenzene-1, 2-diol (24.2 g,0.128 mol) in toluene (200 mL) was added TsOH (44 mg,0.256 mmol). The mixture was stirred at 80℃for 2h. It was then evaporated to dryness and the crude residue was purified by silica gel column chromatography (petroleum ether) to give the title product (201 b, racemic mixture) (12.2 g, 27.7%) as a brown solid. 1 H NMR(400MHz,CDCl 3 )δppm 7.54(t,J＝8.4Hz,1H),7.11-7.17(m,2H),6.95(dd,J＝8.0,1.4Hz,1H),6.67-6.77(m,2H),2.11(d,J＝1.0Hz,3H)。
Step C.4- ((2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (201 c)
The title product (201 c) was synthesized from 201B in a similar procedure as described in example 173, step B. m/z (ESI, positive ion) =484.1 [ M+Na ]] + 。
Step D.4- ((2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidine (201 d)
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To a solution of 201c (350 mg,0.76 mmol) and 2, 6-lutidine (823mg, 7.60 mmol) in DCM (10 ml) was added TMSOTF (843 mg,3.8 mmol). At 0 DEG CThe reaction was stirred for 2h and washed with brine (10 mL. Times.3). The DCM layer was dried, filtered, and concentrated to provide the crude title product (201 d) (275 mg) as a colorless oil. m/z (ESI, positive ion) =362.1 [ m+h ] ] + 。
Step E.2- ((4- ((2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (201 e)
To a solution of 201d (55 mg,0.15 mmol) and Ih (45 mg,0.15 mmol) in DMF (3 mL) was added K 2 CO 3 (41 mg,0.30 mmol). After stirring at 20 ℃ for 16h, the mixture was diluted with EtOAc (20 mL) and washed with brine (20 ml×3). The organic layer was purified by Na 2 SO 4 Dried, filtered, concentrated and the crude residue was purified by silica gel column chromatography (5% meoh/DCM) to provide the title product (201 e) as a white solid (85 mg, 91.4%). m/z (ESI, positive ion) =620.2 [ m+h ]] + 。
Step F.2- ((4- ((2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxol-4-yl) methyl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (201)
To 201e (85 mg,0.14 mmol) in THF/H 2 To a solution of O (1:1, 3 mL) was added LiOH (6.6 mg,0.27 mmol). After stirring at 20 ℃ for 2h, the reaction was adjusted to ph=6 with TFA and purified by reverse phase HPLC (40% ch 3 CN/H 2 O, with 0.05% tfa as modifier) to afford the title product (201) as a white solid (97 mg, 98.2%). m/z (ESI, positive ion) =606.2 [ m+h ] ] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.33(s,1H),8.03(dd,J＝8.5,1.5Hz,1H),7.79(d,J＝8.7Hz,1H),7.58(t,J＝8.1Hz,1H),7.25(dt,J＝10.9,2.4Hz,1H),7.18-7.22(m,1H),6.72-6.82(m,2H),6.68(dd,J＝7.4,1.3Hz,1H),5.15-5.24(m,1H),4.58-4.82(m,5H),4.35-4.43(m,1H),3.56-3.68(m,2H),3.00-3.15(m,2H),2.73-2.84(m,1H),2.57-2.70(m,2H),2.43-2.54(m,1H),2.03(s,3H),1.76-2.02(m,3H),1.45-1.60(m,2H)。
Example 209 was synthesized in a similar procedure as described in example 201.
Examples 222 and 223 were synthesized as in example 209 (stereochemistry is arbitrarily specified), with SFC chiral separation added at the penultimate step (DaicelCHIRALCEL AD column, mobile phase: CO) prior to final hydrolysis 2 IPA (0.2% NH) 3 (7M in MeOH))=60/40). Example 222 resulted from early elution peaks from chiral separation.
EXAMPLE 213 (S) -2- ((3- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) oxy) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (213)
Step A.3- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester (213 a)
NaH (8.66 mg,0.22mmol,60% dispersion in mineral oil) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (25 mg,0.144 mmol) in anhydrous DMF (0.2M) under Ar at 0deg.C. The mixture was stirred at room temperature for 10min, then heated to 50 ℃ for 25min, followed by the addition of 474e (51.3 mg,0.16 mmol) at the same temperature. After 30min, reaction H was used 2 O was quenched and extracted with EtOAc (×2). The combined organic layers were treated with H 2 Washing with O and brine, passing through Na 2 SO 4 Drying and concentrating. The crude residue was purified by silica gel column chromatography (gradient elution, 0-60% etoac/hexanes) to afford the impurityThe title product (213 a) (26 mg). m/z (ESI, positive ion) =415.2 [ m+h ]] + 。
Step b. (S) -2- ((3- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) oxy) azetidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (213)
The title product (213) was synthesized from 213a in a similar procedure as described in step D of example 177. m/z (ESI, positive ion) =559.2 [ m+h ]] + 。
Example 219.2- ((3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) azetidin-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (219)
Step A.2- ((3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) azetidin-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid tert-butyl ester (219 a)
219a (prepared in analogy to 193d, 6.4mg, 0.020mmol), 2- (chloromethyl) -1- (oxazol-2-ylmethyl) -1H-benzo [ d ] at room temperature]A solution of imidazole-6-carboxylic acid tert-butyl ester (6.8 mg, 0.020mmol) and DIPEA (68.6. Mu.L, 0.39 mmol) in DMF (0.2 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. The resulting crude residue was purified by silica gel column chromatography (gradient elution, 80-100% etoac/hexanes followed by 0-20% meoh/DCM) to afford the title product (219 b) as a pale yellow oil (9.6 mg, 77%). m/z (ESI, positive ion) =636.3 [ m+h ]] + 。
Step B.2- ((3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) azetidin-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (219)
A solution of 219b (10.0 mg,0.016 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. The resulting residue was diluted with water to 1mL and purified by reverse phase HPLC (gradient elution, 35-65% CH) 3 CN/H 2 O, with 0.1% tfa as modifier) to afford the title product (219) (10.9 mg, 100%) as a white solid. 1 H NMR(600MHz,CD 3 OD) delta ppm8.58 (d, j=8.2 hz, 1H), 8.40 (d, j=1.1 hz, 1H), 8.16 (s, 1H), 8.01-8.03 (m, 1H), 7.74-7.76 (m, 1H), 7.49 (d, j=2.2 hz, 1H), 7.38 (d, j=2.6 hz, 1H), 7.35 (s, 1H), 7.31 (dd, j=8.8, 2.6hz, 1H), 7.16-7.19 (m, 2H), 5.72 (s, 2H), 5.46 (tt, j=6.2, 4.4hz, 1H), 5.33 (s, 2H), 4.98 (s, 2H), 4.78-4.88 (m, 2H), 4.48 (br, j=12.1, 3.7 hz). m/z (ESI, positive ion) =580.2 [ m+h ] ] + 。
Examples 228 (from 192 d), 236, 237 (from 192 d) and 238 (from 192 d) were synthesized in a similar procedure to that described in example 219. Example 229 was synthesized in a similar procedure as described in example 228.
Example 233.2- (((2S, 3S) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) -2-methylazetidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid
Step a. (2 s,3 s) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) -2-methylazetidine-1-carboxylic acid tert-butyl ester (233)
Pd was added to a solution of 197a (80 mg,0.24 mmol) and tert-butyl (2S, 3S) -3-hydroxy-2-methylazetidine-1-carboxylate (45 mg,0.24 mmol) in anhydrous toluene (2.4 mL) at room temperature 2 (dba) 3 (9.6 mg,0.012 mmol), t-BuXphos (5.1 mg,0.012 mmol) and Cs 2 CO 3 (157 mg,0.48 mmol). The mixture was purged with argon for 15min and heated to 90 ℃. After stirring for 3h, the reaction was cooled to room temperature and 1N HCl (2 mL) was added. The reaction was extracted with EtOAc (3 mL. Times.3) and treated with 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 (233 a) as a colorless oil (41 mg, 43%). m/z (ESI, positive ion) =462.3 [ m+na ] ] + 。
Step B.2- (((2S, 3S) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenoxy) -2-methylazetidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (233)
The title product (233) was synthesized in analogy to the procedure described in example 177 step D. m/z (ESI, positive ion) =620.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm9.05(s,1H),8.23(s,1H),8.05(d,J＝8.80Hz,1H),7.82(d,J＝8.80Hz,1H),7.41(d,J＝2.57Hz,1H),7.37(t,J＝8.07Hz,1H),7.24(dd,J＝8.80,2.20Hz,1H),7.14(br d,J＝7.70Hz,1H),7.09-7.12(m,2H),7.05(s,1H),6.90(br d,J＝8.44Hz,1H),5.82(br d,J＝2.57Hz,2H),5.24-5.29(m,1H),5.18(s,2H),4.58(br d,J＝2.93Hz,1H),4.39-4.45(m,1H),4.33(q,J＝7.34Hz,2H),1.60(br d,J＝6.97Hz,3H),1.54(t,J＝7.34Hz,3H)。
Examples 234 and 235 were synthesized in a similar procedure to that described in example 233.
EXAMPLE 244 (S) -2- ((3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) pyrrolidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (244)
Step A methyl (S) -4- ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) oxy) picolinate (244 a)
To (R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (128 mg,0.69 mmol), 4-hydroxypyridine-2-carboxylic acid methyl ester (0.1 g,0.65 mmol) and PPh at room temperature 3 (214 mg,0.82 mmol) to a stirred suspension in THF was added DIAD (165 mg,0.82 mmol) dropwise. After 15min, the reaction was heated at 55 ℃ overnight. After cooling, the reaction was filtered through a pad of celite and rinsed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography (gradient elution, 10-60% acetone/hexane) to afford the impure product with triphenylphosphine oxide as a white solid (244 a). m/z (ESI, positive ion) =323.3 [ m+h ] ] + 。
Step B. (S) -3- ((2- (hydroxymethyl) pyridin-4-yl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (244 b)
CaCl was added to a stirred solution of 244a (211 mg, impure, 0.653 mmol) in EtOH (3.3 mL) at 0deg.C 2 (217 mg,1.96 mmol) followed by NaBH addition 4 (70.2 mg,1.96 mmol). After stirring at room temperature for 1h, the reaction was cooled in an ice bath, quenched with 1N HCl, and saturated with NH 4 Dilute Cl and extract 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 to 15% meoh/DCM) to provide the title product (244 b) (87 mg,45%, over 2 steps). m/z (ESI, positive ion) =295.4 [ m+h ]] + 。
Step C. (S) -2- ((3- ((2, 4-dichlorophenoxy) methyl) pyridin-4-yl) oxy) pyrrolidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (244)
The title product (244) was synthesized in a similar procedure as described in example 193, steps D and E. m/z (ESI, positive ion) =621.3 [ M+H ]] + 。
Examples 245, 289 and 298 were synthesized in a similar procedure to that described in example 244.
Example 273 was prepared from 177a in a similar procedure to that described in example 213, step a, example 147, step E, followed by a similar procedure to that described in example 201, steps E and F.
Example 293 was synthesized in a similar procedure as described in example 273.
Example 281.2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (281)
Step A.4- ((3- (((methylsulfonyl) oxy) methyl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (281 a)
A solution of 127b (105 mg,0.36 mmol), msCl (61 mg,0.53 mmol) and DIPEA (184 mg,1.42 mmol) in anhydrous DCM (2 mL) was stirred for 1h at 20deg.C. After completion, the organic layer was dried and concentrated to afford crude title product (281 a) as a yellow oil (105 mg, 83%). m/z (ESI, positive ion) =310.1 [ M-OMs+OMe ]] + 。
Step B.4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (281 b)
To a solution of 2, 4-dichlorophenol (46 mg,0.28 mmol) and 281a (105 mg,0.28 mmol) in DMF (2 mL) was added K 2 CO 3 (117 mg,0.84 mmol) and KI (47 mg,0.28 mmol). At 80℃under N 2 The reaction mixture was stirred for 3h. After completion, the mixture was taken up with H 2 O (5 mL) was quenched and extracted with EtOAc (5 mL. Times.3). The combined organic layers were treated with H 2 O (5 mL), brine (5 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give a crude residue which was purified by preparative TLC (DCM: meoh=10:1) to afford the title product (281 b) as a yellow oil (65 mg, 51%). m/z (ESI, positive ion) =462.1 [ m+na ]] + 。
Step C.4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidine (281 c)
A solution of 281b (65 mg,0.15 mmol) in DCM/TFA (2 mL, 4:1) was stirred at 20deg.C for 1h. 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 (10 mL) was diluted and extracted with EtOAc (10 mL. Times.3). The combined organic layers were dried, filtered, and concentrated to afford the crude title product (281 c) as a yellow oil (51 mg, 96%). m/z (ESI, positive ion) =340.0 [ m+h ]] + 。
Step D.2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (281 d)
To 281c (43 mg,0.13 mmol) and 1- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- (((methylsulfonyl) oxy) methyl) -1H-benzo [ d) at 20 ℃C]To a solution of imidazole-6-carboxylic acid methyl ester (51 mg,0.13 mmol) in DMF (2 mL) was added K 2 CO 3 (53 mg,0.38 mmol) and KI (21 mg,0.13 mmol). At 20℃under N 2 The reaction was stirred for 3h. After completion, the reaction was completed with H 2 O (5 mL) was quenched and extracted with EtOAc (5 mL. Times.3). The combined organic layers were treated with H 2 O (5 mL), brine (5 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 (DCM: meoh=10:1) to afford the title product (281 d) as a yellow oil (42 mg, 49.6%). m/z (ESI, positive ion) =636.2 [ m+h ]] + 。
Step E.2- ((4- ((3- ((2, 4-dichlorophenoxy) methyl) -1H-pyrazol-1-yl) methyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (281)
281d (42 mg,0.066 mmol) and LiOH (8 mg,0.33 mmol) in THF/H at 20deg.C 2 The solution in O (2 mL, 1:1) was stirred for 12h. After completion, 1N HCl was added to the mixture in an ice bath to adjust to ph=5 and the reaction mixture was extracted with EtOAc (10 ml×3). The combined organic layers were dried, filtered, concentrated and purified by reverse phase HPLC (30% ch 3 CN/H 2 O, with 0.05% tfa as modifier) to afford the title product (281) as a white solid (17.5 mg, 42%). m/z (ESI, positive ion) =622.1 [ m+h ] ] + 。
Example 282 was synthesized in a similar procedure as described in example 281.
In the same manner as in example 192, step A (using Ms 2 O) and B, followed by a procedure similar to that described in example 127, step B and examples 281, steps A to E, from (3R) -3-hydroxypyrrolidineTert-butyl 1-carboxylate and Ih Synthesis example 350.
Example 351 was synthesized in a similar procedure as described in example 350.
Example 360.2- (((S) -3- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (360)
Step A.4-chloro-2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidine (360 a)
To 4-chloro-2- (chloromethyl) pyrimidine (230 mg,1.41 mmol) and K 2 CO 3 To a solution of (3838 mg,2.81 mmol) in DMF (5 mL) was added 4-chloro-2-fluorophenol (206 mg,1.41 mmol). The reaction was stirred at 25℃for 16h, diluted with EtOAc (30 mL) and washed with brine (30 mL. Times.2). The organic layer was dried, filtered, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: etoac=2:1) to afford the title product (360 a) (230 mg, 47.8%). m/z (ESI, positive ion) =269.1 [ M+H ]] + 。
Step B. (S) -3- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (360 b)
To a solution of tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate (16 mg,0.88 mmol) in THF (10 mL) at 0deg.C was added NaH (35 mg,0.88 mmol) and stirred at the same temperature for 0.5h. 360a (200 mg,0.73 mmol) was added to the reaction and the resulting mixture was stirred at 25℃for 16h. The reaction was diluted with EtOAc (30 mL) and washed with brine (30 ml×2). The organic layer was dried, filtered, evaporated to dryness and the crude residue was passed through a silica gel columnChromatography (35% etoac/petroleum ether) afforded the title product (360 b) (210 mg, 67.7%) as a colorless oil. m/z (ESI, positive ion) =424.1 [ M+H ]] + 。
Step C. (S) -2- ((4-chloro-2-fluorophenoxy) methyl) -4- (pyrrolidin-3-yloxy) pyrimidine (360 c)
A solution of 360b (200 mg,0.47 mmol) in 4N HCl in dioxane (5 mL) was stirred for 2h at 25 ℃. The mixture was then concentrated in vacuo to afford the crude title product (360 c) (170 mg) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =324.1 [ m+h ]] + 。
Step D.2- (((S) -3- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (360 d)
To 360c (35 mg,0.11 mmol) and K 2 CO 3 To a mixture of (30 mg,0.22 mmol) in DMF (1 ml) was added Ih (32 mg,0.11 mmol). The reaction was stirred at 25 ℃ for 16h and filtered. The filtrate was purified by reverse phase HPLC (45% CH) 3 CN/H 2 O,0.05% tfa as modifier) to afford the title product (360 d) as a yellow solid with some impurities (35 mg). m/z (ESI, positive ion) =582.1 [ m+h ]] + 。
Step E.2- (((S) -3- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (360)
360d (35 mg,0.06 mmol) inTHF/H 2 To a solution in O (1 mL, 1:1) was added LiOH (3 mg,0.125 mmol). The reaction was stirred at 25℃for 2h. After completion, the reaction was adjusted to ph=7 with 1N HCl. The resulting residue was purified by reverse phase HPLC (40% CH) 3 CN/H 2 O) to afford the title product (360) (20 mg, 55.8%) as a white solid. m/z (ESI, positive ion) =568.1 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.41(d,J＝5.92Hz,1H),8.29(s,1H),7.95(dd,J＝8.52,1.4Hz,1H),7.63(d,J＝8.52Hz,1H),7.13(dd,J＝10.36,1.72Hz,1H),6.94-7.06(m,2H),6.77(d,J＝5.92Hz,1H),5.42(d,J＝6.12Hz,1H),5.16-5.28(m,3H),4.80(dd,J＝9.84,5.52Hz,1H),4.56-4.71(m,2H),4.43(dt,J＝9.16,5.92Hz,1H),4.11(d,J＝13.72Hz,1H),3.99(d,J＝13.72Hz,1H),2.83-2.96(m,2H),2.76(dt,J＝14.92,8.4Hz,2H),2.43-2.62(m,2H),2.28(td,J＝13.8,7.60Hz,1H),1.92(dd,J＝8.90,6.24Hz,1H)。
Example 361 was synthesized in a similar procedure as described in example 360.
Example 383.2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (383)
Step A.3- (3- (hydroxymethyl) phenyl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (383 a)
(3-bromophenyl) methanol (450 mg,2.4 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (0.5 g,1.6 mmol), pd (dppf) Cl at 95℃ 2 (0.24 g,0.32 mmol) and K 2 CO 3 (0.67 g,4.8 mmol) in dioxane/H 2 The mixture in O (10/2.5 mL) was stirred for 2h. After completion, water (30 mL) was added. The reaction was extracted with EtOAc (10 ml×3) and the combined organic layers were extracted with water (10)mL), brine (10 mL), with anhydrous Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=1:1) to afford the title product (383 a) (0.42 g,79% as white oil). m/z (ESI, positive ion) =220.1 [ M ] t Bu+H] + 。
Step B.3- (3- (((methylsulfonyl) oxy) methyl) phenyl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (383 b)
To a solution of 383a (0.5 g,1.8 mmol) in THF (10 mL) at 0deg.C was added Et 3 N (0.367 g,3.6 mmol) and methanesulfonic anhydride (0.47 g,2.7 mmol). The reaction mixture was stirred for 1h at 20deg.C, quenched with water (10 mL), and extracted with EtOAc (10 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo to afford the crude title product (383 b) (0.62 g) as a white solid. m/z (ESI, positive ion) =376.1 [ m+na ] ] + 。
Step C.3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (383 c)
Cs was added to a solution of 383b (0.41 g,1.16 mmol), 2, 4-dichlorophenol (0.19 g,1.16 mmol) in DMF (10 mL) at 20deg.C 2 CO 3 (0.76 g,2.23 mmol). After stirring for 1h at 55deg.C, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL). Using H for the organic layer 2 O (10 mL), brine (10 mL), washed with anhydrous Na 2 SO 4 Dried, filtered, concentrated and purified by reverse phase HPLC (70% ch 3 CN/H 2 O, with 0.05% formic acid as modifier) to afford the title product (383 c) as a white solid (0.42 g, 84%). m/z (ESI, positive ion) =364.0 [ M ] t Bu+H] + 。
Step D.3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (383 d)
To a solution of 383c (0.2 g,0.48 mmol) in THF (5 mL) at 20deg.C was added PtO 2 (5.4 mg,0.024 mmol). At 20℃at 50psi H 2 The reaction mixture was stirred for 10h. After completion, the reaction was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (70% ch) 3 CN/H 2 O, with 0.05% formic acid as modifier) to afford the title product (383 d, rac) (120 mg, 60%) as a white oil. m/z (ESI, positive ion) =444.0 [ M+Na ] ] + 。
Step E.3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidine (383 e)
To a solution of 383d (200 mg,0.4 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 0deg.C. At 20℃under N 2 The mixture was stirred for 1h. After completion, the mixture was concentrated in vacuo to afford the crude title product (383 e) (102 mg) as a white solid, which was used in the next step without any further purification. m/z (ESI, positive ion) =322.0 [ m+h ]] + 。
Step F.2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (383 f)
Toward Ih (76 mg,0.26 mmol) at CH 3 To a solution in CN (2 mL) was added 383e (84 mg,0.26 mmol) and K 2 CO 3 (216 mg,1.56 mmol). The reaction mixture was stirred at 20℃for 5h. After completion, mixThe mixture was quenched with water (10 mL), extracted with EtOAc (10 mL. Times.3), washed with water and brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (gradient elution, 0-50% etoac/petroleum ether) to afford the title product (383 f) as a white solid (50 mg, 34.4%). m/z (ESI, positive ion) =580.2 [ m+h ]] + 。
Step G.2- ((3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (383)
To 383f (40 mg,0.07 mmol) in MeOH/THF/H 2 To a solution of O (1:1:1, 3 mL) in a mixed solvent was added LiOH (8.25 mg,0.7 mmol). The reaction mixture was stirred at 20℃for 5h. After completion, the reaction was adjusted to ph=6 by 10% citric acid and extracted with EtOAc (20 ml×3). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (60% CH) 3 CN/H 2 O, with 0.05% NH 4 HCO 3 As a modifier) to afford the title product (383) (15 mg,38%, diastereomer mixture) as a white solid. m/z (ESI, positive ion) =566.1 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.29(d,J＝0.88Hz,1H),7.97(dd,J＝8.33,0.88Hz,1H),7.67(d,J＝8.33Hz,1H),7.38-7.45(m,2H),7.18-7.34(m,4H),7.09(dd,J＝8.99,2.85Hz,1H),5.18-5.27(m,1H),5.15(s,2H),4.83(d,J＝7.0Hz,1H),4.65-4.72(m,1H),4.61(td,J＝7.78,5.92,1H),4.38-4.44(m,1H),4.26-4.35(m,1H),4.18(dd,J＝13.59,6.58Hz,1H),3.43-3.56(m,1H),3.14-3.25(m,1H),2.91-3.09(m,2H),2.70-2.88(m,2H),2.33-2.54(m,2H),1.91-2.06(m,1H)。
Examples 400 and 401 were synthesized in a similar procedure to that described in example 383, except that step D (hydrogenation step) was not present.
EXAMPLE 384 (S) -2- ((3- (6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (384)
Step A.3- (6- (hydroxymethyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (384 a)
(6-bromopyridin-2-yl) methanol (191.0 mg,1.02 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (200 mg,0.68 mmol), pd (dppf) Cl 2 (99.2 mg,0.14 mmol) and K 2 CO 3 A solution of (187.0 mg,1.36 mmol) in 1, 4-dioxane (5.0 mL) and water (1.25 mL) was purged with argon for 5min. The reaction was heated at 90℃for 1h. After completion, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered, concentrated and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 30-80% etoac/hexanes) to afford the title product (384 a) as a yellow oil (152.0 mg, 81%). m/z (ESI, positive ion) =277.4 [ m+h ]] + 。
Step B.3- (6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (384 b)
384a (50.0 mg,0.18 mmol), 2, 4-dichlorophenol (31.0 mg,0.19 mmol), PPh 3 To a solution of (71.2 mg,0.27 mmol) in THF (0.9 mL) was added DIAD (53.4. Mu.L, 0.27 mmol). After stirring at room temperature for 1h, the reaction solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, 10-50% etoac/hexanes) to afford a white solidTitle product (384 b) (61.0 mg, 80%). m/z (ESI, positive ion) =421.3 [ m+h ]] + 。
Step C.2- ((2, 4-dichlorophenoxy) methyl) -6- (2, 5-dihydro-1H-pyrrol-3-yl) pyridine 2, 2-trifluoroacetate salt (384 c)
A solution of 384b (19.0 mg,0.045 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 5min. After completion, the reaction solvent was removed under reduced pressure to afford the crude title product (384 c) (19.6 mg) as a yellow oil, which was used in the next reaction without further purification. m/z (ESI, positive ion) =321.3 [ m+h ]] + 。
Step d. (S) -2- ((3- (6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (384 d)
A solution of 384c (8.8 mg, 0.020mmol), ih (7.1 mg,0.024 mmol) and DIPEA (70.4. Mu.L, 0.40 mmol) in DMF (0.2 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 (384 d) as a white solid (6.7 mg, 57%). m/z (ESI, positive ion) =579.3 [ m+h ]] + 。
Step E. (S) -2- ((3- (6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (384)
384d (6.7 mg,0.012 mmol) and LiOH (1.4 mg,0.058 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 with water to 1mL and purified by reverse phase HPLC (gradient elution, 35-65% CH 3 CN/H 2 O, with 0.05% NH 4 OH as a modifier) to afford the title product (384) as a white solid (6.0 mg, 89%). 1 H NMR(600MHz,DMSO-d 6 ) Delta ppm 12.7 (s, 1H), 8.27 (s, 1H), 7.80-7.85 (m, 2H), 7.68 (brd, j=8.4 hz, 1H), 7.59 (br d, j= 7.3,1H), 7.57 (br d, j=2.6 hz, 1H), 7.39 (br d, j=7.7 hz, 1H), 7.32 (br dd, j=8.8, 2.6hz, 1H), 7.25 (d, j=8.8 hz, 1H), 6.68 (s, 1H), 5.24 (s, 2H), 5.08 (ddd, j=14.4, 7.3,2.9hz, 1H), 4.81 (br dd, j=15.2.2.9 hz, 1H), 4.dd (br 48, 7.9hz, 1H), 4.9 (br) 4.48 (d, j=8.8 hz, 1H), 6.68 (s, 1H), 5.24 (s, 2H), 5.08 (ddd, j=14.4, 7.3,2.9hz, 1H), 4.81 (br dd, j=15.2.9 hz, 1H), 4.9 (b, 1H), 4.48 (b, 1.9.9 hz, 1H). m/z (ESI, positive ion) =565.2 [ m+h ]] + 。
Examples 385, 388, 393, 402, 403, 417, 418, 426, 436, 437 and 438 were synthesized in a similar procedure to that described in example 384.
Example 386.2- ((3- (6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (386)
Step A.3- (6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (386 a)
To a solution of 384b (45 mg,0.11 mmol) in THF (2 mL) at 20deg.C was added PtO 2 (1.22 mg,0.005 mmol). The reaction mixture was treated with H 2 Purging for 5min and at H 2 Stirring under balloonOvernight. The reaction was filtered and concentrated to afford the crude title product (386 a, rac) (7.9 mg, 18%) which was taken to the next step without further purification. m/z (ESI, positive ion) =423.3 [ M+H ]] + 。
Step B.2- ((3- (6- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (386)
The title product (386, diastereomer mixture) was synthesized in analogy to the procedure described in steps C to E of example 384. m/z (ESI, positive ion) =567.3 [ m+h ]] + 。
Examples 389, 391, 399, 419 and 420 were synthesized in a similar procedure to that described in example 386.
Example 390.2- ((3- (4- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (390)
Step A.2- ((3- (4- ((2, 4-dichlorophenoxy) methyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxazol-5-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (390)
A solution of 390a (prepared in a similar procedure to 384d, 27.6mg,0.044 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 purified by reverse phase HPLC (gradient elution, 20-60% ch) 3 CN/H 2 O, with 0.1% TFA as modifier) to afford the title product (390) as a white solid(15.0 mg, 50%). m/z (ESI, positive ion) =576.3 [ M+H ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm8.57(d,J＝5.1Hz,1H),8.41(d,J＝1.1Hz,1H),8.15(s,1H),8.04(dd,J＝8.6,1.7Hz,1H),7.87(s,1H),7.80(d,J＝1.2Hz,1H),7.49(br d,J＝5.1Hz,1H),7.46(d,J＝2.2Hz,1H),7.34(s,1H),7.28(dd,J＝8.8,2.6Hz,1H),7.13(d,J＝9.2Hz,1H),6.72-6.74(m,1H),5.75(s,2H),5.28(s,2H),5.12(s,2H),4.77-4.89(m,2H),4.64(br s,2H)。
Examples 387, 392, 394 and 404 were synthesized in a similar procedure to that described in example 390.
Example 398 was synthesized in a similar procedure to that described for example 397, except that the last step was in accordance with example 390, step a.
EXAMPLE 395 (S) -2- ((3- (2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (395)
Step A.4- ((4-chloropyrimidin-2-yl) methoxy) -3-fluorobenzonitrile (395 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, 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 (395 a) (93 mg, 71%) as a white solid. m/z (ESI, positive ion) =264.1 [ m+h ]] + 。
Step B.3- (2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (395 b)
395a (26 mg,0.1 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (29 mg,0.1 mmol) and K 3 A suspension of PO4 (42 mg,0.2 mmol) in 1, 4-dioxane/water (8 mL/4 mL) was degassed with argon and inflated with an argon balloon. Pd (dppf) Cl 2 (7.2 mg,0.01 mmol) was added to the mixture followed by the same degassing and argon protection procedure. The mixture was heated to 100 ℃ overnight. After completion, the reaction was poured into EtOAc (20 mL) and the aqueous phase was extracted with EtOAc (20 ml×2). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (EtOAc/hexanes) to afford the title product (395 b) (10 mg, 23%). m/z (ESI, positive ion) =397.4 [ m+h ]] + 。
Step C.4- ((4- (2, 5-dihydro-1H-pyrrol-3-yl) pyrimidin-2-yl) methoxy) -3-fluorobenzonitrile (395 c)
395b (10 mg,0.025 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL) at room temperature. After 10min, the resulting solution was concentrated in vacuo, redissolved in DMSO (1 mL) and purified by reverse phase HPLC (gradient elution, 0-90% CH) 3 CN/water with 0.1% tfa as modifier) to afford the title product (395 c) as a white solid (7 mg, 68%). m/z (ESI, positive ion) =297.3 [ m+h ]] + 。
Step d. (S) -2- ((3- (2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (395 d)
To a solution of 395c (7 mg,0.024 mmol) and Ih (7 mg,0.024 mmol) in DMF (1 mL) was added Et 3 N (47.8 mg,0.47 mmol). The reaction mixture was stirred at room temperature overnight, followed by reverse phase HPLC (gradient elution, 0-60% CH) 3 CN/water with 0.1% tfa as modifier) to afford the title product (395 d) as a white solid (11 mg, 72%). m/z (ESI, positive ion) =555.3 [ m+h ]] + 。
Step E. (S) -2- ((3- (2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (395)
395d (10 mg,0.018 mmol) is dissolved in CH 3 CN (1 mL) and treated with 2NNaOH (0.5 mL). The mixture was stirred vigorously at room temperature for 24h, then purified by reverse phase HPLC (gradient elution, 0-50% CH) 3 CN/water with 0.05% NH 4 OH as a modifier) to afford the title product (395) (6.3 mg, 63%) as a white solid. m/z (ESI, positive ion) =541.3 [ m+h ] ] + 。 1 H NMR(600MHz,CD 3 OD)δppm8.67(d,J＝5.50Hz,1H),8.25(d,J＝0.73Hz,1H),7.98(dd,J＝8.62,1.65Hz,1H),7.66(d,J＝8.07Hz,1H),7.50(d,J＝5.50Hz,1H),7.40-7.46(m,2H),7.20-7.24(m,1H),6.91-6.94(m,1H),5.42(s,2H),5.25(qd,J＝7.07,2.89Hz,1H),4.87(m,1H),4.69(br dd,J＝15.41,2.93Hz,1H),4.60-4.65(m,1H),4.45(dt,J＝9.17,5.87Hz,1H),4.35(d,J＝13.57Hz,1H),4.27(d,J＝13.57Hz,1H),3.89-3.94(m,2H),3.82-3.87(m,2H),2.78(dtd,J＝11.23,8.14,8.14,6.24Hz,1H),2.51(ddt,J＝11.28,8.99,7.11,7.11Hz,1H)。
EXAMPLE 396 (S) -2- ((3- (6- ((4-chloro-2-fluorophenoxy) methyl) pyrazin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (396)
Step A.6- (1- (tert-Butoxycarbonyl) -2, 5-dihydro-1H-pyrrol-3-yl) pyrazine-2-carboxylic acid methyl ester (396 a)
To 6-chloropyrazine-2-carboxylic acid methyl ester (200 mg,1.16 mmol) and 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (349mg, 1.16 mmol) at room temperature in 1, 4-dioxane/H 2 Pd (dppf) Cl was added to a solution in O (9:1, 3.1 mL) 2 (42 mg,0.058 mmol) and Cs 2 CO 3 (755mg, 2.32 mmol). The mixture was purged with argon for 15min and then heated to 90 ℃. After 2H, the mixture was cooled to room temperature and H was added 2 O (2 mL). The reaction was extracted with EtOAc (3 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, 0-40% etoac/hexanes) to afford the title product (396 a) as a yellow solid (263 mg, 74%). m/z (ESI, positive ion) =328.3 [ m+na ]] + 。
Step B.3- (6- (hydroxymethyl) pyrazin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (396 b)
To a solution of 396a (100 mg,0.33 mmol) in anhydrous EtOH (3.3 mL) at 0deg.C was added NaBH 4 (35 mg,0.99 mmol) and CaCl 2 (109 mg,0.99 mmol). After stirring at room temperature for 1.5h, 1N HCl (1 mL) was added dropwise at 0deg.C and the reaction was extracted with EtOAc (5 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Drying, filtering, concentrating and purifying by silica gel column chromatography (gradient elution, 0-15% MeOH/CH) 2 Cl 2 ) To afford the title product (396 b) (35 mg, 39%). m/z (ESI, positive ion) =278.3 [ m+h ]] + 。
Step C.3- (6- ((4-chloro-2-fluorophenoxy) methyl) pyrazin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (396 c)
At 0deg.C, 396b (35 mg,0.13 mmol) in anhydrous CH 2 Cl 2 PPh was added to the solution in (0.7 mL) 3 (49.7 mg,0.19 mmol), 4-chloro-2-fluorophenol (18.5 mg,0.13 mmol) followed by dropwise addition of DCAD (69.5 mg,0.19 mmol) in anhydrous CH 2 Cl 2 (0.7 mL). The resulting mixture was stirred at room temperature 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 (396 c) (42 mg, 82%). m/z (ESI, positive ion) =428.3 [ m+na ]] + 。
Step d. (S) -2- ((3- (6- ((4-chloro-2-fluorophenoxy) methyl) pyrazin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (16)
The title product (396) was synthesized from 396C in a similar procedure as described in example 384, steps C to E. Formic acid was used as modifier in the final purification step. m/z (ESI, positive ion) =550.2 [ m+h ]]+。 1 H NMR(600 MHz,CD 3 OD)ppmδ8.78(s,1H),8.59(s,1 H),8.33(d,J＝0.73 Hz,1H),7.99(dd,J＝8.44,1.47 Hz,1H),7.71(d,J＝8.44 Hz,1H),7.17-7.21(m,2H),7.07-7.10(m,1H),6.83(t,J＝2.02 Hz,1H),5.23-5.28(m,3H),4.87-4.91(m,1H),4.72(dd,J＝15.41,2.57 Hz,1H),4.61-4.66(m,1H),4.46(dt,J＝9.26,6.01 Hz,1H),4.29-4.42(m,2H),4.01-4.09(m,2H)3.84-3.94(m,2H),2.76-2.83(m,1H),2.49-2.55(m,1H)。
Example 397.2- ((3- (4- ((4-chloro-2-fluorophenoxy) methyl) pyridin-2-yl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (397)
Step A.3- (4- (hydroxymethyl) pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (397 b)
To a solution of 397a (synthesized as 384a, 56.5 mg,0.20 mmol) in THF (5 mL) at 20deg.C was added PtO 2 (2.3 mg,0.01 mmol). The reaction mixture was treated with H 2 Purging for 5min and at H 2 Stir under balloon overnight. The reaction was filtered and concentrated to provide the crude title product with some unreacted starting material 397a (397 b, racemic) which was advanced to the next step without further purification. m/z (ESI, positive ion) =279.4 [ m+h ]] + 。
Step B.3- (4- ((4-chloro-2-fluorophenoxy) methyl) pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (397 c)
The title product (397 c) was synthesized from 397B in a similar procedure as described in step B of example 384. m/z (ESI, positive ion) =407.3 [ m+h ]] + 。
Step C.2- ((3- (4- ((4-chloro-2-fluorophenoxy) methyl) pyridin-2-yl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (397)
The title product (397, diastereomer mixture) was synthesized from 397C in analogy to the procedure described in steps C to E of example 384. m/z (ESI, positive ion) =551.3 [ m+h ]] + 。 1 HNMR(600MHz,DMSO-d 6 )δppm 8.50(d,J＝5.1Hz,1H),8.08(s,1H),7.77 (dd, j=8.3, 1.3hz, 1H), 7.42-7.49 (m, 2H), 7.35 (s, 1H), 7.18-7.26 (m, 3H), 5.22 (s, 2H), 5.05 (qd, j=7.0, 3.1hz, 1H), 4.71 (ddd, j=15.2, 7.0,4.2hz, 1H), 4.57 (ddd, j=15.2, 8.6,3.3hz, 1H), 4.43-4.48 (m, 1H), 4.33 (dq, j=9.1, 5.9hz, 1H), 4.07 (dd, j=13.4, 5.7hz, 1H), 3.90 (dd, j=13.2, 7.7hz, 1H), 3.48-3.56 (m, 1H), 2.98-3.08 (m, 1.2, 1H), 4.43-4.48 (m, 1H), 4.33 (dq, j=9.1, 5.9hz, 1H), 4.07 (dd, 1.7.7 hz), 3.7.7H). m/z (ESI, positive ion) =551.30 [ m+h ]] + 。
Examples 456 and 457 were synthesized as described in example 397 from (6-bromo-5-fluoropyridin-2-yl) methanol.
Examples 405 and 406.2- (((S) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (405) and 2- (((R) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (406)
Step A. (S) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (383 d-P1) and (R) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (383 d-P2)
800mg 383d was isolated by SFC chiral separation (acquisition UPC 2 column; daicel CHIRALPAK OX-33 mm. Times.150 mm,3 μm) at a flow rate of 2.0 mL/min. Mobile phase: CO 2 MeOH (0.1% dea) =85:15. 383d-P1 (300 mg) and 383d-P2 (305 mg) were obtained respectively (stereochemistry was arbitrarily specified). 383d-P1 is the early elution peak.
Step B.2- (((S) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (405) and 2- (((R) -3- (3- ((2, 4-dichlorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (406)
The title product was synthesized (405) from 383d-P1 in a similar procedure as described in steps E to G of example 383. m/z (ESI, positive ion) =566.1 [ m+h ]] + 。 1 H NMR(400MHz,MeOD)δppm 8.27(d,J＝0.9Hz,1H),7.96(dd,J＝8.5,1.5Hz,1H),7.66(d,J＝8.5Hz,1H),7.42(br s,1H),7.39(d,J＝2.5Hz,1H),7.24-7.34(m,3H),7.21(dd,J＝8.8,2.5Hz,1H),7.09(d,J＝8.9Hz,1H),5.16-5.25(m,1H),5.15(d,J＝7.4Hz,2H),4.81-4.83(m,1H),4.69(dd,J＝15.4,2.7Hz,1H),4.60(td,J＝7.9,6.0Hz,1H),4.41(dt,J＝9.1,6.0Hz,1H),4.28(d,J＝13.8Hz,1H),4.14(d,J＝13.8Hz,1H),3.41-3.53(m,1H),3.14(dd,J＝10.8,6.4Hz,1H),2.88-3.03(m,2H),2.81(dd,J＝9.5,7.2Hz,1H),2.69-2.77(m,1H),2.32-2.53(m,2H),1.96(dt,J＝15.6,7.4Hz,1H)。
The title product was synthesized (406) from 383d-P2 in a similar procedure as described in steps E to G of example 383. m/z (ESI, positive ion) =566.2 [ m+h ]] + 。 1 H NMR(400MHz,MeOD)δ8.16(s,1H),7.93(dd,J＝8.4,1.3Hz,1H),7.57(d,J＝8.4Hz,1H),7.40(d,J＝2.5Hz,2H),7.19-7.32(m,4H),7.09(d,J＝8.9Hz,1H),5.21-5.25(m,1H),5.14(s,2H),4.88-4.91(m,1H),4.69(dd,J＝15.3,2.9Hz,1H),4.56-4.63(m,1H),4.43(dd,J＝6.0,3.1Hz,1H),4.17(d,J＝13.5Hz,1H),4.04(d,J＝13.5Hz,1H),3.38-3.45(m,1H),3.07(t,J＝8.5Hz,1H),2.83-2.92(m,1H),2.84-2.70(m,2H),2.65(dd,J＝9.1,7.0Hz,1H),2.45-2.55(m,1H),2.31-2.40(m,1H),1.88-1.96(m,1H)。
EXAMPLE 407 (S) -2- ((3- (6- ((4-chloro-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (407)
Step A.3- (5-fluoro-6- (hydroxymethyl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (407 a)
(6-chloro-3-fluoropyridin-2-yl) methanol (185.0 mg,1.15 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (260 mg,0.88 mmol), pd (dppf) Cl 2 (129.0 mg,0.18 mmol) and K 2 CO 3 A solution of (243.0 mg,1.76 mmol) in 1, 4-dioxane (5.0 mL) and water (1.25 mL) was purged with argon for 5min. It was stirred at 90℃for 2h. After completion, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 20-70% etoac/hexanes) to afford the title product (407 a) as a colorless oil (183.0 mg, 71%). m/z (ESI, positive ion) =317.3 [ M+Na ]] + 。
Step B.3- (6- ((4-chloro-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (407 b)
To 407a (90.0 mg,0.31 mmol), 4-chloro-2-fluorophenol (47.1 mg,0.32 mmol), PPh 3 To a solution of (120.0 mg,0.46 mmol) in THF (1.5 mL) was added DIAD (90.3. Mu.L, 0.46 mmol). After stirring at room temperature for 1h, the reaction solvent was removed under reduced pressure. The resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-40% etoac/hexanes) to afford the title product (407 b) as a white solid (115.0 mg, 89%). m/z (ESI, positive ion) =445.3 [ m+na ] ] + 。
Step C. (S) -2- ((3- (6- ((4-chloro-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (407)
The title product (407) was synthesized in a similar procedure as described in example 384, steps C to E. m/z (ESI, positive ion) =567.3 [ m+h ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δppm 8.00(s,1H),7.72-7.79(m,3H),7.34-7.42(m,3H),7.17-7.20(m,1H),6.60-6.63(m,1H),5.27(s,2H),5.07(ddd,J＝14.31,6.97,3.30Hz,1H),4.70(br dd,J＝15.22,7.15Hz,1H),4.53-4.58(m,1H),4.44-4.50(m,1H),4.36(dt,J＝8.89,6.01Hz,1H),4.23(d,J＝13.57Hz,1H),4.11(br d,J＝13.57Hz,1H),3.83-3.92(m,2H),3.68-3.80(m,2H),2.64-2.71(m,1H),2.40-2.46(m,1H)。
Examples 408, 413, 416, 421, 422, 424, 429, 430, 440, 451, 452 and 458 were synthesized in a similar procedure to that described in example 407.
Example 423 was a by-product isolated in the last synthesis step of example 422.
Example 425 is a by-product isolated in the last synthesis step of example 424.
Example 409 was synthesized from 407b in a similar procedure to that described in example 386, step a, followed by a similar procedure to that described in example 384, steps C to E.
Example 410 was synthesized in a similar procedure as described in example 409.
Examples 411 and 412.2- (((S) -3- (3- ((4-chloro-2-fluorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (411) and 2- (((R) -3- (3- ((4-chloro-2-fluorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (412)
Step A.2- (((S) -3- (3- (hydroxymethyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (411 a-P1) and 2- (((R) -3- (3- (hydroxymethyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (411 a-P2)
Following a procedure similar to that described in example 383, steps D to F, chiral separation was followed: daicel CHIRALPAK AZ-3, mobile phase: CO 2 MeOH (containing 0.2% NH) 3 (7M in MeOH)) =60/40, the title products (411 a-P1 and 411 a-P2) were synthesized from 383 a. 411a-P1 is the early elution peak. Stereochemistry is arbitrarily specified. m/z (ESI, positive ion) =436.2 [ M+H ]] + 。
Step B.2- (((S) -3- (3- (((methylsulfonyl) oxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (411 b)
To a stirred solution of 411a-P1 (40 mg,0.09 mmol), methanesulfonic anhydride (40 mg,0.23 mmol) in DCM (2 mL) was added DIPEA (36 mg,0.28 mmol) at 25deg.C. After stirring for 2H, reaction H was taken up 2 O (10 mL) was diluted and extracted with EtOAc (10 mL. Times.3). The combined organic layers were dried and concentrated to afford the crude title product (411 b) as a white solid (50 mg, 95%). m/z (ESI, positive ion) =514.2 [ m+h ] ] + 。
Step C.2- (((S) -3- (3- ((4-chloro-2-fluorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (411 c)
At 80℃to 411b (50 mg,0.10 mmol), 4-chloro-2-fluorophenol (14 mg,0.10 mmol) inK was added to a stirred solution in DMF (2 mL) 2 CO 3 (40 mg,0.29 mmol). After heating for 6H, the reaction was carried out with H 2 O (10 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=2:1) to afford the title product (411 c) as a white solid (40 mg,67% yield). m/z (ESI, positive ion) =564.2 [ m+h ]] + 。
Step D.2- (((S) -3- (3- ((4-chloro-2-fluorophenoxy) methyl) phenyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (411)
To a solution of 411c (30 mg,0.05 mmol) in MeOH (1.0 mL) stirred at 25℃was added lithium hydroxide (13 mg,0.53 mmol) in H 2 O (0.5 mL). After stirring for 3h, 1N HCl was added to the mixture in an ice bath to adjust to ph=5. The reaction was then extracted with EtOAc (5 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by silica gel column chromatography (DCM: meoh=10:1) to afford the title product (411) as a white solid (24 mg, 78%). m/z (ESI, positive ion) =550.2 [ m+h ] ] + 。 1 HNMR(400MHz,CD 3 OD)δppm 8.28(d,J＝0.88Hz,1H),7.96(dd,J＝8.55,1.53Hz,1H),7.66(d,J＝8.33Hz,1H),7.39(s,1H),7.23-7.35(m,3H),7.17(dd,J＝10.96,2.19Hz,1H),7.03-7.14(m,2H),5.17-5.26(m,1H),5.12(s,2H),4.81-4.86(m,1H),4.70(dd,J＝15.35,2.63Hz,1H),4.56-4.65(m,1H),4.41(dt,J＝8.99,6.03Hz,1H),4.10-4.31(m,2H),3.41-3.52(m,1H),3.14(t,J＝8.77Hz,1H),2.69-3.03(m,4H),2.33-2.52(m,2H),1.90-2.02(m,1H)。
Example 412 was synthesized from 411a-P2 in a similar procedure as described in example 411. m/z (ESI, positive ion) =550.2 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm8.28(s,1H),7.97(dd,J＝8.56,1.47Hz,1H),7.66(d,J＝8.31Hz,1H),7.39(s,1H),7.23-7.35(m,3H),7.17(dd,J＝10.88,2.32Hz,1H),7.02-7.14(m,2H),5.22(qd,J＝7.17,2.69Hz,1H),5.12(s,2H),4.88-4.91(m,1H),4.69(dd,J＝15.41,2.69Hz,1H),4.61(td,J＝7.83,5.87Hz,1H),4.43(dt,J＝9.11,5.96Hz,1H),4.28(d,J＝13.69Hz,1H),4.11-4.19(m,1H),3.47(dt,J＝16.20,7.92Hz,1H),3.17(t,J＝8.80Hz,1H),2.85-3.05(m,2H),2.70-2.82(m,2H),2.33-2.56(m,2H),1.90-2.03(m,1H)。
Examples 414 and 415 were synthesized in a similar procedure as described in examples 411 and 412; 439 and 443.
Example 427.2- (((R) -3- (2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) pyrrolidin-1-yl) methyl) -4-fluoro-1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (427)
Step A.3- (2- (hydroxymethyl) pyridin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (427 b)
At 25℃at H 2 Next, ptO was added to a stirred solution of 427a (synthesized as described for 383a, 4.5g,16.2 mmol) in THF (50 mL) 2 (0.37 g,1.6 mmol). After stirring for 5H, reaction H was taken up 2 O (50 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 (petroleum ether: etoac=2:1) to afford the title product (427 b) as a colorless oil (2.5 g, 53%). m/z (ESI, positive ion) =279.2 [ m+h ]] + 。
Step B. (S) -3- (2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (427 c-P1) and (R) -3- (2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (427 c-P2)
Step 383 as in exampleChiral separation was followed as described in steps B and C: chiralpak-OJ column, mobile phase: CO 2 MeOH (0.1% DEA) to synthesize the title products (427 c-P1 and 427 c-P2). 427c-P1 is the early elution peak and 427c-P2 is the late elution peak.
Step C. (R) -2- ((4-chloro-2-fluorophenoxy) methyl) -4- (pyrrolidin-3-yl) pyridine (427 d)
A solution of 427c-P2 (20 mg,0.05 mmol) in HCl (4M in 1,4 dioxane, 1 mL) was stirred for 2h at 25deg.C. After completion, 1N NaOH was added to the reaction in an ice bath to adjust to ph=8. The reaction mixture was extracted with EtOAc (15 mL. Times.3). The combined organic layers were dried, filtered and concentrated to afford the crude title product (427 d) as a white solid (15 mg). m/z (ESI, positive ion) =307.1 [ m+h ]] + 。
Step D.2- (((R) -3- (2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) pyrrolidin-1-yl) methyl) -4-fluoro-1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (427)
The title product (427) was prepared in a similar procedure as described in example 383, steps F and G. m/z (ESI, positive ion) =569.2 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.42(d,J＝5.26Hz,1H),8.11(s,1H),7.62(br d,J＝10.96Hz,1H),7.56(s,1H),7.32(dd,J＝5.26,1.32Hz,1H),7.19(dd,J＝10.96,2.63Hz,1H),7.04-7.15(m,2H),5.14-5.25(m,3H),4.84(br d,J＝7.02Hz,1H),4.67(dd,J＝15.57,2.41Hz,1H),4.55-4.63(m,1H),4.41(dt,J＝9.21,5.92Hz,1H),4.06-4.29(m,2H),3.45-3.56(m,1H),3.10(t,J＝8.55Hz,1H),3.02(td,J＝8.77,4.39Hz,1H),2.68-2.88(m,3H),2.36-2.52(m,2H),1.87-1.99(m,1H)。
Example 428 was synthesized from 427c-P1 in a similar procedure as described in example 427. Examples 433 and 434 were synthesized in a similar procedure to that described in example 427.
Examples 431 and 432 were synthesized in a similar procedure as described in example 428.
EXAMPLE 435 (S) -2- ((3- (4- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (435)
Step a. (2-chloropyrimidin-4-yl) methanol (435 a)
2-chloropyrimidine-4-carboxylic acid (793 mg,5 mmol) was dissolved in THF (16.7 mL) and cooled to 0deg.C. Triethylamine (704. Mu.L, 5.05 mmol) was slowly added and stirred for 5min. Isobutyl chloroformate (655 μl,5.05 mmol) was added dropwise, and the reaction mixture was warmed to 21 ℃ and stirred for 1h. The reaction was then filtered and rinsed with THF (5 mL). The filtrate was cooled to 0deg.C and NaBH was added dropwise 4 (378 mg,2 eq, 10 mmol) in water (3 mL). After stirring at 21℃for 2H, the mixture was poured onto H 2 O (40 mL) and extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (15 mL), and with Na 2 SO 4 Dried, concentrated, and purified by silica gel column chromatography (gradient elution, 15 to 100% etoac/DCM) to afford the title product (435 a) (347 mg, 48%). m/z (ESI, positive ion) =145.2 [ m+h ]] + 。
Step B.3- (4- (hydroxymethyl) pyrimidin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (435 b)
435a (347 mg,2.4 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-Tert-butyl formate (709 mg,2.4 mmol), K 2 CO 3 (2.4 mL,4.8mmol,2M in water) and 1, 4-dioxane (9.6 mL) with N 2 And fully purging for 5min. Addition of Pd (dppf) Cl 2 (87.8 mg, 120. Mu. Mol) and heating the reaction mixture to 90℃for 3h. After cooling, the reaction was diluted with EtOAc (20 mL) and with NH 4 Cl(5mL)、H 2 O (5 mL) and brine (5 mL). The organic layer was taken up with Na 2 SO 4 Dried, concentrated, and purified by silica gel column chromatography (gradient elution, 15 to 100% etoac/DCM) to give the title product (435 b) (463mg, 69%). m/z (ESI, positive ion) =300.3 [ m+na ]] + 。
Step C.3- (4- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (435 c)
435b (139 mg,0.5 mmol), 4-chloro-2-fluorophenol (55.8. Mu.L, 525. Mu. Mol), PPh 3 (197mg, 750. Mu. Mol) and DCM (1.97 mL) were cooled to 0deg.C. Slowly adding N- ({ [ (4-chlorophenyl) methoxy group]Carbonyl } imino) [ (4-chlorophenyl) methoxy group]Formamide (DCAD) (275 mg, 750. Mu. Mol). After stirring for 1h at room temperature, the reaction was filtered and purified directly by silica gel column chromatography (gradient elution, 0 to 50% etoac/DCM) to afford the title product (435 c) as a colourless solid (178 mg, 87%). m/z (ESI, positive ion) =428.3 [ m+na ] ] + 。
Step d. (S) -2- ((3- (4- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-2-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (435)
The title product (435) was synthesized from 435C in a similar procedure as described in steps C to E of example 384. m/z (ESI, positive ion) =550.2 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.72(d,J＝5.27Hz,1H),8.17(d,J＝0.75Hz,1H),7.96(dd,J＝8.28,1.51Hz,1H),7.61(d,J＝8.53Hz,1H),7.44(d,J＝5.02Hz,1H),7.20-7.24(m,1H),7.08-7.15(m,2H),6.97(t,J＝1.88Hz,1H),5.26(qd,J＝7.07,2.89Hz,1H),5.21(s,2H),4.72-4.80(m,1H),4.66-4.74(m,1H),4.59-4.66(m,1H),4.46(dt,J＝9.03,6.02Hz,1H),4.35-4.41(m,1H),4.25-4.31(m,1H),3.96-4.06(m,2H),3.80-3.91(m,2H),2.74-2.82(m,1H),2.48-2.57(m,1H)。
As described in example 427, steps A to C, except that chiral separation (SFC separation, daicel CHIRALCEL AD,250mm*30mmI.D, 10 μm; mobile phase: CO) was performed after removal of Boc 2 MeOH (containing 0.2% NH) 3 (7M in MeOH)) = 85/15), then examples 441 and 442 were synthesized as described in example 384, steps D and E.
Following a procedure similar to that described in example 427, step A, followed by a procedure similar to that described in example 383, step B, C, E, F, G, chiral separation was performed (SFC, daicel CHIRALCEL AZ,250mm*30mm I.D, 10 μm; mobile phase: CO 2 MeOH (containing 0.2% NH) 3 (7M in MeOH) =60/40)) to synthesize examples 444 and 445.
Example 446 was synthesized following a procedure similar to that described in example 411, step a, followed by a procedure similar to that described in example 383, steps G, B and C.
Example 447 was synthesized following a procedure similar to that described in example 411, step a, followed by a procedure similar to that described in example 383, steps B, C and G. Example 448 was synthesized by a procedure similar to that described in example 447.
Example 449.2- (((R) -3- (3- ((4-cyano-2-fluorophenoxy) methyl) -4-fluorophenyl) pyrrolidin-1-yl) methyl) -4-fluoro-1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (449)
Step A.3- (4-fluoro-3- (methoxycarbonyl) phenyl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (449 a)
The title product (449 a) was synthesized in a similar procedure to that described in example 383, step a. m/z (ESI, positive ion) =344.0 [ m+na ]] + 。
Step B.3- (4-fluoro-3- (methoxycarbonyl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (449 b)
The title product (449 b) was synthesized in a similar procedure to that described in example 427, step a. m/z (ESI, positive ion) =346.1 [ m+na ]] + 。
Step C.3- (4-fluoro-3- (hydroxymethyl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (449 c)
To a mixture of 449b (1.6 g,4.95 mmol) in THF at 0deg.C was added LiAlH 4 (188 mg,4.95 mmol). The resulting mixture was stirred at 0℃for 1.5h. After completion, the reaction was taken up in Na 2 SO 4 .10H 2 O quench, and filter. The filter cake was rinsed with THF (100 mL). The combined organic layers were concentrated to afford the crude title product (449 c) (1.5 g) as a yellow solid, which was used in the next step without further purification. m/z (ESI, positive ion) =318.1 [ m+na ]] + 。
Step D. (R) -3-fluoro-4- ((2-fluoro-5- (pyrrolidin-3-yl) benzyl) oxy) benzonitrile (449 d-P1) and (S) -3-fluoro-4- ((2-fluoro-5- (pyrrolidin-3-yl) benzyl) oxy) benzonitrile (449 d-P2)
Subsequent chiral procedures were performed in a similar manner to those described in example 383, steps B and CSFC separation: daicel CHIRALCEL OZ,250mm*30mm I.D, 10 μm; mobile phase: CO 2 MeOH (containing 0.2% NH) 3 (7M in MeOH)) = 85/15, the title product was synthesized from 449c ((449 d-P1 and 449 d-P2)). m/z (ESI, positive ion) =437.1 [ m+na ]] + .449d-P1 is the early elution peak. Stereochemistry is arbitrarily specified.
Step E.2- (((R) -3- (3- ((4-cyano-2-fluorophenoxy) methyl) -4-fluorophenyl) pyrrolidin-1-yl) methyl) -4-fluoro-1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (449)
The title product (449) was synthesized from 449d-P1 in a similar procedure to that described in steps C through E of example 384. 1 H NMR(400MHz,DMSO-d6)δppm 7.78-7.83(m,1H),7.75(s,1H),7.61-7.69(m,1H),7.41-7.48(m,2H),7.32-7.38(m,1H),7.25-7.32(m,1H),7.12(dd,J＝9.91,8.66Hz,1H),5.20(s,2H),4.94-5.04(m,1H),4.63(dd,J＝15.31,7.28Hz,1H),4.48-4.56(m,1H),4.33-4.43(m,1H),4.24(dt,J＝8.91,5.96Hz,1H),3.99(d,J＝13.55Hz,1H),3.83(d,J＝13.30Hz,1H),3.13-3.19(m,1H),2.88(t,J＝8.41Hz,1H),2.62-2.75(m,2H),2.28-2.35(m,2H),2.16-2.24(m,2H),1.63-1.75(m,1H)。
Example 450 was synthesized from 449d-P2 (late eluting peak) in a similar procedure as described in example 449.
Following a procedure similar to that described in steps a to C of example 449, followed by a procedure similar to that described in steps B, C, E and F of example 383, chiral UPCC separation of enantiomers was performed (Daicel CHIRALCEL AZ,250mm x 30mm i.d.,10 μm; CO 2 MeOH (containing 0.2% NH) 3 (7M in MeOH)) = 70/30), then example 453 was synthesized from methyl 6-chloro-3-fluoropyridine formate in a similar procedure as described in example 383, step G. 453 are formed by early elution peaks.
Examples 454 (eluting from early stage) and 455 (eluting from late stage) were synthesized in a similar procedure as described in example 453. Chiral separation conditions: UPCC (Daicel CHIRALPAKAZ _3,3 x 150mm,3 μm; flow)Mobile phase: CO 2 MeOH (0.1% dea) =60/40).
Example 459 (S) -2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2-fluorobenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (459)
Step A. Methanesulfonic acid (4-bromopyridin-2-yl) methyl ester (459 a)
To a solution of (4-bromopyridin-2-yl) methanol (3 g,0.016 mol) in DCM (50 mL) was added DIPEA (6.2 g,0.05 mol). After stirring for 3min, methanesulfonic anhydride (4.18 mg,0.02 mol) was added at 0 ℃. After stirring at 20℃for 1H, reaction H was taken up 2 O (80 mL) was quenched and extracted with EtOAc (50 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 (459 a) (3 g), which was used in the next step without further purification. m/z (ESI, positive ion) =267.9 [ m+h ]] + 。
Step B.4-bromo-2- ((4-chloro-2-fluorophenoxy) methyl) pyridine (459 b)
To a solution of 459a (3 g,0.01 mol) in DMF (20 mL) was added 4-chloro-2-fluorophenol (1.82 g,0.01 mol) and K 2 CO 3 (15.62 g,0.113 mol). The resulting mixture was heated at 80℃for 12h. The reaction mixture was treated with H 2 O (8 mL) was quenched and extracted with EtOAc (50 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give the title product (459 b) as a colourless oil (3.0 g, 79%). m/z (ESI, positive ion) =317.9 [ M+H ]] + 。
Step C.2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2-fluorophenyl) acetic acid methyl ester (459 c)
Vials were charged with 459b (1.0 g,3.2 mmol), methyl 2- (2-fluoro-4-hydroxyphenyl) acetate (0.59 g,3.2 mmol), cuI (0.06 g,0.0003 mol), pyridine-2-carboxylic acid (0.08 g,0.6 mmol) and K 3 PO 4 (1.36 g,0.0064 mol) and flushed with argon. DMSO (20 mL) was added. Heating the reaction at 100deg.C for 12H, cooling, and using H 2 O (50 mL) was quenched and extracted with EtOAc (50 mL. Times.3). The combined organic layers were concentrated and purified by preparative HPLC (MeCN/H 2 O, with 0.05% tfa as modifier) to afford the title product (459 c) as a brown solid (300 mg, 22%). m/z (ESI, positive ion) =420.3 [ m+h ]] + 。
Step D.2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2-fluorophenyl) acetic acid (459 d)
To 459c (300 mg,0.71 mmol) in MeOH/THF/H 2 To a stirred solution of O (1:1:2, 20 mL) was added LiOH (171.1 mg,7.146 mmol). After stirring at 20 ℃ for 3h, the reaction was quenched with 1N HCl to adjust to ph=6 and extracted with EtOAc (50 ml×3). The combined organic layers were dried over anhydrous Na 2 SO 4 Drying, filtration, concentration, and purification by preparative HPLC (CH 3 CN/H 2 O, with 0.5% tfa as modifier) to afford the title product (459 d) as a yellow oil (200 mg, 68.2%). m/z (ESI, positive ion) =406.2 [ m+h ]] + 。
Step E. (S) -methyl 4- (2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2-fluorophenyl) acetamido) -3-fluoro-5- ((oxetan-2-ylmethyl) amino) benzoate (459 e)
To a stirred solution of 459d (100 mg,0.24 mmol) in DCM (5 mL) was added 4-amino-3-fluoro-5- { [ (2S) -oxetan-2-ylmethyl]Methyl amino } benzoate (62.65 mg,0.24 mmol), DIPEA (95.5 mg,0.73 mmol). After stirring for 30min, HATU (234.2 mg,0.61 mmol) was added. The resulting mixture was stirred at 20℃for 2H 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 provide the crude title product (459 e) as a white solid (80 mg, 50%). m/z (ESI, positive ion) =642.2 [ m+h] + 。
Step F. (S) -2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2-fluorobenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (459 f)
A solution of 459e (50 mg,0.077 mmol) in HOAc (10 ml) was heated at 100deg.C for 5h. The mixture was concentrated to give the crude title product (459 f) as a white solid (40 mg, 78.2%) which was used in the next step without further purification. m/z (ESI, positive ion) =624.2 [ M+H ] ] + 。
Step g. (S) -2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2-fluorobenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (459)
To 459f (50 mg,0.08 mmol) in CH 3 OH/H 2 To a solution in O (2 mL, 1:1) was added LiOH (19 mg,0.8 mmol). After stirring at room temperature for 2h, the reaction was quenched with 1NHCl and adjusted to ph=7. The mixture was treated with DCM/CH 3 OH (10:1) (5 mL. Times.2) extraction. The combined organic layers were concentrated and purified by preparative TLC (silica gel, DCM: CH 3 Oh=10:1) to afford the title product (459) as a white solid (15 mg, 30.3%). m/z (ESI, positive ion) =610.2 [ m+h ]] + 。 1 H NMR(400MHz,CD3OD)δ8.42(d,J＝5.8Hz,1H),8.08(d,J＝0.9Hz,1H),7.63(d,J＝11.4Hz,1H),7.36(t,J＝8.5Hz,1H),7.03-7.21(m,4H),6.90-7.01(m,3H),5.09-5.23(m,3H),4.33-4.75(m,6H),2.77(dd,J＝18.5,7.0Hz,1H),2.41-2.52(m,1H)。
Examples 462, 466 were synthesized in a similar procedure to that described in example 459.
Example 460.2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-fluorobenzyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (460)
Step A.4- ((4-chloropyrimidin-2-yl) methoxy) -3-fluorobenzonitrile (460 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 (460 a) as a white solid (93 mg, 71%). m/z (ESI, positive ion) =264.1 [ m+h ]] + 。
Step B.2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-fluorophenyl) acetic acid methyl ester (460 b)
The vial was filled with 460a (175 mg,0.66 mmol), methyl 2- (2-fluoro-4-hydroxyphenyl) acetate (134 mg,0.73 mmol), cs 2 CO 3 (433 mg,1.33 mmol) and degassed and inflated with Ar balloon. Anhydrous toluene (27 mL) was added (vial A). The same degassing and Ar protection procedure was applied to Pd-containing 2 (dba) 3 A separate vial of a solution of (27 mg,0.05 mmol) and BINAP (92 mg,0.22 mmol) in anhydrous toluene (3 mL) was then heated to 110℃for 5 and transferred to vial A. The resulting reaction mixture was heated at 110 ℃ overnight. After cooling, the reaction was diluted with water 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 afford the title product (460 b) (233 mg, 85%).
Step C.2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-fluorophenyl) acetic acid (460 c)
460b (66 mg,0.16 mmol) was dissolved in CH 3 CN (4 mL) and 2NNaOH (2 mL) was added. The mixture was stirred at room temperature for 2h and directly subjected to reverse phase HPLC (gradient elution, 20-100% ch) 3 CN/water with 0.1% tfa as modifier) to afford the title product (460 c) (15 mg, 95%). m/z (ESI, positive ion) =398.2 [ m+h ]] + 。
Step D.4- (2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-fluorophenyl) acetamido) -3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzoic acid methyl ester (460 d)
To a stirred solution of 460c (15 mg,0.038 mmol) and HATU (29 mg,0.076 mmol) in DMF (1 mL) was added DIPEA (14.6 mg,0.11 mmol). After 5min IIe (11 mg,0.04 mmol) was added and the mixture was stirred at room temperature for 1h. After completion, the mixture isDirectly by reverse phase HPLC (CH 3 CN/water with 0.1% tfa as modifier) to afford the title product (460 d) as a white solid (8 mg, 32%). m/z (ESI, positive ion) =654.3 [ m+h ]] + 。
Step E.2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-fluorobenzyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (460 e)
460d (8 mg,0.012 mmol) was heated in HOAc (3 mL) at 65deg.C overnight. After completion, the reaction was concentrated, then co-evaporated with hexane and water to afford the crude title product (460 e), which was used in the next step without further purification. m/z (ESI, positive ion) =636.3 [ m+h ] ] + 。
Step F.2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-fluorobenzyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (460)
To 460e (crude) in CH 3 To a solution of CN (1 mL), 2N NaOH (0.5 mL) was added. The reaction was heated at 60℃for 1h and directly by reverse phase HPLC (gradient elution, 0-75% CH 3 CN/water with 0.1% tfa as modifier) to afford the title product (460) as a white solid (3.6 mg,47%,2 steps). m/z (ESI, positive ion) =622.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 9.00(s,1H),8.65(d,J＝5.87Hz,1H),8.22(d,J＝0.73Hz,1H),8.04(dd,J＝8.62,1.65Hz,1H),7.76(d,J＝8.80Hz,1H),7.33-7.39(m,2H),7.30(t,J＝8.44Hz,1H),7.09(t,J＝8.44Hz,1H),7.03(d,J＝5.87Hz,1H),6.80-6.88(m,3H),5.87(d,J＝0.73Hz,2H),5.35(s,2H),4.46(s,2H),4.33(q,J＝7.34Hz,2H),1.56(t,J＝7.34Hz,3H)。
Examples 461 and 463 were synthesized in analogy to the procedure described in example 460, starting from 2-chloro-6- (chloromethyl) pyridine. Example 469 was synthesized in a similar procedure to that described in example 460.
In a similar procedure to that described in example 470, NH was used 4 OH was synthesized as a modifier for the final purification step for examples 464, 465, 467, 468 and 470 (from IIIf).
EXAMPLE 471 (S) -2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -3-fluorobenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (471)
Step A.2- (3-fluoro-4-hydroxyphenyl) acetic acid methyl ester (471 a)
To a stirred solution of (3-fluoro-4-hydroxyphenyl) acetic acid (1.5 g,8.8 mmol) and DMF (0.06 g,0.8 mmol) in MeOH (20 mL) at 0deg.C was added thionyl chloride (1.57 g,13.2 mmol). After stirring at 0deg.C for 2H, reaction H was used 2 O (25 mL) was diluted and extracted with EtOAc (30 mL. Times.3). The combined organic layers were dried and concentrated to afford the crude title product (471 a) (1.6 g, 94%) as a colorless oil. m/z (ESI, positive ion) =185.1 [ M+H ]] + 。
Step B.2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -3-fluorophenyl) acetic acid methyl ester (471 b)
471a (200 mg,1.09 mmol), 471b (378 mg,1.19 mmol), palladium diacetate (49 mg,0.22 mmol), tBuXphos (92 mg,0.22 mmol) and K are reacted under nitrogen at 100deg.C 3 PO 4 A solution of (463mg, 2.17 mmol) in toluene (10 mL) was heated for 6h. After completion, the reaction was cooled, using 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 (EtOAc: petroleum ether=1:3) to afford the title product (471 b) as a white solid (260 mg, 54%). m/z (ESI, positive ion) =420.1 [ M+H ]] + 。
Step C.2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -3-fluorophenyl) acetic acid (471 c)
To a stirred solution of 471b (370 mg,0.88 mmol) in THF (15 mL) at 25deg.C was added lithium hydroxide (211 mg,8.81 mmol) in H 2 O (5 mL). The reaction mixture was stirred at 25℃for 4h. After completion, 1N HCl was added to the mixture in an ice bath to adjust to ph=5. The reaction mixture was then extracted with EtOAc (25 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by silica gel column chromatography (EtOAc: petroleum ether=1:1) to afford the title product (471 c) as a white solid (275 mg, 73%). m/z (ESI, positive ion) =406.1 [ m+h ] ] + 。
Step D. (S) -methyl 4- (2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -3-fluorophenyl) acetamido) -3-fluoro-5- ((oxetan-2-ylmethyl) amino) benzoate (471 d)
To a stirred solution of 471c (30 mg,0.07 mmol), ig (21 mg,0.08 mmol) in DCM (2 mL) at 25℃was added T 3 P (94 mg,0.15mmol,50% in EtOAc), DIPEA (38 mg,0.30 mmol). After stirring at 25℃for 2H, reaction H was taken up 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 (DCM: meoh=20:1) to afford the title product (471 d) as a white solid (24 mg, 48%). m/z (ESI, positive ion) =642.2 [ m+h] + 。
Step E. (S) -2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -3-fluorobenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (471)
The title product (471) was synthesized from 471d in analogy to the procedure described in example 459, steps F and G. m/z (ESI, positive ion) =610.1 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.43(d,J＝5.79Hz,1H),8.11(s,1H),7.67(d,J＝11.31Hz,1H),7.33(d,J＝10.61Hz,1H),7.22-7.29(m,2H),7.02-7.19(m,4H),6.97(dd,J＝5.74,2.43Hz,1H),5.19(s,2H),5.14(dd,J＝9.59,4.47Hz,1H),4.59-4.71(m,2H),4.55(d,J＝5.63Hz,2H),4.52(dd,J＝15.72,2.39Hz,1H),4.43(dt,J＝9.16,5.92Hz,1H),2.77(dt,J＝14.10,7.95Hz,1H),2.47(dt,J＝11.37,7.36Hz,1H)。
EXAMPLE 472 (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 (472)
Step A.4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (472 b)
A solution of 472a (synthesized as 460a, 27.3mg,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 (472 b) (8 mg), which was not further purifiedI.e. directly used in the next 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 (472 c)
A solution of 472b (8 mg, 18.3. Mu. Mol) and trifluoroacetic acid (0.5 mL) in DCM (1 mL) was stirred at 21℃for 2h. After completion, the reaction was concentrated and co-evaporated with DCE (3×2 mL) to afford the title product (472 c) (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 (472 d)
A solution of crude 472c (8 mg), ih (7 mg, 23.8. Mu. Mol) and DIPEA (41.4. Mu.L, 238. Mu. Mol) in DMF (0.5 mL) was stirred at 21℃for 24h. 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 (472 d) (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 (472)
A mixture of 472d (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 at 21℃for 4h. At the endAfter formation, the reaction mixture is taken up in 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 (472) as a colorless solid (7.1 mg, 52%). 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 473 was synthesized in a similar procedure as described in example 472.
EXAMPLE 474 (S) -2- ((3- (2- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (474)
Step A. oxazol-2-yl-methanol (474 a)
To a solution of oxazole-2-carboxylic acid ethyl ester (12.8 g,90.8 mmol) in MeOH (100 mL) at 0deg.C was added LiBH 4 (7.9 g,363.1 mmol). After stirring at 15℃for 16H, reaction H was taken up 2 O (100 mL) was diluted and concentrated to remove MeOH. The resulting mixture was extracted with EtOAc (200 mL. Times.3). The combined organic layers were dried and concentrated to afford crude title product (474 a) (5.7 g, 63%) as a yellow oil, which was not passed throughFurther purification was carried out directly to the next step. m/z (ESI, positive ion) =100.1 [ m+h ]] + 。
Step B.2- (((tert-butyldimethylsilyl) oxy) methyl) oxazole (474 b)
To a solution of 474a (5.7 g,57.0 mmol) and imidazole (5.81 g,85.5 mmol) in THF (50 mL) was added TBSCl (12.9 g,85.5 mmol). After stirring at 15℃for 2H, reaction H was taken up 2 O (100 mL) was diluted and extracted with EtOAc (100 mL. Times.3). The organic layer was dried, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=20:1) to afford the title product (474 b) as a colorless oil (11.2 g, 92.2%). m/z (ESI, positive ion) =214.2 [ m+h ]] + 。
Step C.5-bromo-2- (((tert-butyldimethylsilyl) oxy) methyl) oxazole (474 c)
To a solution of 474b (12.6 g,59.2 mmol) in THF (100 mL) at-60℃was added dropwise n-BuLi (2.5M in hexane) (30.8 mL,77.0 mmol) and TMEDA (4.46 g,38.5 mmol). After stirring for 3h at-60 ℃, CBr was added 4 (29.4 g,88.8 mmol) and the reaction was warmed to room temperature and stirred at 17℃for 4h. After completion, the reaction was completed with H 2 O (100 mL) was quenched and extracted with EtOAc (100 mL. Times.3). The combined organic layers were dried, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=30:1) to afford the title product (474 c) as a yellow oil (10.8 g, 62.5%). m/z (ESI, positive ion) =292.1 [ m+h ]] + 。
Step d. (5-bromooxazol-2-yl) methanol (474 d)
To 474c (10.8 g, 3)7.1 mmol) in MeOH (50 mL) HCl (4N in dioxane, 20 mL) was added. After stirring for 1h at 17℃the reaction was concentrated and purified by reverse phase HPLC (CH 3 CN/H 2 O, with 0.1% formic acid as modifier) to afford the title product (474 d) as a yellow oil (3.9 g, 59%). m/z (ESI, positive ion) =178.1 [ m+h ]] + 。
Step E.5-bromo-2- ((2, 4-dichlorophenoxy) methyl) oxazole (474 e
To 474d (3.9 g,21.9 mmol), 2, 4-dichlorophenol (3.9 g,24.1 mmol), PPh 3 (7.5 g,28.5 mmol) to a solution of DEAD (5.0 g,28.5 mmol) in THF (20 mL) was added. After stirring at 17℃for 3H, reaction H was taken up 2 O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: etoac=3:1) to afford the title product (474 e) as a pale yellow solid (4.2 g, 60%). m/z (ESI, positive ion) =323.9 [ m+h ] ] + 。
Step F. (S) -2- ((3- (2- ((2, 4-dichlorophenoxy) methyl) oxazol-5-yl) -2, 5-dihydro-1H-pyrrol-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (474)
The title product (474) was synthesized from 474E in a similar procedure as described in example 4, steps A, C, D and E. m/z (ESI, positive ion) =555.3 [ m+h ]] + 。 1 H NMR(600MHz,CD 3 OD)δppm 8.17(s,1H),7.95(dd,J＝8.44,1.47Hz,1H),7.59(d,J＝8.44Hz,1H),7.43(d,J＝2.20Hz,1H),7.27(dd,J＝8.80,2.57Hz,1H),7.21(d,J＝8.80Hz,1H),7.07(s,1H)6.23-6.28(m,1H),5.21-5.29(m,3H),4.84-4.87(m,1H),4.68(br dd,J＝15.41,2.93Hz,1H),4.58-4.64(m,1H),4.44(dt,J＝9.17,5.87Hz,1H),4.33(d,J＝13.94Hz,1H),4.25(d,J＝13.94Hz,1H),3.73-3.89(m,4H),2.74-2.80(m,1H),2.49-2.61(m,1H)。
Examples 516 and 517 were synthesized by a procedure similar to that described in example 449, except that SFC chiral separation was performed in the penultimate step (CHIRALPAK AY-H,0.46cm I.D.. Times.25 cm, meOH/CH) prior to ester hydrolysis 3 CN/dea=80/20/0.1 (V/V)). Example 516 is the first peak eluting from the separation and 517 is the second peak. Stereochemistry is arbitrarily specified.
Example 518 and example 519 were synthesized in a similar procedure as described in examples 516 and 517. SFC chiral separation conditions: CHIRALPAK AY-3 (0.46 cm I.D.×15cm, hexane/EtOH/DEA=50/50/0.1). Example 518 is the first peak eluting from separation and 519 is the second peak. Stereochemistry is arbitrarily specified.
Examples 520 and 521 were synthesized in a similar procedure as in example 397.
Example 522.2- ((1- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -3-azabicyclo [3.1.0] hexane-3-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (522)
(6-chloro-3-fluoropyridin-2-yl) methanol (522 a)
Methyl 6-chloro-3-fluoropyridine-2-carboxylate (2.16 g,11.4 mmol) was dissolved in ethanol (57 mL) and cooled to 0deg.C. Slowly add CaCl 2 (1.9 g,17.1 mmol) and NaBH 4 (647 mg,17.1 mmol) and the reaction mixture was warmed to 21℃and stirred for 3h. After completion, the reaction was slowly poured into H 2 O (30 mL) and 30% IPA/CHCl 3 (30 mL. Times.3) extraction. The combined organic layers were taken up with Na 2 SO 4 Dried, filtered, and concentrated to provide the title product 522a (1.84 g, 100%) as a colorless solid, which was not further purifiedThe conversion is used directly in the next step. m/z (ESI, positive ion) =162.1 [ m+h ]] + 。
Step B4- ((6-chloro-3-fluoropyridin-2-yl) methoxy) -3-fluorobenzonitrile (522B)
522a (32.3 mg,0.2 mmol), 3-chloro-4-hydroxybenzonitrile (30.7 mg,0.2 mmol), PPh 3 A mixture of (78.7 mg,0.3 mmol) and DCM (1 mL) was cooled to 0deg.C. Slowly adding N- ({ [ (4-chlorophenyl) methoxy group]Carbonyl } imino) [ (4-chlorophenyl) methoxy group]Formamide (110 mg,0.3 mmol) and the reaction was warmed to 21 ℃ and stirred for 1h. After completion, the reaction mixture was filtered and purified directly by silica gel column chromatography (gradient elution, 0 to 75% etoac/hexanes) to give 522b (50 mg, 84%) as a colorless solid. m/z (ESI, positive ion) =297.1 [ m+h ] ] + 。
Step C:1- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (522 c)
522b (140 mg,0.5 mmol), {3- [ (tert-butoxy) carbonyl]-3-azabicyclo [3.1.0]Hexane-1-yl } trifluoroborane onium (144 mg,0.5 mmol), cataCXium-A-Pd-G3 (18.2 mg, 25. Mu. Mol), cs 2 CO 3 (4819 mg,3 equivalents, 1.5 mmol), toluene (12 mL) and H 2 The mixture of O (1.2 mL) was thoroughly purged with Ar for 10min. The reaction mixture was heated to 90 ℃ for 18h. After completion, the reaction was concentrated and purified directly by silica gel column chromatography (0 to 30% etoac/DCM) to give 522c (214 mg, 76%) as a colourless solid. m/z (ESI, positive ion) =450.3 [ m+na ]] + 。
Step D.2- ((1- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -3-azabicyclo [3.1.0] hexane-3-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (522)
The title compound (522) was synthesized from 522C in analogy to the procedure described in steps C to E of example 384. m/z (ESI, positive ion) =572.4 [ m+h ]] + 。 1 H NMR(400MHz,DMSO-d 6 ))δppm 8.16(s,1H),7.88-7.83(m,1H),7.79(dd,J＝1.2,8.3Hz,1H),7.65-7.73(m,2H),7.50-7.57(m,2H),7.22-7.28(m,1H),5.40(s,2H),5.04(q,J＝7.2Hz,1H),4.72(ddd,J＝4.7,7.1,15.2Hz,1H),4.57(td,J＝2.9,15.1Hz,1H),4.45-4.53(m,1H),4.28-4.44(m,1H),4.09(d,J＝13.3Hz,1H),3.87-3.98(m,1H),3.15(br d,J＝8.8Hz,1H),2.86-3.01(m,1H),2.82-2.94(m,1H),2.56-2.75(m,2H),2.37-2.45(m,1H),1.85-1.93(m,1H),1.35(t,J＝3.9Hz,1H),1.00-1.06(m,1H)。
Examples 523, 524, 525, 531 and 532 were synthesized in a similar procedure to that described in example 522. Examples 531 and 532 result from chiral separation 522 c.
Example 528.2- (((2R) -4- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2- (fluoromethyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (528)
Step A. (R) -4- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid 1- (tert-butyl) ester 2-methyl ester (528 a)
4- [ (6-chloro-3-fluoropyridin-2-yl) methoxy group]-3-fluorobenzonitrile (140 mg,0.5 mmol), (2R) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl 2-methyl ester (212 mg,0.6 mmol), pd (dppf) Cl 2 (36.6mg,50μmol)、K 2 CO 3 A mixture of (2M) (0.5 mL,1 mmol) and 1, 4-dioxane (2 mL) was purged with Ar and heated to 100deg.C for 3h. After completion, the reaction mixture was diluted with EtOAc (5 mL), with Na 2 SO 4 Dried, and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution, 0 to 30% etoac/DCM) to provide the title compound (528 a) (169 mg, 72%). m/z (ESI, positive ion) =472.4 [ m+h ]] + 。
(R) -4- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2- (hydroxymethyl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (528 b)
528a (165 mg,0.35 mmol) and THF (3.5 mL) were cooled to 0deg.C. Slowly add LiBH 4 (15.2 mg,0.7 mmol) and the reaction mixture was warmed to 21℃and stirred for 24h. The reaction mixture was quenched with ice, with EtOAc (30 mL) and H 2 O (10 mL) dilution. The organic layer was washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (gradient elution, 0 to 100% etoac/DCM) to give 528b (103 mg, 66%) as a colorless oil. m/z (ESI, positive ion) =444.4 [ M+H ]] + 。
Step C. (2R) -4- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (528 c)
At 1atm H 2 528b (22.2 mg, 50. Mu. Mol), meOH (1 mL) and 10% Pd/C (0.5 mg, 5. Mu. Mol) were stirred for 3h. The reaction mixture was filtered through celite and rinsed with MeOH (5 mL). The filtrate was concentrated to afford the title product (528 c) which was used directly in the next step without further purification. m/z (ESI, positive ion) =446.4 [ M+H ]] + 。
Step D.3-fluoro-4- ((3-fluoro-6- ((5R) -5- (hydroxymethyl) pyrrolidin-3-yl) pyridin-2-yl) methoxy) benzonitrile (528 d)
A solution of 528c (from crude above), TFA (0.2 mL) in DCM (1 mL) was stirred at 21℃for 2h. After completion, the reaction mixture was concentrated and co-evaporated with DCE (2 ml×3) to afford the title product (528 d), which was used directly in the next step without further purification. m/z (ESI, positive ion) =346.4 [ m+h ]] + 。
Step E.2- (((2R) -4- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (528 e)
A mixture of 528d (23 mg, 50. Mu. Mol), ih, DMF (250. Mu.L) and DIPEA (43.5. Mu.L, 250. Mu. Mol) was stirred for 18h at 21 ℃. After completion, the reaction is carried out using H 2 O (20 mL) was diluted and stirred for 1h. The aqueous layer was decanted. The residual solid was taken up in H 2 O (5 mL) was washed and dried to yield 528e, which was used directly in the next step without further purification. m/z (ESI, positive ion) =604.3 [ m+h ]] + 。
Step F.2- (((2R) -4- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2- (fluoromethyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (528 f)
528e (15.1 mg, 25. Mu. Mol) was dissolved in DCM (3 mL) and cooled to-78 ℃. DAST (6.61. Mu.L, 50. Mu. Mol) in DCM (3 mL) was added dropwise and the reaction mixture was stirred for 3h at-78 ℃. After completion, the reaction mixture was taken up in saturated NaHCO 3 Aqueous (1 mL) quench and the organic layer was quenched with H 2 O (1 mL), brine (1 mL), and Na 2 SO 4 Dried, filtered, and concentrated to provide the title compound (528 f) which was used directly in the next step without further purification. LCMS indicated a 3:1 mixture of isomers. m/z (ESI, positive ion) =606.5 [ m+h ]] + 。
Step G.2- (((2R) -4- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2- (fluoromethyl) pyrrolidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (528)
528f (30.3 mg, 50. Mu. Mol), THF (250. Mu.L) and isopropanol (250. Mu.L) were cooled to 0deg.C. LiOH (1M) (245 μl,250 μmol) was slowly added and the reaction mixture was warmed to 21 ℃ and stirred for 7h. After completion, the reaction mixture was taken up with 2mL of H 2 O was diluted and directly passed through reverse phase HPLC (Gemini 5um C18 110A, 250X 21.2 mm) at 15ml/min (15-35% CH 3 CN/H 2 O, with 0.05% NH 4 OH as a modifier) to afford the title compound (528) (1.1 mg,4% of isomer in 3:1 mixture) as a colorless solid. m/z (ESI, positive ion) =592.3 [ m+h ]] + 。
Examples 526 and 527 are a pair of diastereomers and were synthesized in a similar procedure as described in example 528, and separated in the final step by reverse phase HPLC. 527 is the major isomer and post-elution peak. Stereochemistry is arbitrarily specified.
Example 533.2- (((S) -1- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (533)
Step a. tert-butyl (S) -3- (2- ((4- (methoxycarbonyl) -2- ((((S) -oxetan-2-yl) methyl) amino) phenyl) amino) -2-oxoethyl) pyrrolidine-1-carboxylate (533 a)
To a solution of (S) -2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid (28.0 mg,0.122 mmol), ig (28.9 mg,0.122 mmol) and HATU (43.1 mg, 0.183mmol) in THF (0.6 mL) was added DIPEA (42.5 μl,0.244 mmol) at room temperature. The reaction mixture was stirred for 1h. After completion, the reaction solvent was removed under reduced pressure to afford the title product (533 a) (55.0 mg) as crude material, which was used in the next step without further purification. m/z (ESI, positive ion) =448.3 [ m+h ] ] +
Step B.2- (((S) -1- (tert-Butoxycarbonyl) pyrrolidin-3-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (533 b)
A solution of 533a (55.0 mg,0.123 mmol) in glacial acetic acid (1.0 mL) is stirred for 16h. After completion, the acetic acid was removed in vacuo. The resulting residue was diluted with EtOAc (20 mL). The organic layer was saturated with NaHCO 3 (20 mL. Times.2), brine (5 mL), washed with Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (gradient elution, 50-90% etoac/hexanes) to afford the title product (533 b) as a yellow oil (31 mg, 59%). m/z (ESI, positive ion) =430.2 [ m+h ]] + 。
Step C.1- (((S) -oxetan-2-yl) methyl) -2- (((S) -pyrrolidin-3-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (533 c)
533b (31.0 mg,0.072 mmol) was taken up in DCM at room temperature0.5 mL) and TFA (0.5 mL) 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 give the title product (533 c) as a colorless oil (26.5 mg), which was used in the next step without further purification. m/z (ESI, positive ion) =330.2 [ m+h ] ] +
Step D.2- (((S) -1- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (533 d)
4- ((6-chloro-3-fluoropyridin-2-yl) methoxy) -3-fluorobenzonitrile (22.6 mg,0.080 mmol), 533c (26.5 mg,0.080 mmol), pd (OAc) 2 (1.81 mg,0.008 mmol), BINAP (10.0 mg,0.016 mmol) and Cs 2 CO 3 A solution of (52.4 mg,0.161 mmol) in toluene (0.8 mL) was purged with argon for 5min. It was stirred at 110℃for 16h. After completion, the reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated, and the resulting crude residue was purified by silica gel column chromatography (50-90% etoac/hexanes) to afford the title product (533 d) as a colorless oil (12.4 mg, 27%). m/z (ESI, positive ion) =574.2 [ M+1 ]] + 。
Step E.2- (((S) -1- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (533)
533d (12.4 mg,0.022 mmol) and LiOH (2.6 mg,0.11 mmol) were combined in THF: iPrOH: H at room temperature 2 Solution stirring in o=1:1:1 (0.6 mL) 16h. After completion, the reaction solvent was removed under reduced pressure and the resulting residue was diluted to 2mL with water/acetonitrile (1:1) and purified by reverse phase HPLC (gradient elution, 20-60% ch) 3 CN/H 2 O, with 20mM NH 4 HCO 3 As a modifier) to afford the title product (533) (4.3 mg, 36%) as a white solid. m/z (ESI, positive ion) =560.3 [ m+h ]] + 。 1 H NMR(400MHz,DMSO-d6)δppm 8.18(s,1H),7.76-7.84(m,2H),7.46-7.68(m,4H),6.48(dd,J＝9.2,2.8Hz,1H),5.25(d,J＝1.7Hz,2H),4.97-5.06(m,1H),4.57-4.66(m,1H),4.38-4.54(m,2H),4.29(dt,J＝9.2,5.9Hz,1H),3.69(dd,J＝10.3Hz,1H),3.45-3.53(m,1H),3.35-3.42(m,1H),3.04-3.18(m,3H),2.91-3.02(m,1H),2.62-2.72(m,1H),2.28-2.40(m,1H),2.16-2.27(m,1H),1.73-1.86(m,1H)。
Examples 529, 530 and 534 were synthesized in a similar procedure to that described in example 533.
EXAMPLE 535 (S) -2- ((3- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2-oxoimidazolidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (535)
Step A.4- ((6-chloro-3-fluoropyridin-2-yl) methoxy) -3-fluorobenzonitrile (535 a)
To a stirred solution of (6-chloro-3-fluoropyridin-2-yl) methanol (0.75 g,4.64 mmol), 3-fluoro-4-hydroxybenzonitrile (0.643 g,4.64 mmol) and triphenylphosphine (1.83 g,4.64 mmol) in anhydrous DCM (10 mL) at 0deg.C was added di (4-chlorobenzyl) azodicarboxylate (2.56 g,4.64 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 2h. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure and purified by silica gel column chromatography to afford the title compound (535 a) (910 mg, 70%) as a white solid. m/z (ESI, positive ion) =281.3 [ m+h ] ] + 。
Step B.3-fluoro-4- ((3-fluoro-6- (2-oxoimidazolidin-1-yl) pyridin-2-yl) methoxy) benzonitrile (535 b)
535a (30 mg,0.107 mmol) was dissolved in anhydrous dioxane (2 mL) and degassed using an argon balloon for 10min. Imidazolidin-2-one (0.046 mg,0.534 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (6 mg,10 mol%), pd (OAc) 2 (5 mol%) and Cs 2 CO 3 (52 mg,0.16 mmol) was added to the degassed solution and stirred overnight at 100 ℃. The reaction mixture was treated with saturated NH 4 Cl quench and remove solvent under reduced pressure. The crude residue was diluted with brine and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure, which was purified by silica gel column chromatography to give the title product (535 b) as a colorless gum-like liquid (14 mg, 40%). m/z (ESI, positive ion) =331.3 [ m+h ]] + 。
Step C. (S) -2- ((3- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2-oxoimidazolidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (535 c)
To a stirred solution of 535b (14 mg,0.042 mmol) in anhydrous DMF (2 mL) was added Ih (16 mg,0.055 mmol) and DIPEA (0.022 mL,0.127 mmol). After stirring overnight at 60 ℃, the reaction mixture was quenched with water and diluted with brine. The aqueous layer was extracted with ethyl acetate (5 ml×3) and 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 using methanol and DCM to give the title product (535 c) (12 mg, 48%). m/z (ESI, positive ion) =589.3 [ m+h ]] + 。
Step d. (S) -2- ((3- (6- ((4-cyano-2-fluorophenoxy) methyl) -5-fluoropyridin-2-yl) -2-oxoimidazolidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (535)
To a stirred solution of 535c (12 mg,0.02 mmol) in THF/methanol/water (6:1:1, 2 mL) was added lithium hydroxide (4 mg,0.102 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with acetic acid and the solvent was removed under reduced pressure. The crude mixture was diluted with brine and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, concentrated, and purified by silica gel column chromatography using methanol/DCM to give the title product (535) as a white solid (4 mg, 34%). m/z (ESI, positive ion) =575.3 [ m+h ]] + 。 1 H NMR(400MHz,CDCl 3 )δppm 8.25(dd,J＝9.2,3.3Hz,1H),8.09(s,1H),7.96(d,J＝8.4Hz,1H),7.73(d,J＝8.6Hz,1H),7.36(d,J＝8.1Hz,1H),7.26-7.31(m,2H),7.13(t,J＝8.4Hz,1H),5.20(s,2H),5.07-5.10(m,1H),4.94(d,J＝15.6Hz,1H),4.81(d,J＝15.6Hz,1H),4.66-4.70(m,1H),4.42-4.52(m,2H),4.31-4.36(m,1H),3.86-3.90(m,2H),3.55-3.60(m,2H),2.62-2.71(m,1H),2.32-2.40(m,1H)。
EXAMPLE 536 (S) -2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2, 5-difluorobenzyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (536)
Step A.2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2, 5-difluorophenyl) acetic acid tert-butyl ester (536 a)
459b (250 mg,0.79 mmol), IIIf (212 mg,0.87 mmol),tBuXphos (67 mg,0.16 mmol) and Pd (OAc) 2 (35 mg,0.16 mmol) in toluene (8 mL) K was added 3 PO 4 (218 mg,1.58 mmol). At 100℃under N 2 After heating for 8h, the reaction was filtered and concentrated. The crude residue was purified by preparative TLC (EtOAc: petroleum ether=1:1) to afford the title product (536 a) (200 mg, 48%). m/z (ESI, positive ion) =480.1 [ M+H ]] + 。
Step B.2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2, 5-difluorophenyl) acetic acid (536 b)
To a stirred solution of 536a (100 mg,0.21 mmol) in DCM (2 mL) at 0deg.C was added 0.5mL TFA. After stirring at 25 ℃ for 2h, the reaction mixture was concentrated under reduced pressure to afford crude product (536 b) (70 mg) as a yellow oil. m/z (ESI, positive ion) =424.1 [ M+H ]] + 。
Step C. (S) -methyl 4- (2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2, 5-difluorophenyl) acetamido) -3- ((oxetan-2-ylmethyl) amino) benzoate (536 c)
To a stirred solution of 536b (109 mg,0.21 mmol), ig (49 mg,0.21 mmol) and DIPEA (134 mg,1.04 mmol) in DCM (2 mL) at 0deg.C was added T 3 P (198mg, 0.31mmol,50% in EtOAc). After stirring at 25 ℃ for 5h, the reaction was quenched by addition of aqueous sodium bicarbonate (10 mL) and extracted with DCM (10 ml×3). The combined organic layers were taken up over Na 2 SO 4 Drying, filtration, concentration, and purification by reverse phase HPLC (45% ch) 3 CN/H 2 O) to afford the title product (536 c) as a yellow oil (42 mg, 30%). m/z (ESI, positive ion) =643.1 [ m+h ]] + 。
Step D.2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2, 5-difluorobenzyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (536 d)
A solution of 536c (42 mg,0.07 mmol) in HOAc was heated at 100deg.C for 3h. The reaction mixture was then poured into water (5 mL) and extracted with EtOAc (15 ml×2). The organic layer was dried, filtered and concentrated in vacuo. The crude residue was purified by preparative TLC (10% meoh/DCM) to give the title product (536 d) as a yellow oil (16 mg, 38%). m/z (ESI, positive ion) =625.1 [ M+H ]] + 。
Step E. (S) -2- (4- ((2- ((4-chloro-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -2, 5-difluorobenzyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (536)
To a stirred solution of 536d (16 mg,0.03 mmol) in THF (1 mL) at 25deg.C was added dropwise lithium hydroxide (6 mg,0.26 mmol) in H 2 O (1 mL). The reaction mixture was stirred at 25℃for 3h. After completion, 1N HCl (about 2.0 mL) was added to the mixture in an ice bath to adjust to ph=6. The reaction mixture was then extracted with EtOAc (15 mL. Times.3). The combined organic layers were dried, filtered, concentrated and purified by reverse phase HPLC (CH 3 CN/H 2 O, with 0.1% nh4oh as modifier) to afford the title product (536) as a white solid (1.7 mg, 10%). m/z (ESI, positive ion) =610.1 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.47(d,J＝5.80Hz,1H),8.18(s,1H),7.99(d,J＝8.40Hz,1H),7.58(d,J＝8.43Hz,1H),7.32(dd,J＝10.59,6.74Hz,1H),7.21-7.26(m,1H),7.20(d,J＝2.49Hz,1H),7.14-7.18(m,1H),7.12(d,J＝7.45Hz,1H),7.07-7.11(m,1H),7.05(dd,J＝5.79,2.53Hz,1H),5.18-5.29(m,3H),4.69(dd,J＝15.63,6.72Hz,1H),4.62-4.66(m,1H),4.61(d,J＝3.54Hz,1H),4.56-4.58(m,1H),4.50(s,1H),4.41-4.47(m,1H),2.75-2.84(m,1H),2.52(dt,J＝16.39,7.14Hz,1H)。
Examples 537 and 538 were synthesized in a similar procedure as described in example 536. For example 537, methyl 2- (2-fluoro-4-hydroxyphenyl) acetate was used instead of IIIf.
Example 539 (S) -2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -3-fluorobenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (539)
Step A.2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -3-fluorophenyl) acetic acid (539 a)
460a (100 mg,0.38 mmol), 2- (3-fluoro-4-hydroxyphenyl) acetic acid (64.5 mg,0.38 mmol) and K are combined at room temperature 2 CO 3 The solution (105 mg,0.76 mmol) was stirred for 2h. The reaction was diluted with EtOAc and washed with brine. The organic layer was taken up with Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 50-90% etoac/hexanes) to afford the title compound (539 a) as a yellow oil (151 mg, 36.5%). m/z (ESI, positive ion) =398.3 [ M+H ]] + 。
Step b. (S) -2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -3-fluorobenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (539)
The title product (539) was synthesized from 539a in a similar procedure as described in steps C to E of example 536. HATU is used in step C. m/z (ESI, positive ion) =602.3 [ m+h ]] + 。
EXAMPLE 540 (S) -2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylbenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (540)
Step A.2- (2-bromo-4-hydroxyphenyl) acetic acid tert-butyl ester (540 b)
540a (synthesized from 2- (2-bromo-4-hydroxyphenyl) acetic acid in a similar procedure to that described in IIIf steps D to F), 420mg,1.46 mmol), methylboronic acid (262.67 mg,4.39 mmol) and K 2 CO 3 (303 mg,2.19 mmol) in dioxane/H 2 Pd (dppf) Cl was added to a solution in O (4:1, 10 mL) 2 (107 mg,0.15 mmol). At 95℃under N 2 The mixture was stirred for 16h. The mixture was then diluted with EtOAc (50 mL) and washed with brine (50 ml×2). The combined organic layers were dried, evaporated to dryness and purified by silica gel column chromatography (20% etoac/petroleum ether) to afford the title product (540 b) as a white solid (290 mg, 85%). m/z (ESI, positive ion) =245.1 [ m+na ]] + 。
Step B.2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylphenyl) acetic acid tert-butyl ester (540 c)
To a solution of 460a (264 mg,1 mmol) and 540b (222 mg,1 mmol) in DMF (5 mL) was added K 2 CO 3 (138 mg,1 mmol). The mixture was stirred at 50 ℃ for 16h, diluted with EtOAc (30 mL) and washed with brine (30 ml×2). The combined organic layers were dried, evaporated to dryness and the residue purified by silica gel column chromatography (25% etoac/petroleum ether) to afford the title product as a white solidProduct (540 c) (290 mg, 61%). m/z (ESI, positive ion) =450.1 [ m+h ]] + 。
Step C. (S) -2- (4- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyrimidin-4-yl) oxy) -2-methylbenzyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (540)
The title product (540) was synthesized in a similar procedure as described in example 536, steps B to E. m/z (ESI, positive ion) =598.1 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.60(d,J＝5.83Hz,1H),8.11(d,J＝1.09Hz,1H),7.65(d,J＝11.37Hz,1H),7.33-7.51(m,2H),7.11(t,J＝8.47Hz,1H),6.99(d,J＝6.01Hz,3H),6.84(dd,J＝8.36,2.47Hz,1H),5.31(s,2H),5.11(td,J＝6.99,4.80Hz,1H),4.62(ddd,J＝15.59,12.18,7.54Hz,2H),4.51(s,2H),4.39-4.48(m,2H),2.67-2.81(m,1H),2.45(ddd,J＝16.48,11.56,7.43Hz,1H),2.33(s,3H)。
Example 541 was synthesized in a similar procedure as described in example 540.
EXAMPLE 542 (S) -2- ((5- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -3-fluoropyridin-2-yl) methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (542)
Step A.2- (5- (phenylmethyloxy) -3-fluoropyridin-2-yl) malonic acid diethyl ester (542 a)
At 90℃under N 2 Next, 5- (phenylmethyloxy) -2-chloro-3-fluoropyridine (2.0 g,8.4 mmol), diethyl malonate (1.61 g,10.0 mmol), K 3 PO 4 (5.35 g,25.2 mmol), BINAP (520 mg,0.8 mmol) and Pd 2 (dba) 3 A mixture of (230 mg,0.2 mmol) in toluene (20 mL) was stirred for 18h. The mixture was filtered, concentrated, and purified by silica gel column chromatography (EtOAc: petroleum ether=1:4) to afford the title compound (542 a) (0.67 g, 25%) as a colorless oil. m/z (ESI, positive ion) =362.1 [ m+h ]] + 。
Step B.2- (5- (phenylmethyloxy) -3-fluoropyridin-2-yl) acetic acid (542 b)
To 542a (610 mg,1.688 mmol) in EtOH/H 2 NaOH (202 mg,5.064 mmol) was added to the mixture in O (2:1, 10 mL). The reaction was heated at 80℃for 2h. After cooling, the reaction was adjusted to ph=6 with 6N HCl and extracted with EtOAc (25 ml×2). The combined organic layers were treated with H 2 O (20 mL), brine (20 mL), washed with Na 2 SO 4 Dried, filtered, and concentrated to give the title product (542 b) (400 mg, 81.6%). m/z (ESI, positive ion) =262.0 [ m+h ]] + 。
Step C.2- (5- (phenylmethyloxy) -3-fluoropyridin-2-yl) acetic acid methyl ester (542 c)
542b (400 mg,1.53 mmol), thionyl chloride (803 mg,3.06 mmol) was added to CH at 60 ℃ 3 The mixture in OH (5 mL) was stirred for 2h. The mixture was concentrated, diluted with EtOAc (80 mL), and concentrated with NaHCO 3 Aqueous solution (30 mL. Times.2), H 2 O (20 mL) and brine (20 mL). The organic layer was purified by Na 2 SO 4 Dried, filtered, and concentrated in vacuo to afford the title product (542 c) as a colorless oil (410 mg, 86.4%). m/z (ESI, positive ion) =276.1 [ m+h ] ] + 。
Step D.2- (3-fluoro-5-hydroxypyridin-2-yl) acetic acid methyl ester (542 d)
To 542c (410 mg,1.50 mmol) on CH 3 To a mixture in OH (6 mL) was added 10% Pd/C (100 mg). At 20℃at H 2 The reaction was stirred for 2h. It was then filtered and concentrated in vacuo to afford the title product (542 d) (220 mg, 71.8%) as a white solid, which was used in the next step without further purification. m/z (ESI, positive ion) =186.1 [ m+h ]] + 。
Step E. (S) -2- ((5- ((2- ((4-cyano-2-fluorophenoxy) methyl) pyridin-4-yl) oxy) -3-fluoropyridin-2-yl) methyl) -4-fluoro-1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (542)
The title compound (542) was synthesized from 542d and 4- ((4-bromopyridin-2-yl) methoxy) -3-fluorobenzonitrile (synthesized in a similar procedure to 536 a) in a similar procedure as described in steps B to E of example 471. m/z (ESI, positive ion) =602.1 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.50(d,J＝5.75Hz,1H),8.27(d,J＝2.00Hz,1H)8.03(s,1H),7.51-7.65(m,4H),7.27-7.35(m,2H),7.08(dd,J＝5.88,2.38Hz,1H),5.31(s,2H),5.19-5.27(m,1H),4.69-4.82(m,3H),4.59-4.65(m,2H),4.43(dt,J＝9.19,5.91Hz,1H),2.74-2.83(m,1H),2.45-2.54(m,1H)。
In a similar procedure to that described in steps A to D of example 536, subsequent use of Zn (CN) 2 、tBuXphosPdG 3 Conversion of bromo to cyano is performed, followed by synthesis of example 543 from 540a and 4- ((4-bromopyridin-2-yl) methoxy) -3-fluorobenzonitrile according to step E in example 536.
EXAMPLE 544 (S) -2- ((6- ((2- ((2-fluoro-4-methylphenoxy) methyl) pyridin-4-yl) oxy) pyridin-3-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (544)
Step A.2- ((2-fluoro-4-methylphenoxy) methyl) pyridin-4-ol (544 b)
544a ((prepared in a similar procedure to 459b from (4- (phenylmethyloxy) pyridin-2-yl) methanol, 1.02g,3.2 mmol) in TFA (20 mL) was stirred at 80℃for 12H. After completion, the solvent was removed under reduced pressure reaction H was used 2 O (30 mL) was diluted and extracted with EtOAc (30 mL. Times.3). The organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: etoac=7:3) to afford the title product (544 b) as a white solid (0.7 g, 90.6%). m/z (ESI, positive ion) =234.1 [ m+h ]] + 。
Step B.2- (6- ((2- ((2-fluoro-4-methylphenoxy) methyl) pyridin-4-yl) oxy) pyridin-3-yl) methyl acetate (544 c)
544b (200 mg,0.86 mmol), methyl 2- (6-chloropyridin-3-yl) acetate (175 mg,0.94 mmol), pd at 120℃under microwaves 2 (dba) 3 (157 mg,0.17 mmol), BINAP (213 mg,0.34 mmol) and Cs 2 CO 3 A solution of (838 mg,2.57 mmol) in toluene (10 mL) was reacted for 3h. 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 (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=1:1) to afford the title product (544 c) as a yellow oil (195 mg, 59%). m/z (ESI, positive ion) =383.3 [ m+h ] ] + 。
Step C. (S) -2- ((6- ((2- ((2-fluoro-4-methylphenoxy) methyl) pyridin-4-yl) oxy) pyridin-3-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (544)
The title compound (544) was synthesized from 544C in a similar procedure as described in example 471, steps C to E. m/z (ESI, positive ion) =555.2 [ m+h ]] + 。 1 H NMR(400MHz,CD 3 OD)δppm 8.46(d,J＝5.69Hz,1H),8.24(s,1H),8.12(s,1H),7.94(d,J＝8.40Hz,1H),7.87(dd,J＝8.39,2.03Hz,1H),7.55(d,J＝8.42Hz,1H),7.30(s,1H),7.09-7.19(m,2H),6.81-7.01(m,3H),5.13-5.25(m,3H),4.57-4.69(m,2H),4.45-4.56(m,3H),4.40(dd,J＝5.92,3.12Hz,1H),2.72-2.82(m,1H),2.46-2.54(m,1H),2.24(s,3H)。
Examples 545, 546, 547, 548, 549 and 550 were synthesized in analogy to the procedure described in example 360, with the Boc group removed by TFA.
Example 551 was synthesized from 460a and methyl 2- ((1 s,3 s) -3-hydroxycyclobutyl) acetate in analogy to the procedure described in examples 471, steps B to E. In step B, pd 2 (dba) 3 BINAP and K 3 PO 4 For coupling.
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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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 in other combinations and subcombinations of features, functions, elements, and/or properties, may be claimed in this or a related application claiming priority from this application. 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 (38)

1. A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein a is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted bicyclic ring;
Ring C is substituted or unsubstituted C 4 -C 6 Heterocycloalkyl, substituted or unsubstituted C 5 Heterocycloalkenyl or substituted or unsubstituted phenyl, wherein heterocycloalkyl and heterocycloalkenyl each comprise 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 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 -and-OCH 2 -；
L 2 Selected from the group consisting of: bond, -CH 2 -, -C (H) =and-O-;
L 3 is-CH 2 -；
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 selectA 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 or methyl;
wherein when the C ring is C 6 When the heterocycloalkyl group is, the B ring is pyrazole or
2. The compound of claim 1 according to formula Ia or Ib or Ic, or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein a is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
ring B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
ring C is further unsubstituted or further substituted, and/or bridged, and/or fused;
C 1 、C 2 、C 3 and C 4 One, or both of zero are N, and the remainder are CH or CR 6 ；
D 1 、D 2 And D 3 One, or both of zero are N, and the remainder are CH or CR 6 ；
W is 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 -and OCH 2 -；
L 2 Selected from the group consisting of: bond, -CH 2 -、-C(H)＝、-CF 2 -and-O-;
L 3 is-CH 2 -；
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; and is also provided with
R 13 Is hydrogen orAn alkyl group.
3. The compound of claim 1, according to formula lie, IIf or IIi-IIn, 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;
C 1 、C 2 、C 3 and C 4 One, or both of zero are N, and the remainder are CH or CR 6 ；
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, haloalkyl, haloalkoxy and R 11 R 12 NCO-；
R 4 Is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstitutedA substituted heteroarylalkylene, an unsubstituted heterocycloalkylalkylene, or a 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;
o is 1, 2, 3 or 4;
p is 0 or 1; and is also provided with
q is 0 or 1.
4. 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 3 Independently selected from the group consisting of: alkyl, substituted alkyl, halo, cyano, azido, alkoxy, haloalkyl, haloalkoxy and R 11 R 12 NCO-；
R 4 Is alkyl, substituted alkyl, unsubstituted arylalkylene, substituted arylalkylene, heteroalkyl, substituted heteroalkyl, unsubstituted heteroarylalkylene, substituted heteroarylalkylene, unsubstituted heterocycloalkylalkylene, or substituted heterocycloalkylalkylene;
R 5 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 or methyl; and is also provided with
n is an integer from 0 to 5; o is an integer from 0 to 4; p is 0 or 1; q is 0 or 1.
5. The compound of any one of the preceding claims, wherein each R 2 And R is 3 Is H or F.
6. The compound of any one of the preceding claims, wherein m is 0 and o is 0.
7. The compound of any one of the preceding claims, wherein W is N or CH.
8. The compound of any one of the preceding claims, wherein W is C.
9. The compound of any one of the preceding claims, wherein W is CH.
10. The compound of any one of the preceding claims, wherein W is N.
11. The compound of any one of the preceding claims, wherein R 4 Selected from the group consisting of: 1- (cyanomethyl) -cyclopropan-1-yl-methyl, (1-ethyl-1H-imidazol-5-yl) -methyl, 1- (fluoromethyl) -cyclopropan-1-yl-methyl, isoxazol-5-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 tetrahydrofuran-2-yl-methyl.
12. 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, oxolane-3 -methyl, (3R) -oxolan-3-yl-methyl and 1, 3-oxazol-2-yl-methyl.
13. The compound of any one of the preceding claims, wherein R 4 Selected from the group consisting of: 1- (cyanomethyl) -cyclopropan-1-yl-methyl, 1- (fluoromethyl) -cyclopropan-1-yl-methyl, isoxazol-5-yl-methyl and tetrahydrofuran-2-yl-methyl.
14. The compound of any one of the preceding claims, wherein R 4 Selected from the group consisting of oxetan-2-yl-methyl and (1-ethyl-1H-imidazol-5-yl) -methyl.
15. The compound of any one of the preceding claims, wherein R 4 Is oxetan-2-yl-methyl.
16. The compound of any one of the preceding claims, wherein R 4 Is (2S) -oxetan-2-yl-methyl.
17. The compound of any one of the preceding claims, wherein R 4 Is (1-ethyl-1H-imidazol-5-yl) -methyl.
18. The compound of any one of the preceding claims, wherein R 4 Selected from the group consisting of oxacyclopentane-3-yl-methyl and 1, 3-oxazol-2-yl-methyl.
19. The compound of any one of the preceding claims, wherein R 4 Is (3R) -oxolane-3-yl-methyl.
20. The compound of any one of the preceding claims, wherein R 4 Is 1, 3-oxazol-2-yl-methyl.
21. The compound of any one of the preceding claims, wherein R 5 is-COOH or-COOMe。
22. The compound of any one of the preceding claims, wherein R 5 is-COOH.
23. The compound of any one of the preceding claims, wherein R 5 Is tetrazolyl.
24. The compound of any one of the preceding claims, wherein R 5 Is 1H-1,2,3, 4-tetrazol-5-yl.
25. The compound of any one of the preceding claims, wherein L 2 is-CH 2 -。
26. The compound of any one of the preceding claims, wherein L 2 is-ch=or-O-.
27. The compound of any one of the preceding claims, wherein L 2 Is-ch= -.
28. The compound of any one of the preceding claims, wherein L 2 is-O-.
29. The compound of any one of the preceding claims, wherein L 3 is-CH 2 -。
30. The compound of any one of the preceding claims, wherein L 1 is-OCH 2 -; and L is 2 is-CH 2 -or-O-.
31. The compound of any one of the preceding claims, wherein L 1 is-O-.
32. 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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33. A compound selected from compounds 529, 530, 533, 534, 535 and 551, or a pharmaceutically acceptable salt or solvate thereof:
34. 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.
35. 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 1-33, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 34.
36. A compound according to any one of claims 1 to 33 or a pharmaceutical composition according to claim 35 for use in therapy.
37. A compound according to any one of claims 1 to 33 or a pharmaceutical composition according to claim 35 for use in the treatment of a metabolic disease or disorder.
38. Use of a compound according to any one of claims 1 to 35 or a pharmaceutical composition according to claim 36 in the manufacture of a medicament for the treatment of a metabolic disease or disorder.
CN202280040978.3A 2021-05-03 2022-05-03 Benzimidazolyl GLP-1GPCR receptor agonists, pharmaceutical compositions comprising the same, and methods of use thereof Pending CN117545748A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US63/183,612 2021-05-03
US202163282686P 2021-11-24 2021-11-24
US63/282,686 2021-11-24
PCT/US2022/027535 WO2022235717A1 (en) 2021-05-03 2022-05-03 Benzimidazoyl glp-1 receptor agonists, pharmaceutical compositions comprising the same, and methods for their use

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