CN115215787A - Somatostatin receptor 5 antagonists and uses thereof - Google Patents
Somatostatin receptor 5 antagonists and uses thereof Download PDFInfo
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- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses a somatostatin receptor 5 antagonist and application thereof. The somatostatin receptor 5 antagonist structure of the invention is shown as a general formula I, wherein the definition of each substituent group is shown as the specification and the claims. The compounds of the invention, useful as somatostatin receptor 5 antagonists, can be used in the treatment and prevention of SSTR 5-mediated diseases and diagnostics.
Description
Technical Field
The invention relates to the fields of medicinal chemistry, pharmacology and pharmacotherapeutics, in particular to SSTR5 antagonist compounds, a preparation method thereof, and a pharmaceutical composition using the compounds as active components, wherein the compounds are used for treating and preventing diseases and diagnosis in the fields related to SSTR 5.
Background
SSTR5, somatostatin receptor 5, is an inhibitory G (Gi) protein-coupled receptor whose endogenous ligands are somatostatin-14 (SST-14) and somatostatin-28 (SST-28). SSTR5 is distributed primarily in the pituitary, gastrointestinal tract, and pancreatic islets, and SSTR5 can be activated when SST-14 or SST-28 is bound to SSTR5, mediating the effect of inhibiting hormone secretion. Wherein, the activation of SSTR5 in the gastrointestinal tract can antagonize the secretion of gastrointestinal tract hormones such as GLP-1, GLP-2, GIP, PYY, CCK and the like; SSTR5 activation in islet tissue can inhibit insulin secretion. GLP-1 has multiple physiological functions, such as promoting insulin secretion dependent on blood sugar, inhibiting glucagon secretion, promoting satiety, slowing down gastric emptying, and protecting liver, kidney, and myocardium, and can be used for treating type II diabetes, obesity, and non-alcoholic fatty liver disease; GLP-2 can promote the growth of small intestine and the absorption of nutrient substances, is vital to maintaining intestinal homeostasis, and is further used for treating inflammatory bowel disease and short bowel syndrome; GIP has synergistic effect with GLP-1 in blood sugar regulation, and can be used for treating type II diabetes, obesity and non-alcoholic fatty liver disease; PYY can slow down gastric emptying and promote satiety, and can be used for treating obesity patients; insulin is mainly involved in sugar metabolism and can be used for treating type II diabetes. Pharmacological studies have shown that antagonism of SSTR5 can relieve the hormone secretion inhibitory effect mediated by the binding of SSTR5 to SSTR5, and therefore SSTR5 antagonists have been developed for use in the treatment of chronic metabolic diseases such as type ii diabetes, non-alcoholic fatty liver/hepatitis, inflammatory bowel disease, obesity.
Further research shows that the SSTR5 antagonist has a remarkable synergistic effect with GLP-1 secretion promoting receptors (such as TGR5, GPR40, GPR119, GPR41 and GPR 43) and a DPP4 inhibitor for inhibiting GLP-1 degradation in rodent mice, the GLP-1 level can be greatly improved by combining the three, the GLP-1 activity at a super-treatment level is realized, and the potential treatment method for type II diabetes, obesity and non-alcoholic fatty liver disease is provided.
In addition, SSTR5 antagonizes cholecystokinin (CCK) secretion, which promotes gallbladder contractile movement and bile flow from the gallbladder, where gallbladder emptying function is associated with various gallbladder diseases such as gallstones, cholestasis, and primary sclerosing cholangitis. Antagonizing SSTR5 is therefore a potential therapy for gallstones, cholestasis, and primary sclerosing cholangitis.
Therefore, the development of a novel SSTR5 antagonist is expected to be applied to chronic metabolic diseases such as type II diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), inflammatory bowel disease, obesity, gallstone, primary cholangitis and the like, and can be combined with TGR5 agonist, GPR40 regulator, GPR119 agonist, GPR41 agonist, GPR43 agonist and DPP4 inhibitor for exploration.
Disclosure of Invention
The invention aims to provide SSTR5 antagonist compounds.
In a first aspect of the invention, there is provided a compound, solvate, hydrate or pharmaceutically acceptable salt thereof represented by formula I:
wherein m is 1, 2 or 3; n is 1, 2 or 3;
R 1 is H, OH, NH 2 CN, halogen or C 1 -C 6 An alkyl group;
R 2 、R 3 、R 4 、R 5 、R 6 each independently selected from the group consisting of: hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, halogen, C 1 -C 6 Haloalkyl, OH, NH 2 、N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl), substituted or unsubstituted C 6 -C 14 An aryl group; wherein said substitution means that one or more hydrogen atoms on the aryl group are substituted with a group selected from the group consisting of: halogen, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl groups);
or R 2 、R 3 、R 4 、R 5 、R 6 Any two adjacent substituents of (a) together with the phenyl ring form a benzo 5-7 membered heterocyclic ring or a benzo 5-7 membered carbocyclic ring, which heterocyclic ring or carbocyclic ring is unsubstituted or substituted with one or more groups selected from: halogen, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl groups);
In a further preferred embodiment of the method,
is- (CH) 2 ) r -NR 9 -A、-(CH 2 ) r -O-A、-(CH 2 ) r -S-A or- (CH) 2 ) r -CONR 9 -a, wherein r, s are each independently 0, 1 or 2; r 9 Is H or C 1 -a C4 alkyl group.
In a further preferred embodiment of the method,
is- (CH) 2 )-NH-A、-NH-A、-(CH 2 ) -O-A, -O-A or-CONH-A.
In another preferred embodiment, L is-NR 9 -(CH 2 ) r -、-O-(CH 2 ) r -、-S-(CH 2 ) r -or-NR 9 CO-(CH 2 ) r -. In another preferred embodiment, L is-NH-CH 2 -、-NH-、-O-、-O-CH 2 -、-S-、-S-CH 2 -or-NR 9 CO-CH 2 -。
In another preferred embodiment, A is substituted or unsubstituted phenyl, or substituted or unsubstituted C 4 -C 6 A cycloalkyl group; wherein said substitution means that 1, 2 or 3 hydrogen atoms on the aryl or cycloalkyl group are substituted by a group selected from the group consisting of: halogen, carboxyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C) 1 -C 4 Alkyl groups).
In another preferred embodiment, A is
Wherein R is 7 Is H, fluorine, chlorine, bromine, carboxyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 3 Alkyl) (C 1 -C 3 Alkyl); r 8 Is H, C 1 -C 4 Alkyl, fluoro, chloro, bromo or hydroxy.
In another preferred embodiment, A is
Wherein R is 7 Is H, fluorine, chlorine, bromine, carboxyl, trifluoromethoxy, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, trifluoroethyl, cyclopropyl, OH, NH 2 、N(C 1 -C 3 Alkyl) (C) 1 -C 3 Alkyl groups); r is 8 Is H, C 1 -C 4 Alkyl, fluoro, chloro, bromo or hydroxy.
In another preferred embodiment, A is
R 7 H and methoxyl.
In another preferred embodiment, R 1 Is H, OH, NH 2 CN, F, cl, br, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
In another preferred embodiment, R 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from the group consisting of: hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, F, cl, br, C 1 -C 4 Haloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C) 1 -C 4 Alkyl), substituted or unsubstituted phenyl; wherein said substitution means that 1, 2 or 3 hydrogen atoms on the phenyl group are substituted by a group selected from the group consisting of: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C 1 -C 4 Alkyl groups);
or R 2 、R 3 、R 4 、R 5 、R 6 All ofTwo adjacent substituents together with the phenyl ring form a benzo 5-6 membered heterocyclic ring or a benzo 5-6 membered carbocyclic ring, which heterocyclic ring or carbocyclic ring is unsubstituted or substituted with 1, 2 or 3 groups selected from: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C) 1 -C 4 Alkyl).
In another preferred embodiment, R 2 、R 6 Each independently selected from the group consisting of: hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, F, cl, br, C 3 -C 6 A cycloalkyl group.
In another preferred embodiment, R 3 、R 5 Each independently selected from the group consisting of: H. c 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, F, cl, br, C 1 -C 4 Haloalkyl, OH, NH 2 。
In another preferred embodiment, R 4 Is H, F, cl, br, C 1 -C 4 Alkyl, or substituted or unsubstituted phenyl; wherein said substitution means that 1 or 2 hydrogen atoms on the phenyl group are substituted by a group selected from the group consisting of: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 An alkyl group.
In another preferred embodiment, R 4 And R 3 Or R is 4 And R 5 Taken together with the phenyl ring to form a benzo 5-6 membered heterocycle which is unsubstituted or substituted with 1 or 2 groups selected from: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 An alkyl group.
In another preferred embodiment, the heterocyclic ring comprises 1, 2, 3 heteroatoms selected from: n, O.
In another preferred embodiment, R 2 、R 6 Each independently selected from the group consisting of: hydrogen, cyclopropyl, methyl, ethyl, methoxy, ethoxy, F, cl, br.
In another preferred embodiment, R 3 、R 5 Each independently selected from the group consisting of: H. methoxy, ethoxy, trifluoromethyl, trifluoroethyl, methyl, ethyl, cyclopropyl, F, cl, br, OH, NH 2 。
In another preferred embodiment, R 4 Is substituted or unsubstituted phenyl, H, methyl, F, ethyl, cl or Br; the substitution means that 1 or 2 hydrogen atoms on the phenyl group are substituted by a group selected from the group consisting of: F. cl, br, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, methyl, ethyl.
In another preferred embodiment, R 4 And R 3 Or R is 4 And R 5 Together with the phenyl ring, form a benzo 5-6 membered heterocycle containing 1, 2, 3 heteroatoms selected from: n, O.
In another preferred embodiment, the compound is selected from the group consisting of:
in another preferred embodiment, the pharmaceutically acceptable salt of the invention is a salt of an anion with a positively charged group on a compound of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, for example tetramethylammonium.
In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the general formula I and organic base.
In another preferred embodiment, the pharmaceutically acceptable salt is trifluoroacetate salt.
In a second aspect of the present invention, there is provided a method for preparing the compound of the first aspect, the method comprising the steps of, wherein the compound of formula I has a structure represented by formula If,
obtaining Ic by coupling reaction of a compound Ia and Ib; deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id;
id and
obtaining Ie through nucleophilic substitution reaction; hydrolyzing the Ie under alkaline condition to obtain If;
or the preparation method comprises the following steps:
the compound Ia and Ib are subjected to Mitsunobu reaction to obtain Ic; deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id;
id and
obtaining Ie through nucleophilic substitution reaction; hydrolyzing the Ie under an alkaline condition to obtain If;
or the preparation method comprises the following steps:
carrying out amide condensation reaction on the compound Ia and Ib to obtain Ic; deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id;
id and
obtaining Ie through nucleophilic substitution reaction; hydrolyzing the Ie under an alkaline condition to obtain If;
in the above formulas, Q is- (CH) 2 ) r -；R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 R, m, n are as defined above.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:
a compound, solvate, hydrate or pharmaceutically acceptable salt thereof of the general formula I according to the first aspect; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises one or more additional agents for the treatment of a disease mediated by SSTR 5; preferably, the other drug is selected from hypoglycemic agents; including but not limited to metformin, insulinotropic drugs, insulin sensitizing drugs, alpha-glucosidase inhibitors, DPP4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists anti-type II diabetes drugs.
The compound provided by the invention can be used alone or mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to prepare tablets, capsules, granules, syrups and the like for oral administration. The pharmaceutical composition can be prepared according to a conventional method in pharmacy.
In a fourth aspect of the present invention, there is provided a use of a compound represented by general formula I, a solvate, a hydrate or a pharmaceutically acceptable salt thereof as described in the first aspect, or a pharmaceutical composition as described in the third aspect, as a somatostatin receptor 5 antagonist; for the preparation of medicaments which antagonize SSTR5 or for the preparation of medicaments for the prevention or treatment of diseases which are mediated by SSTR 5.
In another preferred embodiment, the disease mediated by SSTR5 is type ii diabetes, obesity, non-alcoholic steatohepatitis (NAFLD), non-alcoholic steatohepatitis (NASH), gallstones, cholestasis, primary cholangitis (e.g., primary sclerosing cholangitis), or inflammatory bowel disease.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a graph showing the results of an oral glucose tolerance (OGTT) test in normal mice after a single continuous dose of the compound.
FIG. 2 shows the results of gallbladder emptying experiments.
Detailed Description
Definition of
Unless otherwise indicated, the terms used in the present invention have the following definitions:
in the present invention, the term "C 1 -C 6 "isMeans having 1, 2, 3, 4, 5 or 6 carbon atoms, "C 1 -C 4 "means having 1, 2, 3, or 4 carbon atoms, and so forth. "3-6 membered" means having 3-6 ring atoms, and so on.
"substituted" as used herein means substituted with one or more groups (e.g., 2, 3, 4, or 5 groups). When a plurality of groups are selected from the same series of candidate substituents, they may be the same or different.
The term "optionally" as used herein means that the defined group may or may not be selected from a list of candidate groups.
The "alkyl group" in the present invention represents saturated straight-chain and branched-chain alkyl groups in a specific number of atoms, and specific examples thereof include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and tert-pentyl groups. The "C1-3 alkyl group" represents a saturated straight-chain or branched-chain alkyl group having 1, 2 or 3 carbon atoms, and specific examples thereof include, but are not limited to, methyl, ethyl, n-propyl, isopropyl and the like.
The "cycloalkyl group" as referred to in the present invention represents a non-aromatic, saturated, cyclic aliphatic hydrocarbon group having a ring-forming atom of a specific carbon number. Representative examples of "C3-6 cycloalkyl" include: : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The "alkoxy group" as used herein means all linear or branched alkoxy groups having a specific number of carbon atoms, and specific examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.
The "halogen" represents fluorine, chlorine, bromine, iodine.
In the present invention, the substitution on the alkyl group or the cycloalkyl group, if it is not specified to occur on a specific carbon atom, means that it may occur on any carbon atom for which the number of substituents has not yet reached saturation. When a plurality of substituents are selected from the same series, they may be the same or different.
In the present invention, the term "heterocyclyl" denotes a saturated cyclic group comprising at least one ring heteroatom (e.g. N, O or S).
In the present invention, the substitution on the benzene ring, the aromatic heterocyclic ring or the heterocyclic ring, if it is not specified to occur on a specific atom, means that it may occur at any position not substituted by other atoms than hydrogen. When a plurality of substituents are selected from the same series, they may be the same or different.
By "pharmaceutically acceptable salt" is meant that the compound of formula (I) retains the desired biological activity with minimal toxic side effects. The pharmaceutically acceptable salts may be obtained directly during the preparation and purification of the compound or indirectly by reacting the free acid or free base of the compound with another suitable base or acid.
The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water.
Preparation method
The compounds of the present invention may be prepared by a variety of procedures and synthetic routes, representative procedures and synthetic methods are as follows, but are not limited to
A. Preparation of the Compound of the formula If
The compound Ia and Ib are subjected to coupling reaction to obtain Ic; the coupling reaction is conventional in the art. Dissolving the compounds Ia and Ib in an organic solvent, adding an alkaline reagent, a metal catalyst and a ligand, and reacting at 60-140 ℃ for 1-24 hours. Any solvent that does not adversely affect the reaction can be used as the solvent, and 1,4-dioxane, N-Dimethylformamide (DMF), and the like are preferred. The basic agent includes, but is not limited to, cesium carbonate, potassium phosphate, potassium fluoride, triethylamine (TEA), N-diisopropylethylamine, etc. (DIPEA), and cesium carbonate, potassium phosphate are preferred. The metal catalyst includes, but is not limited to, cuprous iodide, tris (dibenzylideneacetone) dipalladium, palladium acetate, etc., preferably cuprous iodide, tris (dibenzylideneacetone) dipalladium. Such ligands include, but are not limited to, triphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, etc., preferably 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl.
Deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id; the deprotection reaction is carried out by a method conventional in the art. Dissolving the compound IId in an organic solvent, adding hydrochloric acid/dioxane or hydrochloric acid/ethanol or hydrochloric acid/dichloromethane solution or trifluoroacetic acid and the like, and reacting at room temperature for 1-24 hours. The organic solvent is any solvent which does not adversely affect the reaction, and is preferably Dichloromethane (DCM), dioxane, methanol, or the like.
Id and
obtaining Ie through nucleophilic substitution reaction; the nucleophilic substitution reaction is carried out by methods conventional in the art. Dissolving the compound Id and different organic building block segments in an organic solvent, adding an alkaline reagent, and reacting for 1-24 hours at 0-140 ℃. Any solvent that does not adversely affect the reaction may be used as the solvent, and acetonitrile, DMF, and the like are preferred.
Hydrolyzing the Ie under an alkaline condition to obtain If; the hydrolysis reaction is carried out by a conventional method in the field, and the compound I is dissolved in a mixed solvent of an organic solvent and water, added with an alkaline reagent and reacted for 1 to 24 hours at room temperature to 100 ℃. The organic solvent is any solvent which does not adversely affect the reaction, and is preferably dioxane, methanol, tetrahydrofuran, or the like.
B. Preparation of Compounds of the formula IIf
Obtaining Ic from the compound Ia by reacting with Ib through Mitsunobu; the Mitsunobu reaction is carried out as is conventional in the art. Dissolving Ia and the corresponding alcohol-based connecting segment in an organic solvent, adding triphenylphosphine and an azo reagent, and reacting for 1-24 hours at 0-60 ℃. Any solvent that does not adversely affect the reaction may be used as the solvent, and dichloromethane, tetrahydrofuran, and the like are preferred. The azo reagent is diisopropyl azodicarboxylate, diethyl azodicarboxylate, N, N, N ', N' -tetramethyl azodicarboxamide, etc., and diisopropyl azodicarboxylate and diethyl azodicarboxylate are preferable.
Deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id; the deprotection reactions are carried out by methods conventional in the art. The compound IId is dissolved in an organic solvent, and hydrochloric acid/dioxane or hydrochloric acid/ethanol or hydrochloric acid/dichloromethane solution or trifluoroacetic acid and the like are added for reaction at room temperature for 1 to 24 hours. The organic solvent is any solvent which does not adversely affect the reaction, and is preferably Dichloromethane (DCM), dioxane, methanol, or the like.
Id and
obtaining Ie through nucleophilic substitution reaction; the nucleophilic substitution reaction is carried out by methods conventional in the art. Dissolving the compound Id and different organic building block segments in an organic solvent, adding an alkaline reagent, and reacting for 1-24 hours at 0-140 ℃. Any solvent that does not adversely affect the reaction may be used as the solvent, and acetonitrile, DMF, and the like are preferred.
Hydrolyzing the Ie under an alkaline condition to obtain If; the hydrolysis reaction is carried out by a conventional method in the field, and the compound I is dissolved in a mixed solvent of an organic solvent and water, added with an alkaline reagent and reacted for 1 to 24 hours at room temperature to 100 ℃. The organic solvent is any solvent which does not adversely affect the reaction, and is preferably dioxane, methanol, tetrahydrofuran, or the like.
Performing amide condensation reaction on the compound Ia and Ib to obtain Ic; the amide condensation reaction is carried out by a method conventional in the art. Dissolving a compound Ib in an organic solvent, and adding a condensing agent and an alkaline reagent; then adding Ia, and reacting for 1-24 hours at room temperature to 100 ℃. The organic solvent is any solvent which does not adversely affect the reaction, and preferably N, N-Dimethylformamide (DMF), dichloromethane (DCM), or the like. The condensing agent is a condensing agent commonly used in the art, and includes, but is not limited to, 2- (7-benzotriazole oxide) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazole-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), 1,3-Dicyclohexylcarbodiimide (DCC), diethyl azodicarboxylate (DEAD)/triphenylphosphine, N, N ' -carbonyldiimidazole, 1-ethyl- (3-dimethylaminopropyl) carbonyldiimidate hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBt), etc., preferably HATU. The alkaline conditions include, but are not limited to, organic bases such as triethylamine, diisopropylethylamine (DIPEA), dimethylaminopyridine (DMAP), and inorganic bases such as potassium carbonate, cesium carbonate, and sodium bicarbonate; preferred are triethylamine, diisopropylethylamine (DIPEA), dimethylaminopyridine (DMAP).
Deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id; the deprotection reaction is carried out by a method conventional in the art. Dissolving the compound Id in an organic solvent, adding hydrochloric acid/dioxane or hydrochloric acid/ethanol or hydrochloric acid/dichloromethane solution or trifluoroacetic acid and the like, and reacting at room temperature for 1-24 hours. The organic solvent is any solvent which does not adversely affect the reaction, and is preferably Dichloromethane (DCM), dioxane, methanol, or the like.
Id and
obtaining Ie through nucleophilic substitution reaction; the nucleophilic substitution reaction is carried out by methods conventional in the art. Dissolving the compound Id and different organic building block segments in an organic solvent, adding an alkaline reagent, and reacting for 1-24 hours at 0-140 ℃. Any solvent that does not adversely affect the reaction may be used as the solvent, and acetonitrile, DMF, and the like are preferred.
Hydrolyzing the Ie under an alkaline condition to obtain If; the hydrolysis reaction is carried out by a conventional method in the field, and the compound I is dissolved in a mixed solvent of an organic solvent and water, added with an alkaline reagent and reacted for 1-24 hours at room temperature to 100 ℃. The organic solvent is any solvent which does not adversely affect the reaction, and is preferably dioxane, methanol, tetrahydrofuran, or the like.
In the above formulas, Q is- (CH) 2 ) r -；R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 R, m, n are as defined above.
Pharmaceutical composition
For therapeutic use, the compounds within the invention will generally be administered in the form of a standard pharmaceutical composition. The compound comprises one or more compounds shown in a general formula (I) with effective treatment dose and pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable auxiliary materials are pharmaceutically acceptable carriers, excipients or sustained-release agents and the like.
The compounds and pharmaceutical compositions provided herein can be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and the like, and can be presented in a suitable solid or liquid carrier or diluent. The pharmaceutical compositions of the present invention may also be stored in a suitable injection or drip sterilization device. The pharmaceutical composition may also comprise flavoring agent, etc.
In the present invention, the pharmaceutical composition comprises a safe and effective amount (e.g. 0.1-99.9 parts by weight, preferably 1-90 parts by weight) of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof; and the balance of pharmaceutically acceptable auxiliary materials, wherein the total weight of the composition is 100 parts by weight. Alternatively, the pharmaceutical composition of the present invention comprises 0.1 to 99.9% by weight, preferably 1 to 90% by weight, of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof; and the balance of pharmaceutically acceptable excipients, wherein the total weight of the composition is 100% by weight.
The compound represented by the general formula (I) and a pharmaceutically acceptable carrier, excipient or sustained-release agent are preferably used in such a ratio that the compound represented by the general formula (I) as an active ingredient accounts for 60% or more of the total weight, the remainder accounts for 0 to 40% of the total weight, and the amount of the remainder is preferably 1 to 20%, most preferably 1 to 10%.
The compound shown in the general formula (I) or the pharmaceutical composition containing the compound shown in the general formula (I) can be clinically used for mammals including human and animals, and the administration route can comprise oral administration, nasal cavity inhalation, transdermal absorption, pulmonary administration, gastrointestinal tract administration or the like. The preferred route of administration is oral. Preferably in unit dosage form, and each dose contains 0.01mg-200mg, preferably 0.5mg-100mg of the active ingredient, and is administered once or in divided portions. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.
The pharmaceutical composition of the present invention can be administered orally as well as intravenously, intramuscularly or subcutaneously. Preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules, from the standpoint of ease of preparation and administration. Oral administration of the pharmaceutical composition is preferred.
The solid support comprises: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, kaolin, and the like, and liquid carriers include: sterile water, polyethylene glycols, non-ionic surfactants, edible oils (e.g., corn, peanut and sesame oils), and the like, as appropriate to the nature of the active ingredient and the particular mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, for example flavouring agents, colours, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
Injectable formulations include, but are not limited to, sterile, injectable, aqueous, oleaginous solutions, suspensions, emulsions, and the like. These formulations may also be formulated with parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable formulations can be sterilized by filtration through a bacteria-retaining filter. These formulations may also be formulated with an antimicrobial agent dissolved or dispersed in an injectable medium or by other methods known in the art.
Combination therapy
The compounds of the present invention may be used in combination with other drugs for the prevention or treatment of SSTR 5-mediated diseases.
The compounds of the present invention may be used in combination with one or more other drugs to treat, prevent or ameliorate diseases in which the compounds of the present invention or the other drugs may be effective, wherein the combination of these drugs is safer or more effective than either drug alone. The other agents may be administered by the usual route of administration and dosage, either simultaneously with, prior to or after the compounds of the invention. When the compounds of the present invention are used contemporaneously with one or more other drugs, a unit dosage form of a pharmaceutical composition containing the other drugs and a compound of the present invention is preferred. However, combination therapy may also include therapies in which a compound of the formula described herein and one or more other drugs are administered in different overlapping regimens. When used in combination with one or more other active ingredients, the compounds of the present invention and the other agents may be used in lower doses than when used alone. Wherein the other drugs include, but are not limited to, TGR5 agonists, GPR119 agonists, GPR40 agonists, PDE4 inhibitors, DPP4 inhibitors, SGLT2 inhibitors, metformin, insulin sensitizers, insulin and analogs thereof, alpha-glucosidase inhibitors, sulfonylurea or non-sulfonylurea insulin secretion enhancers, incretin analogs, and the like.
The invention will be further illustrated by the following examples. It is specifically noted that these examples are only intended to illustrate the invention and do not limit it in any way. All parameters in the examples and the rest of the description are based on mass unless otherwise stated. If not, all the fillers used for column chromatography are silica gel. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The preferred embodiments and materials described herein are exemplary only.
Example 1
4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetic acid salt
Step 1: preparation of 4- (chloromethyl) -2,6-diethoxy-4 '-fluoro-1,1' -biphenyl (A1 a)
Reference to preparation methods: ACS Med. Chem.Lett.2018,9,11,1082-1087
1 H NMR (500 MHz, chloroform-d) delta 7.39-7.31 (m, 2H), 7.12-7.05 (m, 2H), 6.68 (s, 2H), 4.61 (s, 2H), 4.01 (q, J =7.0Hz, 4H), 1.28 (t, J =6.9Hz, 6H). MS (ESI): m/z 309.2[ M + H ]] + .
And 2, step: preparation of tert-butyl ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methyl) carbamate (A1 b)
A1a (1 eq), 4- (Boc-aminomethyl) piperidine (1 eq), and potassium carbonate (1.4 eq) were dissolved in acetonitrile and reacted at 80 ℃ for 5 hours under nitrogen protection, completion of the reaction was confirmed by thin layer chromatography, the reaction solution was cooled to room temperature, solids such as potassium carbonate were removed by filtration, and the filtrate was purified by Flash silica gel column chromatography (DCM/MeOH = 50). MS (ESI) m/z 487.3[ 2 ] M + H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.34 (dd, J =8.8,5.6hz, 2h), 7.04 (t, J =8.8hz, 2h), 6.60 (s, 2H), 4.61 (s, 1H), 3.96 (q, J =7.0hz, 4h), 3.47 (s, 2H), 3.03 (t, J =6.5hz, 2h), 2.93 (t, J =11.9,3.3hz, 2h), 1.97 (t, 2H), 1.68 (d, 2H), 1.44 (s, 9H), 1.30 (t, J =12.5,3.4hz, 2h), 1.24 (t, J =7.0hz, 6h).
And step 3: preparation of (1- (((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methylamine, hydrochloride salt (A1 c)
A1b was dissolved in methylene chloride, and 3 to 5mL of hydrochloric acid-dioxane solution (4N) was added to the solution to react at room temperature for 2 hours, and completion of the reaction was confirmed by thin layer chromatography. And (4) carrying out suction filtration on the reaction liquid to obtain a solid, namely the product A1c without purification. MS (ESI) m/z 387.2[ m ] +H] + .
And 4, step 4: preparation of methyl 4- (((1- ((2-, 6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methyl) amino) benzoate (A1 d)
A1c (1 eq), methyl p-bromobenzoate (1.5 eq), potassium phosphate (3 eq), pd (dba) (0.05 eq) and Xanphos ligand (0.1 eq) were dissolved in 1,4-dioxane, and after displacement of nitrogen, the reaction was sealed at 100 ℃ for 3 hours, and thin chromatography confirmed the completion of the reaction. The reaction was cooled to room temperature, the solid was removed by filtration, and the filtrate was purified by Flash silica gel column chromatography (DCM/MeOH = 50. MS (ESI) m/z 521.2[ m ] +H] + .
1 H NMR (500 MHz, chloroform-d) δ 7.89-7.81 (m, 2H), 7.37-7.30 (m, 2H), 7.10-7.00 (m, 2H), 6.64-6.58 (m, 2H), 6.57-6.51 (m, 2H), 4.22 (s, 1H), 4.00-3.92 (m, 4H), 3.89-3.82 (m, 3H), 3.51 (s, 2H), 3.09 (t, J =5.6hz, 2H), 3.00 (d, J =11.1hz, 2H), 2.10-1.96 (m, 2H), 1.78 (d, J =12.8hz, 2h), 1.49-1.35 (m, 2H), 1.24 (t, J =7.0,4.3, 2.6H).
And 5: preparation of 4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate salt (A1 e)
Dissolving A1d (1 eq) in 1,4-dioxygenAdding lithium hydroxide monohydrate (2 eq) into a mixed solvent of hexacyclic compound and water (volume ratio = 4:1), reacting at 50 ℃ for 12 hours, confirming the reaction completion by thin-layer chromatography, concentrating the reaction solution to dryness, and purifying by a semi-preparative liquid phase to obtain the trifluoroacetate A1e. MS (ESI) m/z 507.2[ m + H ]] + .
1 H NMR(500MHz,DMSO-d 6 )δ7.66(d,J＝8.7Hz,2H),7.29(dd,J＝8.6,5.8Hz,2H),7.17(t,J＝8.9Hz,2H),6.86(s,2H),6.59(d,J＝8.7Hz,2H),4.25(s,2H),3.98(q,J＝6.9Hz,4H),3.24–3.13(m,1H),3.01(d,J＝6.6Hz,2H),2.98–2.91(m,2H),2.01–1.93(m,2H),1.89–1.76(m,2H),1.49–1.39(m,2H),1.17(t,J＝7.0Hz,6H).
Example 2
Preparation of 4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl ] methyl) -4-fluoropiperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate
Step 1: preparation of 4-fluoro-4- ((((4- (methoxycarbonyl) phenyl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester (A2 a)
Tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate (1 eq), methyl p-bromobenzoate (1.5 eq), potassium phosphate (3 eq), pd (dba) (0.05 eq), and Xantphos ligand (0.1 eq) were dissolved in 1,4-dioxane, and after nitrogen substitution, the reaction was carried out for 3 hours at 100 ℃ with tube sealing, and thin-layer chromatography was carried out to confirm completion of the reaction. The reaction was cooled to room temperature, the solid was removed by filtration, and the filtrate was purified by Flash silica gel column chromatography (DCM/MeOH = 50. MS (ESI) m/z 267.2[ m ] +H] + .
1 H NMR (500 MHz, chloroform-d) δ 7.86 (d, J =8.8hz, 2h), 6.59 (d, J =8.8hz, 2h), 4.39 (t, J =6.3hz, 1h), 4.09-3.91 (m, 2H), 3.85 (s, 3H), 3.35 (dd, J =19.8,6.3hz, 2h), 3.16-3.01 (m, 2H), 1.99-1.88 (m, 2H), 1.70-1.50(m,2H),1.46(s,9H).
And 2, step: preparation of methyl 4- ((((4-fluoropiperidin-4 yl) methyl) amino) benzoate, hydrochloride salt (A2 b)
A2a was dissolved in methylene chloride, and 3 to 5mL of hydrochloric acid-dioxane solution (4N) was added to the solution to react at room temperature for 2 hours, and completion of the reaction was confirmed by thin layer chromatography. And (4) carrying out suction filtration on the reaction liquid to obtain a solid, namely the product A2b without purification. MS (ESI) m/z 267.2[ m ] +H] + .
And step 3: preparation of methyl 4- (((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-fluoropiperidin-4-yl) methyl) amino) benzoate (A2 c)
A1a (1 eq), A2b (1 eq), and potassium carbonate (1.4 eq) were dissolved in acetonitrile and reacted at 80 ℃ for 5 hours under nitrogen protection, thin layer chromatography confirmed the reaction was complete, the reaction was cooled to room temperature, solids such as potassium carbonate were removed by filtration, and the filtrate was purified by Flash silica gel column chromatography (DCM/MeOH = 50. MS (ESI) m/z 539.3[ 2 ], [ M + H ]]+. 1 H NMR (500 MHz, chloroform-d) δ 7.86 (d, J =8.7hz, 2h), 7.33 (dd, J =8.7,5.7hz, 2h), 7.04 (t, J =8.9hz, 2h), 6.65-6.56 (m, 4H), 4.37 (t, J =6.2hz, 1h), 3.96 (q, J =7.0hz, 4h), 3.85 (s, 3H), 3.53 (s, 2H), 3.36 (dd, J =19.8,6.2hz, 2h), 2.76 (d, J =11.2hz, 2h), 2.38 (t, J =11.6hz, 2h), 1.98 (t, J =12.2hz, 2h), 1.80-1.59 (m, 2H), 1.24 (t, J = 7.6h, 7H).
And 4, step 4: preparation of 4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl ] methyl) -4-fluoropiperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate (A2 d)
The preparation method is the same asA1e；MS(ESI):m/z 525.2[M+H] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.66(d,J＝8.5Hz,2H),7.33–7.26(m,2H),7.17(t,J＝8.9Hz,2H),7.12–7.07(m,2H),6.69(d,J＝8.6Hz,2H),4.30(d,J＝5.4Hz,2H),4.01(q,J＝7.0Hz,4H),3.37(dd,J＝29.0,16.7Hz,4H),3.14–3.02(m,2H),2.33–2.05(m,4H),1.18(t,J＝6.9Hz,6H).
Example 3
Preparation of 4- (((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) azetidin-3-yl) methyl) amino) benzoic acid, trifluoroacetate salt
The procedure was as in example 1 except that 3- (Boc-aminomethyl) azetidine hydrochloride was used in place of 4- (Boc-aminomethyl) piperidine. MS (ESI) m/z 479.3[ 2 ], [ M + H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.66(d,J＝8.5Hz,2H),7.27(dd,J＝8.5,5.8Hz,2H),7.14(t,J＝8.8Hz,2H),6.63(s,2H),6.57(d,J＝8.6Hz,2H),3.94(q,J＝6.9Hz,4H),3.64–3.57(m,2H),3.50(s,2H),3.08–2.95(m,2H),2.78–2.65(m,2H),1.79–1.74(m,1H),1.17(t,J＝7.1Hz,6H).
Example 4
Preparation of 4- ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) azetidin-3-yl) amino) benzoic acid, trifluoroacetate
Example 1 was repeated except that 3- (Boc-amino) azetidine hydrochloride was used in place of 4- (Boc-aminomethyl) piperidine. MS (ESI) m/z 465.3[ m/z ] H] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.66(d,J＝7.7Hz,2H),7.31–7.25(m,2H),7.14(t,J＝9.0Hz,2H),6.62(s,2H),6.40(d,J＝8.3Hz,2H),6.14(d,J＝6.4Hz,1H),4.01(p,J＝6.5Hz,1H),3.95(q,J＝6.9Hz,4H),3.70(t,J＝6.7Hz,2H),3.60(s,2H),2.89(t,J＝6.6Hz,2H),1.15(t,J＝6.9Hz,6H).
Example 5
Preparation of 4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl ] methyl) -4-fluoropiperidin-4-yl) methyl) amino) -2-methoxybenzoic acid, trifluoroacetate
The procedure is as in example 2 except that methyl 4-bromo-2-methoxybenzoate is used instead of methyl p-bromobenzoate. MS (ESI) m/z 555.3[ m ] +H] + .
1 H NMR(500MHz,DMSO-d 6 )δ7.53(d,J＝8.6Hz,1H),7.27(dd,J＝8.6,5.7Hz,2H),7.16(t,J＝8.9Hz,2H),6.88(s,2H),6.32–6.22(m,2H),4.32(s,2H),3.97(q,J＝6.9Hz,4H),3.74(s,3H),3.47–3.35(m,2H),3.20–3.05(m,2H),2.16–1.91(m,4H),1.16(t,J＝6.9Hz,6H).
Example 6
Preparation of 4- (((1- (2-cyclopropyl-5- (trifluoromethyl) benzyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate salt
Step 1: preparation of 2-cyclopropyl-5- (trifluoromethyl) benzaldehyde (A6 a)
2-bromo-5-trifluoromethylbenzaldehyde (1 eq), cyclopropylboronic acid (1.5 eq) and cesium carbonate (3 eq) are dissolved in dioxane, 1,1' -bis (diphenylphosphino) ferrocene palladium chloride (0.1 eq) is added and the mixture is protected by nitrogen, and the tube is sealed at 100 ℃ for reaction for 3 hours. And (3) confirming the reaction is complete by thin layer chromatography, filtering off insoluble substances in the system, washing filter residues by ethyl acetate, and directly mixing the filtrate with a Flash column for separation and purification to obtain A6a.
MS(ESI):m/z 215.1[M+H] + .
Step 2: preparation of methyl 4- ((piperidin-4-ylmethyl) amino) benzoate, hydrochloride (A6 b)
The preparation method is the same as A2b except that 1-tert-butyloxycarbonyl-4-aminomethyl piperidine is used instead of 4- (aminomethyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester; MS (ESI) m/z 248.0[ m ] +H] + .
And 3, step 3: preparation of methyl 4- ((((1- (2-cyclopropyl-5- (trifluoromethyl) benzyl) piperidin-4-yl) methyl) amino) benzoate (A6 c)
A6b (1 eq) and triethylamine (1 eq) were dissolved in anhydrous methanol, and after stirring at room temperature for 0.5 hour, A1a (1 eq) and acetic acid (0.05 eq) were added, and after reaction at room temperature for 12 hours, sodium borohydride (1.2 eq) was added, and the reaction was continued for 2 hours, and thin-layer chromatography was performed to confirm completion of the reaction. Slowly adding saturated ammonium chloride aqueous solution into the reaction solution to quench the reaction, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating sample-mixing silica gel, carrying out Flash column chromatography purification to obtain colorless oily matter A6c, and solidifying into white solid after standing. MS (ESI) m/z 447.2[ m + H ] +.
And 4, step 4: preparation of 4- (((1- (2-cyclopropyl-5- (trifluoromethyl) benzyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate salt (A6 d)
Except that A6c is used to replace A1d, the other preparation method is the same as A1e.MS (ESI) m/z 433.0[ m ] +H ]] + .
1 H NMR(500MHz,DMSO-d 6 )δ10.22(s,1H),8.10(d,J＝2.1Hz,1H),7.67(dd,J＝8.8,6.6Hz,3H),7.22(d,J＝8.3Hz,1H),6.65(d,J＝9.6Hz,1H),6.60(d,J＝8.7Hz,2H),4.56(d,J＝5.5Hz,2H),3.12(dt,J＝13.1,9.8Hz,2H),3.00(d,J＝6.6Hz,2H),2.37–2.28(m,1H),2.00–1.90(m,2H),1.90–1.79(m,1H),1.63–1.47(m,2H),1.24(s,1H),1.14–1.03(m,2H),0.83–0.78(m,2H).
Example 7
4- (((1- ((2-, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) methyl) piperidin-4-yl) methyl) amino) benzoic acid
The procedure is as in example 6 except that 1,4-benzodioxane-6-carbaldehyde is used in place of A6a.
MS(ESI):m/z 383.1[M+H]+.
1 H NMR(600MHz,DMSO-d 6 )δ10.14(s,1H),7.65(d,J＝8.7Hz,2H),7.12(d,J＝4.7Hz,1H),6.99(d,J＝8.4Hz,1H),6.90(d,J＝8.5Hz,1H),6.57(d,J＝8.6Hz,2H),4.25(s,4H),4.11(d,J＝4.8Hz,2H),3.31(d,J＝12.1Hz,2H),3.07(s,1H),2.97(d,J＝6.7Hz,2H),2.83(q,J＝11.7Hz,2H),1.91(d,J＝13.9Hz,2H),1.77(s,1H),1.54–1.39(m,2H).
Example 8
Preparation of 4- (((1- ((2,6-diethoxy-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate salt
Step 1: preparation of 2,6-diethoxy-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-carbaldehyde (A8 a)
Reference to preparation methods: WO2010129729; MS (ESI) m/z 355.2[ m ] +H] + .
And 2, step: preparation of 4- (((1- ((2,6-diethoxy-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate salt (A8 b)
The procedure is as in example 6 except A8a is used instead of A6a. MS (ESI) m/z 573.1[ 2 ] M + H] + .
1 H NMR(600MHz,DMSO-d6)δ7.62(d,J＝8.9Hz,2H),7.35(d,2H),7.27(d,2H),6.66(s,2H),6.54(d,2H),6.46(t,J＝5.7Hz,1H),3.92(q,J＝7.0Hz,4H),3.51(s,2H),2.98–2.85(m,4H),1.98(s,2H),1.73(d,J＝12.6Hz,2H),1.56(t,J＝9.0Hz,1H),1.28–1.19(m,2H),1.11(t,J＝7.0Hz,6H).
Example 9
4- ((((1- (2-cyclopropylbenzyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetate salt
The procedure was as in example 6 except that 2-cyclopropylbenzaldehyde was used in place of A6a. MS (ESI) m/z 365.0[ m + H ]] + .
1 H NMR(500MHz,DMSO-d6)δ7.64(d,J＝8.4Hz,2H),7.24(dd,J＝7.2,1.9Hz,1H),7.17–7.07(m,2H),6.93(dd,J＝7.3,1.7Hz,1H),6.43(d,2H),5.75(t,J＝5.7Hz,1H),3.56(s,2H),2.89(t,J＝6.2Hz,2H),2.83(dt,J＝11.8,3.4Hz,2H),2.15(tt,J＝8.5,5.4Hz,1H),1.95(td,J＝11.6,2.4Hz,2H),1.77–1.69(m,2H),1.61–1.49(m,1H),1.17(qd,J＝12.1,3.8Hz,2H),0.94–0.85(m,2H),0.61–0.56(m,2H).
Example 10
4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl ] methyl) -4-methylpiperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetic acid salt
Except that 4- (aminomethyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester is replaced by 4- (aminomethyl) -4-methylpiperidine-1-carboxylic acid tert-butyl esterThe preparation method is the same as example 2.MS (ESI) m/z 521.0[ m ] +H] + .
1 H NMR(500MHz,DMSO-d6)δ9.89(s,1H),7.92(d,J＝8.6Hz,2H),7.84(d,J＝8.6Hz,2H),7.33–7.26(m,2H),7.21–7.15(m,2H),7.01(s,2H),4.19(s,1H),4.00(q,J＝6.9Hz,4H),2.44(s,2H),2.07–1.74(m,2H),1.31(s,3H),1.25(d,J＝4.7Hz,2H),1.17(t,J＝7.0Hz,6H).
Example 11
4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl ] methyl) -4-hydroxypiperidin-4-yl) methyl) amino) benzoic acid
The procedure is as in example 2 except that tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate is replaced with tert-butyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate. MS (ESI) m/z 523.1[ m ] +H] + .
1 H NMR(500MHz,DMSO-d6)δ7.66(d,J＝8.5Hz,2H),7.33–7.27(m,2H),7.21–7.12(m,2H),7.02(s,2H),6.67(d,J＝8.3Hz,2H),6.43(s,1H),4.98(s,1H),4.24(s,2H),4.00(q,J＝7.0Hz,4H),3.21–3.06(m,4H),2.08–1.85(m,2H),1.75(d,J＝13.8Hz,2H),1.23(d,J＝6.7Hz,2H),1.17(t,J＝7.0Hz,6H).
Example 12
4- (((1- ((2,6-diethoxy-4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetic acid salt
Step 1:2,6-diethoxy-4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-carbaldehyde (A12 a)
Reference to preparation methods: WO2010129729
Step 2: the procedure is as in example 6 except A12a is used instead of A6a. MS (ESI) m/z 557.0[ m + H ]] + .
1 H NMR(500MHz,DMSO-d6)δ7.71(d,J＝8.1Hz,2H),7.67(d,J＝8.4Hz,2H),7.50(d,J＝8.1Hz,2H),7.05(s,2H),6.59(d,J＝8.4Hz,2H),4.24(s,1H),4.03(q,J＝6.9Hz,4H),3.35(s,2H),3.15(s,2H),3.10–2.71(m,4H),2.12–1.42(m,5H),1.18(t,J＝6.9Hz,6H).
Example 13
4- ((((1- ((2,6-diethoxy-4 '-methoxy- [1,1' -biphenyl ] -4-yl ] methyl) piperidin-4-yl) methyl) amino) benzoic acid, trifluoroacetic acid salt
The preparation process is as in example 6.MS (ESI): m/z 519.0[ M ] +H, except that A8a is used instead of A6a] + .
1 H NMR(500MHz,DMSO-d6)δ11.95(s,1H),7.66(d,J＝8.4Hz,2H),7.19(d,J＝8.3Hz,2H),6.98(s,2H),6.91(dd,J＝8.6,1.7Hz,2H),6.59(d,J＝8.5Hz,2H),4.39–4.15(m,2H),3.99(q,J＝7.0Hz,4H),3.78(s,3H),3.22–2.81(m,4H),1.97–1.49(m,5H),1.20–1.16(m,6H).
Example 14
4- ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) oxy) benzoic acid, trifluoroacetate
Step 1: preparation of 1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-ol (B14 a)
The procedure was as in A1b except that 4-hydroxypiperidine was used instead of 4- (Boc-aminomethyl) piperidine.
MS(ESI):m/z 374.2[M+H] + .1H NMR(500MHz,CDCl3)
Step 2:
dissolving methyl p-hydroxybenzoate, B14a and triphenylphosphine in dichloromethane, dropwise adding diisopropyl azodicarboxylate in an ice water bath, removing the ice bath after 0.5 h, reacting at room temperature overnight, and performing thin layer chromatography to confirm that the reaction is complete. Concentrating the reaction solution, evaporating to dryness, redissolving in ethyl acetoacetate, adding zinc chloride, stirring at room temperature for 12 hours, filtering to remove solids, mixing the filtrate with silica gel, and performing Flash silica gel column chromatography to purify to obtain B14B. MS (ESI) m/z 508.2[ m ] +H] + .1H NMR(500MHz,CDCl3)
And 3, step 3:
except that B14B is used instead of A1d, the preparation method is the same as A1e.MS (ESI) that m/z 494.2[ 2 ], [ M + H ] +.
1H NMR(500MHz,CDCl3)
Example 15
4- ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidin-4-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 14 except that 4-hydroxymethylpiperidine is used instead of 4-hydroxypiperidine.
MS(ESI):m/z 508.2[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ7.78(d,J＝8.6Hz,2H),7.32–7.26(m,2H),7.14(t,J＝8.9Hz,2H),6.78(d,J＝8.7Hz,2H),6.65(s,2H),3.94(q,J＝7.0Hz,4H),3.83(d,J＝5.9Hz,2H),3.46(s,2H),2.89(d,J＝11.6Hz,2H),2.04–1.93(m,2H),1.81–1.71(m,2H),1.39–1.19(m,3H),1.15(t,J＝6.9Hz,6H).
Example 16
4- ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) azetidin-3-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 14 except that 3-azetidinemethanol is used instead of 4-hydroxypiperidine.
MS(ESI):m/z 480.2[M+H] + . 1 H NMR(500MHz,DMSO-d 6 )δ10.79(d,J＝54.3Hz,1H),7.90(dd,J＝8.4,5.4Hz,2H),7.30–7.22(m,2H),7.20–7.11(m,2H),7.05(t,J＝8.6Hz,2H),6.85(d,J＝13.4Hz,2H),4.45–4.31(m,2H),4.30–4.15(m,4H),4.10–4.01(m,2H),3.97(dd,J＝8.6,4.9Hz,4H),3.32–3.20(m,1H),1.15(t,J＝6.9Hz,6H).
Example 17
4- ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-fluoropiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 14 except that (4-fluoropiperidin-4-yl) methanol is used instead of 4-hydroxypiperidine.
MS(ESI):m/z 526.0[M+H] + .
1 H NMR(500MHz,MeOH-d4)δ8.02(d,J＝8.4Hz,2H),7.30(dd,J＝8.4,5.5Hz,2H),7.14–7.04(m,4H),6.90(s,2H),4.42(s,2H),4.25(d,J＝17.6Hz,2H),4.06(q,J＝7.0Hz,4H),3.60(s,2H),3.41(s,2H),2.39(d,J＝11.1Hz,2H),2.20(d,J＝38.8Hz,2H),1.27(t,J＝7.0Hz,6H).
Example 18
4- ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-methylpiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 14 except that 4-hydroxymethyl-4-methyl-piperidine is used instead of 4-hydroxypiperidine.
MS(ESI):m/z 522.0[M+H] + . 1 H NMR(500MHz,MeOH-d4)δ7.96(d,2H),7.32–7.26(m,2H),7.12–7.05(m,2H),6.96(s,2H),6.93(d,2H),4.44(t,J＝9.3Hz,2H),4.26–4.17(m,2H),4.03(q,J＝7.0Hz,4H),3.57(s,3H),3.22(d,J＝12.2Hz,1H),2.25–2.10(m,2H),2.09–1.99(m,2H),1.31(s,3H),1.24(t,J＝6.9Hz,6H).
Example 19
4- ((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-hydroxypiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 14 except that 4- (hydroxymethyl) -4-hydroxypiperidine is used instead of 4-hydroxypiperidine.
MS(ESI):m/z 524.1[M+H] + .
1 H NMR(500MHz,DMSO-d6)δ12.62(s,1H),10.45(s,1H),7.94–7.87(m,2H),7.30(ddd,J＝8.8,5.5,2.6Hz,2H),7.21–7.14(m,2H),7.10–6.94(m,4H),5.24(d,J＝13.8Hz,1H),4.30(d,J＝4.3Hz,2H),4.01(q,J＝6.9Hz,4H),3.91(s,2H),3.20(d,J＝12.3Hz,2H),2.09(t,J＝13.3Hz,2H),1.81(d,J＝14.1Hz,2H),1.24(d,J＝4.8Hz,2H),1.19(t,J＝6.9Hz,6H).
Example 20
4- ((1- (2-cyclopropyl-5- (trifluoromethyl) benzyl) -4-fluoropiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate salt
Step 1: preparation of 4-fluoro-4- ((4- (methoxycarbonyl) phenoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (B20 a)
The preparation process is the same as B14B except that 1-tert-butoxycarbonyl-4-fluoro-4- (hydroxymethyl) piperidine is used instead of B14 a.
MS(ESI):m/z 368.0[M+H] + .
1 H NMR (500 MHz, chloroform-d) δ 8.06-8.00 (m, 2H), 6.99-6.93 (m, 2H), 4.05 (d, J =17.2hz, 4H), 3.92 (s, 3H), 3.17 (s, 2H), 2.02 (dd, J =13.7,10.2hz, 2H), 1.88-1.70 (m, 2H), 1.50 (s, 9H).
Step 2: preparation of methyl 4- ((4-fluoropiperidine but-4-yl) methoxy) benzoate hydrochloride (B20B)
Preparation of B20B the preparation method is the same as A2b. MS (ESI): m/z 268.0[ M ] +H except that B20a is used instead of A2a] + .
And step 3:
the procedure is as in example 6 except that B20B is used instead of A6B. MS (ESI) m/z 452.0[ m ] +H] + .
1 H NMR(500MHz,DMSO-d 6 )δ12.65(s,1H),7.89(d,J＝8.5Hz,2H),7.63(s,1H),7.53–7.47(m,1H),7.15(d,J＝8.1Hz,1H),7.06(d,J＝8.5Hz,2H),4.17(d,J＝20.8Hz,2H),3.74(s,2H),2.71(d,J＝10.6Hz,2H),2.37(t,J＝11.4Hz,2H),2.28–2.18(m,1H),1.94(t,J＝12.1Hz,2H),1.85(dt,J＝13.2,6.8Hz,1H),1.77(td,J＝13.1,4.5Hz,1H),1.01(dd,J＝8.3,2.2Hz,2H),0.76–0.67(m,2H).
Example 21
4- ((1- (2-cyclopropyl-5-ethoxybenzyl) -4-fluoropiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 20 except that 2-cyclopropyl-5-ethoxy is used in place of B20 a.
MS(ESI):m/z 428.1[M+H] + . 1 H NMR(500MHz,DMSO-d 6 )δ12.63(s,1H),7.87(d,J＝8.4Hz,2H),7.04(d,J＝8.5Hz,2H),6.88(s,2H),6.68(s,1H),4.49(s,1H),4.30–4.06(m,2H),4.06–3.83(m,2H),3.59(s,1H),2.68(s,1H),2.36–1.65(m,7H),1.28(t,J＝6.9Hz,3H),0.87–0.82(m,2H),0.68–0.37(m,2H).
Example 22
4- ((1- (3-ethoxy-4-fluorobenzyl) -4-fluoropiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate salt
The procedure is as in example 20 except that 3-ethoxy-4-fluorobenzaldehyde is used instead of B20 a.
MS(ESI):m/z 406.0[M+H] + 。 1 H NMR(500MHz,DMSO-d6)δ7.89(d,J＝8.5Hz,2H),7.62(s,1H),7.27(t,J＝9.9Hz,1H),7.12(s,1H),7.06(d,J＝8.5Hz,2H),4.32(s,2H),4.26–4.12(m,4H),3.11(s,2H),2.20(s,4H),1.37(t,J＝7.0Hz,3H).
Example 23
4- ((1- (3-ethoxy-4-methylbenzyl) -4-fluoropiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 20 except that 3-ethoxy-4-methylbenzaldehyde is used in place of B20 a.
MS(ESI):m/z 402.1[M+H] + 。 1 H NMR(500MHz,DMSO-d6)δ7.89(d,J＝8.9Hz,2H),7.11(s,1H),7.06(d,J＝8.9Hz,2H),6.84(m,2H),4.17(d,J＝20.4Hz,2H),4.04(d,J＝7.5Hz,2H),3.47(s,2H),2.70(s,2H),2.26(s,1H),2.14(s,3H),2.07–1.73(m,3H),1.35(t,J＝6.9Hz,3H).
Example 24
4- ((1- (3,5-diethoxybenzyl) -4-fluoropiperidin-4-yl) methoxy) benzoic acid, trifluoroacetate
The procedure is as in example 20 except that 3,5-diethoxybenzaldehyde is used instead of B20 a.
MS(ESI):m/z 432.1[M+H] + 。 1 H NMR(500MHz,DMSO-d6)δ7.89(d,J＝8.8Hz,2H),7.05(d,J＝8.8Hz,2H),6.47(s,2H),6.35(s,1H),4.15(d,J＝20.6Hz,2H),3.98(q,J＝7.0Hz,4H),3.46(s,2H),2.70(s,2H),2.28(s,2H),2.04–1.72(m,4H),1.30(t,J＝7.0Hz,6H).
Example 25
4- ((1- ((2,6-diethoxy-4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) methyl) -4-fluoropiperidin-4-yl) methoxy) benzoic acid, trifluoroacetic acid salt
The procedure is as in example 20 except that A12a is used instead of B20 a. MS (ESI) m/z 576.0[ m ] +H] + 。 1 H NMR(500MHz,DMSO-d6)δ7.89(d,J＝8.9,2H),7.68(d,J＝8.1Hz,2H),7.50(d,J＝8.0Hz,2H),7.06(d,J＝8.9,2H),6.71(s,2H),4.17(d,J＝20.7Hz,2H),3.97(q,J＝6.9Hz,4H),3.54(s,2H),2.74(dt,J＝11.7,3.8Hz,2H),2.37–2.27(m,2H),1.99–1.75(m,4H),1.15(t,J＝6.9Hz,6H).
Example 26
4- (1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidine-4-carboxamido) benzoic acid, trifluoroacetate
Step 1: preparation of tert-butyl 4- ((4- (methoxycarbonyl) phenyl) carbamoyl) piperidine-1-carboxylate (C26 a)
1-Boc-4-piperidinecarboxylic acid (1 eq), HATU (1.2 eq) and DIPEA (2 eq) were dissolved in dichloromethane, stirred at room temperature for half an hour, added with methyl p-aminobenzoate (1 eq), and allowed to react at room temperature for 3 hours. And (4) confirming the reaction is complete by thin layer chromatography, stirring the reaction solution with silica gel, and purifying by a Flash silica gel column to obtain C26a.
MS(ESI):m/z 363.0[M+H] + 。 1 H NMR(500MHz,CDCL 3 -d)δ8.00(d,2H),7.61(d,2H),4.32–3.96(m,4H),3.89(s,3H),2.46–2.38(m,1H),1.92–1.88(m,2H),1.80–1.71(m,2H),1.46(s,9H).
And 2, step: 4- (1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) piperidine-4-carboxamido) benzoic acid, trifluoroacetic acid salt
The procedure is as in example 2 except that C26a is used instead of A2 a.
MS(ESI):m/z 521.1[M+H] + 。 1 H NMR(500MHz,DMSO-d6)δ10.83(s,1H),10.62(s,1H),7.89(d,2H),7.76(d,J＝8.5Hz,2H),7.34–7.28(m,2H),7.22–7.15(m,2H),7.07(s,2H),4.29(s,2H),4.03(q,J＝6.9Hz,4H),2.95(d,J＝36.0Hz,2H),2.72(s,1H),2.18(d,J＝6.0Hz,1H),2.16–1.91(m,4H),1.20(t,J＝6.9Hz,6H).
Example 27
4- (1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-methylpiperidine-4-carboxamido) benzoic acid, trifluoroacetic acid salt
The procedure was conducted in the same manner as in example 26 except that 1-Boc-4-methyl-4-piperidinecarboxylic acid was used in place of 1-Boc-4-piperidinecarboxylic acid.
MS(ESI):m/z 535.0[M+H] + 。 1 H NMR(500MHz,DMSO-d6)δ9.89(s,1H),7.92(d,J＝8.6Hz,2H),7.84(d,J＝8.6Hz,2H),7.33–7.26(m,2H),7.21–7.15(m,2H),7.01(s,2H),4.19(s,2H),4.00(q,J＝6.9Hz,4H),2.44(s,2H),2.07–1.74(m,2H),1.31(s,3H),1.25(d,J＝4.7Hz,2H),1.17(t,J＝7.0Hz,6H).
Example 28
4- (1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -3-fluoroazetidine-3-carboxamido) benzoic acid, trifluoroacetate
The procedure is as in example 26 except that 1- (tert-butoxycarbonyl) -3-fluoroazabutane-3-carboxylic acid is used in place of 1-Boc-4-piperidinecarboxylic acid. MS (ESI) m/z 511.2[ m ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ10.64(s,1H),7.95(d,J＝8.8Hz,2H),7.88(d,J＝8.8Hz,2H),7.28(dd,J＝8.7,5.8Hz,2H),7.17(t,J＝9.0Hz,2H),6.91(s,2H),4.66(s,2H),4.55(s,2H),4.43(s,2H),4.00(q,J＝7.0Hz,4H),1.18(t,J＝6.9Hz,6H).
Example 29
4- (1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-hydroxypiperidine-4-carboxamido) benzoic acid, trifluoroacetate
The procedure was conducted in the same manner as in example 26 except that 1-Boc-4-hydroxy-4-piperidinecarboxylic acid was used in place of 1-Boc-4-piperidinecarboxylic acid.
MS(ESI):m/z 537.1[M+H] + 。 1 H NMR(500MHz,DMSO-d6)δ12.69(s,1H),10.20(s,1H),7.89(s,4H),7.31(dd,J＝8.4,5.7Hz,2H),7.18(t,J＝8.8Hz,2H),7.08–7.01(m,2H),6.35(d,J＝21.7Hz,1H),4.38–4.29(m,2H),4.02(q,J＝7.0Hz,4H),3.20(d,J＝12.2Hz,2H),2.39(s,2H),2.10–1.85(m,2H),1.24(s,2H),1.19(t,J＝6.9Hz,6H).
Example 30
4- (1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-fluoropiperidine-4-carboxamido) benzoic acid, trifluoroacetic acid salt
The same procedure used in EXAMPLE 26 was repeated except that 1-Boc-4-fluoro-4-piperidinecarboxylic acid was used in place of 1-Boc-4-piperidinecarboxylic acid.
MS(ESI):m/z 539.0[M+H] + 。 1 H NMR(500MHz,DMSO-d6)δ12.79(s,1H),10.44(s,1H),7.92(d,J＝8.6Hz,2H),7.86(d,J＝8.7Hz,2H),7.33–7.27(m,2H),7.18(t,J＝8.7Hz,2H),7.00(s,2H),4.38(s,2H),4.02(q,J＝6.8Hz,4H),3.46(s,2H),3.20(s,2H),2.43–2.09(m,4H),1.19(t,J＝7.1Hz,6H).
Example 31
4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-fluoropiperidin-4-yl) methyl) (methyl) amino) -2-methoxybenzoic acid;
the synthetic route is as follows:
preparation of 4-fluoro-4- (((3-methoxy-4- (methoxycarbonyl) phenyl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester
4- (aminomethyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester (1 eq), methyl 4-bromo-2-methoxybenzoate (1.5 eq), potassium phosphate (3 eq), pd 2 (dba) 3 (0.05 eq) and BrettPhos ligand (0.1 eq) were dissolved in 1,4-dioxane, and after displacement with nitrogen, the reaction was carried out for 3 hours at 100 ℃ with the tube sealed, and thin-layer chromatography was carried out to confirm completion of the reaction. The reaction mixture was cooled to room temperature, filtered to remove solids, and the filtrate was purified by Flash silica gel column chromatography (PE/EA =10, 1 to 2:1) to give a yellow oilState A7a. MS (ESI) m/z 396.2[ m ] +H] + .
Preparation of tert-butyl 4-fluoro-4- (((3-methoxy-4- (methoxycarbonyl) phenyl) (methyl) amino) methyl) piperidine-1-carboxylate
Sodium hydride (1.5 eq) was added to a solution of A7a (1 eq) in N, N-dimethylformamide, and after stirring at room temperature for 0.5 hour, methyl iodide (1.2 eq) was added, and the reaction was continued at room temperature overnight. After confirming completion of the reaction by thin layer chromatography, a saturated aqueous solution of sodium chloride was added to the reaction mixture, extracted 3 times with ethyl acetate, and the organic phases were combined and washed 3 times with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was purified by Flash silica gel column chromatography (PE/EA =10, 1 to 4:1) to give a yellow oil A7b. MS (ESI) m/z 410.2[ m + H ]] + .
Preparation of 4- ((((1- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -4-fluoropiperidin-4-yl) methyl) (methyl) amino) -2-methoxybenzoic acid
The procedure is as in example 2 except that intermediate A7b is used instead of intermediate A2 a. MS (ESI) m/z 569.2[ 2 ], [ M + H ]] + . 1 H NMR(500MHz,Chloroform-d)δ12.14(s,1H),7.95(dd,J＝9.0,1.6Hz,1H),7.30(dd,J＝8.7,5.6Hz,2H),7.06(t,J＝8.8Hz,2H),6.71(s,2H),6.44(dd,J＝9.0,2.3Hz,1H),6.30(d,J＝2.3Hz,1H),4.16(s,2H),4.03(s,3H),3.95(q,J＝6.9Hz,4H),3.72(d,J＝22.9Hz,2H),3.57–3.49(m,2H),3.11(s,3H),3.04(t,J＝12.6Hz,2H),2.62–2.43(m,2H),2.11–2.02(m,2H),1.24(t,J＝6.9Hz,6H).
Example 32 calcium flux assay to test SSTR5 antagonistic Activity in vitro
The experimental principle is as follows: activation of the receptor-binding ligand results in activation of the G.alpha.16 protein, which in turn activates phospholipase C (PLC) to produce IP3 and DAG, IP3 binding to the IP3 receptor on the endoplasmic reticulum and mitochondria within the cell, resulting in release of intracellular calcium. Therefore, the determination of the change in intracellular calcium can be used as a method for detecting the activation state of hSSTR 5. Fluo-4/AM is a calcium fluorescent probe indicator used for measuring calcium ions, is used as a nonpolar fat-soluble compound, and after entering cells, under the action of cell lipolytic enzyme, an AM group is dissociated to release Fluo-4; since Fluo-4 is a polar molecule and does not readily pass through a lipid bilayer membrane, it allows Fluo-4 to remain in the cell for a long period of time. The level of activation of the G.alpha.protein can ultimately be reflected by measuring the intensity of the fluorescence that is excited. The agonist somastatin of SSTR5 can excite SSTR5 receptors, so that the calcium flow response is greatly increased. Antagonists of SSTR5 to be tested can inhibit the agonistic activity of SSTR5 receptors, resulting in a reduction in the elevated calcium flux response of the receptors stimulated by agonists.
The experimental steps are as follows:
(1) hSSTR5-CHO-G alpha 16 and mSTR 5-CHO-G alpha 16 cell lines stably expressing hSSTR5 or mSTR 5 receptors were cultured in a 96-well plate at a density of 3 ten thousand per well in an incubator at 37 ℃ overnight.
(2) The culture medium was aspirated off, 40. Mu.l/well of freshly prepared dye was added, and incubation was carried out in an incubator at 37 ℃ for 45 minutes at constant temperature.
(3) The dye was removed by blotting and replaced with 50. Mu.l of freshly prepared calcium buffer.
(4) The agonist somastatin-14 was diluted with calcium buffer and mixed well.
(5) Detection was performed using a Flexstation instrument, and 25. Mu.l of the pre-formulated agonist was automatically added by the instrument beginning at 15 seconds, and the fluorescence was read at 525 nm. Agonist EC 50 At 9.7nM, 100nM agonist concentration was chosen for antagonist activity assay.
(6) Diluting the positive control antagonist and the compound to be detected by using a calcium buffer solution and uniformly mixing; among these, the positive control antagonist was 4- (8- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -3-oxo-2,8-diazaspiro [4.5] decan-2-yl) benzoic acid, from the article ACS med. Chem.lett.2018,9,1082-1087.
(7) The dye was aspirated off and discarded, and after one wash with freshly prepared calcium buffer, replaced with 50. Mu.l of 10-fold concentration-gradient diluted antagonist.
(8) Using a Flextation instrument, 25. Mu.l of a pre-formulated agonist at 100nM concentration was automatically added to the instrument beginning at 15 seconds, and the fluorescence at 525nM was read.
The experimental results are as follows: the results of in vitro activity tests of some compounds are shown in table 1.
TABLE 1
| Examples | hSSTR5 | mSSTR5 | Examples | hSSTR5 | mSSTR5 |
| 1 | B | - | 16 | B | - |
| 2 | A | A | 17 | A | A |
| 3 | B | - | 19 | A | - |
| 4 | B | - | 20 | C | - |
| 5 | A | - | 21 | A | - |
| 8 | C | - | 22 | C | - |
| 9 | C | - | 23 | B | - |
| 10 | B | - | 24 | B | - |
| 11 | C | - | 25 | A | - |
| 12 | B | - | 28 | B | - |
| 13 | C | - | 29 | A | - |
| 14 | A | A | 30 | A | - |
| 15 | A | A | 31 | A |
Activity range representation method: a is 0-50nM; b, 50-200nM; c, 200-1000nM; d is more than 1000nM; no test
The data show that the compounds have good SSTR5 antagonistic activity.
Example 33
C57BL/6 Normal mouse oral glucose tolerance (OGTT) test of the compound of the invention
The experimental method comprises the following steps: c57BL/6 mice were fasted for 12h before the experiment, and a dosing group and a blank control group were set, each group consisting of 8 mice. Mice in the control group were orally administered with 200. Mu.l of purified water, and mice in the administration group were orally administered with 200. Mu.l of an aqueous solution containing the compound. Glucose (4 g/kg) was administered orally 60min after administration. Blood Glucose was measured using an Accu-Chek Advantage II Glucose Monitor (Roche, indianapolis, IN, USA) by tail bleed prior to dosing, and after 0, 15, 30, 60, 90, 120min, respectively.
Blood glucose reduction rate = (blank control blood glucose value-administration group blood glucose value)/blank control blood glucose value × 100%
AUC 0-120min Glu Rate of decrease =
(blank control AUC 0-120min Glu AUC of the administration group 0-120min Glu ) AUC of blank control group 0-120min Glu ×100％
The results of the oral glucose tolerance (OGTT) test after a single continuous dose of the compound in normal mice are shown in fig. 1 and table 2.
TABLE 2
| Positive control (3 mg/kg) | Example 15 (100 mg/kg) | |
| AUC 0-120min Glu Rate of decline | 19.2％ | 22.1％ |
Among these, the positive control was 4- (8- ((2,6-diethoxy-4 '-fluoro- [1,1' -biphenyl ] -4-yl) methyl) -3-oxo-2,8-diazaspiro [4.5] decan-2-yl) benzoic acid from the article ACS med. The data show that the compound has good hypoglycemic effect.
Example 34
Experiment for promoting gallbladder evacuation
C57BL/6J mice, 8-10 weeks old, were fasted for 17-18 hours prior to the experiment and allowed free access to water. The mice were then divided into groups of 3 mice by weight, and an aqueous solution of the compound of example 5 (30 mg/kg) or an equal volume of distilled water was separately gavaged to a volume of 10mL/kg. One hour after the administration, the mice were orally administered 200 μ l of egg yolk or without any treatment, 15 minutes later, the mice were sacrificed by dislocation and dissected, and the gall bladder was taken out and weighed with an analytical balance.
The results are shown in fig. 2, and show that the example 5 can remarkably promote the emptying of the gall bladder of the mouse, and can be applied to the prevention and treatment of gall bladder related diseases such as gallstone, cholestasis, primary sclerosing cholangitis and the like.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.
Claims (10)
1. A compound, solvate, hydrate or pharmaceutically acceptable salt thereof represented by the general formula I:
wherein m is 1, 2 or 3;
n is 1, 2 or 3;
R 1 is H, OH, NH 2 CN, halogen or C 1 -C 6 An alkyl group;
R 2 、R 3 、R 4 、R 5 、R 6 each independently selected from the group consisting of: hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, halogen, C 1 -C 6 Haloalkyl, OH, NH 2 、N(C 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), substituted or unsubstituted C 6 -C 14 An aryl group; wherein said substitution means that one or more hydrogen atoms on the aryl group are substituted with a group selected from the group consisting of: halogen, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl);
or R 2 、R 3 、R 4 、R 5 、R 6 Any two adjacent substituents of (a) together with the phenyl ring form a benzo 5-7 membered heterocyclic ring or a benzo 5-7 membered carbocyclic ring, which heterocyclic ring or carbocyclic ring is unsubstituted or substituted with one or more groups selected from: halogen, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl);
A-L
is- (CH) 2 ) r -NR 9 -A、-(CH 2 ) r -O-A、-(CH 2 ) r -S-A、-(CH 2 ) r -CONR 9 -A、-(CH 2 ) r CONR 9 (CH 2 ) s -A、-(CH 2 ) r -OOC-(CH 2 ) s -A or- (CH) 2 ) r -COO-(CH 2 ) s -a, wherein r, s are each independently 0, 1, 2 or 3; r 9 Is H or C 1 -C 6 An alkyl group;
a is substituted or unsubstituted C 6 -C 14 Aryl, or substituted or unsubstituted C 3 -C 8 A cycloalkyl group; wherein said substitution means that one or more hydrogen atoms on the aryl or cycloalkyl group are substituted by a group selected from the group consisting of: halogen, carboxyl, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl groups).
2. The compound of claim 1, wherein a is substituted or unsubstituted phenyl, or substituted or unsubstituted C 4 -C 6 A cycloalkyl group; wherein said substitution means that 1, 2 or 3 hydrogen atoms on the aryl or cycloalkyl group are substituted by a group selected from the group consisting of: halogen, carboxyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C) 1 -C 4 Alkyl groups).
3. The compound of claim 1, wherein a-L is
Is- (CH) 2 ) r -NR 9 -A、-(CH 2 ) r -O-A、-(CH 2 ) r -S-A or- (CH) 2 ) r -CONR 9 -a, wherein r, s are each independently 0, 1 or 2; r 9 Is H or C 1 -C4 alkaneAnd (4) a base.
4. The compound of claim 1, wherein R is 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from the group consisting of: hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, F, cl, br, C 1 -C 4 Haloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C 1 -C 4 Alkyl), substituted or unsubstituted phenyl; wherein said substitution means that 1, 2 or 3 hydrogen atoms on the phenyl group are substituted by a group selected from the group consisting of: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C 1 -C 4 Alkyl groups);
or R 2 、R 3 、R 4 、R 5 、R 6 Any two adjacent substituents of (a) together with the phenyl ring form a benzo 5-6 membered heterocyclic ring or a benzo 5-6 membered carbocyclic ring, which heterocyclic ring or carbocyclic ring is unsubstituted or substituted with 1, 2 or 3 groups selected from: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl, OH, NH 2 、N(C 1 -C 4 Alkyl) (C 1 -C 4 Alkyl groups).
5. The compound of claim 1, wherein R is 2 、R 6 Each independently selected from the group consisting of: hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, F, cl, br, C 3 -C 6 A cycloalkyl group;
R 3 、R 5 each independently selected from the group consisting of: H. c 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, F, cl, br, C 1 -C 4 Haloalkyl, OH, NH 2 ；
R 4 Is H, F, cl, br, C 1 -C 4 Alkyl, or substituted or unsubstituted phenyl; wherein said substitution means that 1 or 2 hydrogen atoms on the phenyl group are substituted by a group selected from the group consisting of: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 An alkyl group;
or, R 4 And R 3 Or R is 4 And R 5 Taken together with the phenyl ring to form a benzo 5-6 membered heterocycle which is unsubstituted or substituted with 1 or 2 groups selected from: F. cl, br, C 1 -C 4 Haloalkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 An alkyl group.
6. The compound of claim 1, wherein the compound is selected from the group consisting of:
7. a process for preparing a compound of claim 1, wherein the compound has the structure of formula If, the process comprising the steps of:
the compound Ia and Ib are subjected to coupling reaction to obtain Ic;
deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id;
id and
obtaining Ie through nucleophilic substitution reaction;
hydrolyzing the Ie under alkaline condition to obtain If;
or the preparation method comprises the following steps:
the compound Ia and Ib are subjected to Mitsunobu reaction to obtain Ic;
deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id;
id and
obtaining Ie through nucleophilic substitution reaction;
hydrolyzing the Ie under an alkaline condition to obtain If;
or the preparation method comprises the following steps:
carrying out amide condensation reaction on the compound Ia and Ib to obtain Ic;
deprotection is carried out on Ic under the condition of hydrochloric acid or trifluoroacetic acid to obtain Id;
id and
by passingCarrying out nucleophilic substitution reaction to obtain Ie;
hydrolyzing the Ie under alkaline condition to obtain If;
in the above formulas, Q is- (CH) 2 ) r -；R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 R, m, n are as defined in claim 1.
8. A pharmaceutical composition, comprising:
a compound of formula I, solvate, hydrate or a pharmaceutically acceptable salt thereof according to claim 1; and
a pharmaceutically acceptable carrier.
9. Use of a compound of general formula I, a solvate, hydrate or pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 8 for the preparation of a medicament for antagonizing SSTR5 or for the preparation of a medicament for the prevention or treatment of diseases mediated by SSTR 5.
10. The use of claim 9, wherein the disease mediated by SSTR5 is type ii diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gallstones, primary cholangitis, or inflammatory bowel disease.
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