CN114163408B - Benzo oxygen-containing heterocyclic compound and medical application thereof - Google Patents

Benzo oxygen-containing heterocyclic compound and medical application thereof Download PDF

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CN114163408B
CN114163408B CN202010947830.0A CN202010947830A CN114163408B CN 114163408 B CN114163408 B CN 114163408B CN 202010947830 A CN202010947830 A CN 202010947830A CN 114163408 B CN114163408 B CN 114163408B
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詹正云
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AB Pharma Ltd
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Abstract

The present invention discloses compounds of formula Ia or IIa, cis-, enantiomer, diastereoisomer, racemate, tautomer, solvate, hydrate, or pharmaceutically acceptable salt or mixture thereof, pharmaceutical compositions containing the compounds and use of the compounds as GPR40 agonists 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 5b 、R 6 、R 7 、Ra、Rb、Rc、Rd、Re、Rf、Rg、Ri、Rj、X 1 、X 2 、X 3 、X 4 、Y、Y 1 And the possible isotopic substitution labels of the elements in the compounds are as defined in the specification.

Description

Benzo oxygen-containing heterocyclic compound and medical application thereof
Technical Field
The invention relates to a novel benzo oxygen-containing heterocyclic compound, in particular to a benzo five-membered oxygen-containing heterocyclic compound which can be used as an agonist of a GPR40 target spot, and can be used for safely and effectively treating diseases such as II type diabetes mellitus and the like by stimulating islet beta cells to release insulin to reduce blood sugar level.
Background
Diabetes is a chronic endocrine and metabolic disease characterized by hyperglycemia resulting from insulin secretion deficiency, insulin resistance, or both. Diabetes can severely damage major organ systems of the body, causing heart disease, stroke, nerve damage, renal failure, blindness, and infection that can lead to amputation, with complications of the disease being frequent, with high disability and mortality rates.
Type II diabetes accounts for about 90% of the total number of diabetes cases, and patients often are able to produce insulin themselves, but do not produce enough insulin or do not make good use. The clinically common medicines for treating diabetes have insulinotropic agents which are first-line hypoglycemic agents at present, and the medicines include sulfonylureas such as glipizide and the like and non-sulfonylureas such as metformin and the like. The common main side effects of hypoglycemic drugs are discomfort of gastrointestinal tract, edema, hypoglycemia and the like, and some patients may have phenomena such as intense fasting feeling, cold sweat, general weakness, palpitation, hand and foot tremble, eye blossoming, headache, stupor and the like due to the side effects of the hypoglycemia, and the like, and the coma occurs in serious cases. Therefore, the development of novel anti-type II diabetes drugs with high safety, no hypoglycemia side effects and convenient and effective oral administration is still the direction of scientists' efforts to explore.
Recent studies have found that free fatty acid receptor 1 (FFAR 1), alternatively referred to as G protein-coupled receptor 40 (GPR 40), plays a key role in stimulating and regulating insulin production. GPR40 agonists lower blood glucose levels by stimulating insulin release from islet beta cells when postprandial blood glucose and fatty acids are elevated. Thus, drugs that activate GPR40 can be effective in controlling blood glucose levels by helping diabetics release more insulin. The medicine is characterized in that insulin secretion can be promoted only when the blood sugar concentration is high, so that the risk of hypoglycemia is greatly reduced. A representative of this class of drugs, TAK-875, developed by the Japanese Wuta-tsu company, is a selective GPR40 agonist, and has entered phase III clinic, and the results of the study show that when blood glucose levels are normal, TAK-875 has no effect on insulin secretion, and once a day, the patient has better efficacy and good tolerance with 50mg administration dose, and the risk of causing hypoglycemia is significantly lower than that of sulfonylurea drugs of the control group, and it is verified that the insulin secretion induced by TAK-875 is blood glucose dependent. Although TAK-875 showed good therapeutic effects, japanese wuta-corporation terminated its clinical study in 2013 due to the problem of liver toxicity caused by its drugs. It is worth mentioning that the study of TAK-875 hepatotoxicity problem shows that the medicine has no relation with the action mechanism, and is mainly the problem caused by the insufficient safety of the molecular structure design. Therefore, the GPR40 target is still a good development idea and has very important application prospect.
Structure of Compound TAK-875
A series of patent applications for GPR40 agonists are presently disclosed, including W02005087710, W02007106469A1, WO2004106276A1, W02010143733A1, CN103030646A1, WO2013104257A1, WO2015062486A1, and the like.
Thus, despite advances in the art, there remains a great need in the art for GPR40 agonists for the treatment of diabetes and related metabolic disorders that specifically activate the GPR40 target, and associated compositions and methods of treatment of the disease. The present invention addresses this need and provides other related advantages.
Disclosure of Invention
The present invention relates to compounds that activate the GPR40 target, and to cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts of said compounds, or mixtures thereof. The invention also relates to pharmaceutically acceptable compositions comprising said compounds, and to related methods, for the treatment of disorders, such as diabetes and related metabolic disorders, in which a beneficial effect is obtained from activating a GPR40 target.
The present invention provides a benzo-oxygen-containing heterocyclic compound different from the existing structure. The benzo five-membered oxygen-containing heterocyclic compound has better inhibitory activity on type II diabetes mellitus, can be more effectively used for treating type II diabetes mellitus patients, and has better safety.
A first aspect of the present invention provides a compound of formula Ia, a cis, trans isomer, enantiomer, diastereomer, racemate, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, or a mixture thereof;
wherein,
n=0, 1 or 2;
when n=0, Y is absent, Y 1 Z ortho to Y 1 Directly connecting the two single bonds to form five-membered heterocycle;
E 1 with L and Y 1 A linkage selected from-N-, -C (Ra) -or-OC (Ra) -; wherein Ra is selected from: hydrogen, deuterium (D), alkylCycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl or heteroaryl;
e is not equal to G 1 When linked to form a cyclic compound, E is selected from: hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, -CN, -OH, -COOH, -NH 2 、-H 2 NCO, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, aryl, aryloxy, or heteroaryl; g 1 CH, or C (Rb); wherein Rb is hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclyl, heterocyclylaryl, or heterocyclylaryloxy, or Rb and R 4 Can be connected with each other to form cycloalkyl or heterocyclic groups;
e and G 1 G when connected to form a cyclic compound 1 is-C-; e is-O-, -C (RcRd) -, -OC (RcRd) -, -C (RcRd) O-, or-NRe-; wherein Rc and Rd are each independently hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclyl, heterocyclylaryl, or heterocyclylaryloxy, and Rc and Rd may be linked to each other to form a cycloalkyl group, or a heterocyclic group; re is hydrogen, deuterium (D), alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, alkylsulfonyl, or arylsulfonyl;
l is-O-, -S-, -C (O) -, -S (O) 2 –、-CH 2 -、-C(R f R g )-、-OC(R f R g )-、-C(R f R g )O-、-N(Re)-、-N(Rc)C(R f R g ) -, or-C (R) f R g ) N (Re) -; wherein R is f And R is g Hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, and cyclo, respectivelyAlkylaminocarbonyl, aryl, aryloxy, heterocyclyl, heterocyclylaryl, or heterocyclylaryloxy, re is as defined for Re in E above;
R 1 、R 2 And R is 3 Each independently is hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, aryl, aryloxy, or heteroaryl; wherein R in formula Ia 2 Can be mutually connected with L to form a 4-8 membered heterocyclic compound, and L is-C (H) -O-;
R 4 、R 5 and R is 5b Each independently is hydrogen, deuterium (D), halogen, hydroxy, amino, nitrile, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, aryl, aryloxy, or heteroaryl; wherein R is 5 And R is 5b Can be connected with each other to form cycloalkyl, heterocyclic group or heterocyclic aryl;
R 6 is carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, alkylsulfonylaminocarbonyl, cycloalkylsulfonylaminocarbonyl, heterocyclyl, or heterocyclylaryl; or R is 6 With substituents R in ortho-position 5 Can be connected with each other to form heterocycle or heterocyclic aryl;
X 1 、X 2 、X 3 and X 4 Each independently is hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl (H) 2 NCO), alkyl, heterocycloalkyl, alkoxy, heteroatom-substituted alkyloxy, alkylamino (NR) i R j ) Heteroatom substituted alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, aryloxycarbonylamino, heteroaryl, heterocycloaryloxy, orA heterocyclic arylamino group; wherein R is i And R is j Each independently is hydrogen, deuterium (D), alkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, aryloxycarbonyl, arylaminocarbonyl, heterocycloaryl, or R i And R is j Are mutually connected into 3-8 membered heterocyclic ring containing 1-3 hetero atoms;
y and Y 1 Each independently is-O-, -S-, -CH 2 -、-CHF-、-CF 2 -、-CCl 2 -、-C(R f R g ) -or-N (Re) -; wherein R is f And R is g Are defined separately from L 1 R in (a) f And R is g The definition of Re is the same as that of Re in E;
Z 1 is-O-, -S-, -CH 2 -、-CHF-、-CF 2 -、-C(R f R g ) -N (Re) -, or-C (O) -; wherein R is f And R is g Is defined as R in L f And R is g The definition of Re is the same as that of Re in E above.
In a second aspect, the invention provides a compound of formula IIa, its cis, trans, enantiomer, diastereomer, racemate, tautomer, solvate, hydrate, or pharmaceutically acceptable salt or mixture thereof:
wherein,
n、E、E 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 5b 、Ra、Rb、Rc、Rd、Re、Rf、Rg、Ri、Rj、X 1 、X 2 、X 3 、X 4 y and Y 1 Is as defined in claim 1;
R 7 is hydroxy, alkoxy, alkylamino, cycloalkylamino, heterocyclylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryloxyA group, a heterocyclic aryloxy group, an arylamino group, or a heterocyclic arylamino group; or R is 7 With substituents R in ortho-position 5 Can be connected with each other to form heterocycle.
In some preferred embodiments, n=0 or 1;
when n=0, Y is absent, Y 1 Oxygen at the ortho position of Y is directly connected with a single bond to form five-membered heterocycle;
when n=1, Y is-CH 2 -；
E 1 is-CH-;
e is not equal to G 1 When directly attached to form a cyclic compound, E is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or alkoxy; g 1 is-CH-, or-C (Rb) -; wherein Rb is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, or Rb and R 4 Are mutually connected to form oxygen-containing heterocyclic groups; r is R 4 Is hydrogen, alkyl, alkoxy, optionally substituted alkynyl, or R 4 And Rb are interconnected to form an oxygen-containing heterocyclic group;
e and G 1 When directly linked to form a cyclic compound, E is-OC (RcRd) -; g 1 is-C-; r is R 4 Is hydrogen;
R 1 、R 2 and R is 3 Each independently is hydrogen, halogen, alkyl or alkoxy;
R 5 hydrogen, halogen, hydroxy, amino, alkylamino, alkyl or alkoxy;
R 5b hydrogen, halogen, alkyl or alkoxy;
R 7 is alkoxy, hydroxy, alkylsulfonamido, or cycloalkylsulfonamide;
X 1 is hydrogen, deuterium (D), halogen, nitrile group, amino (NH) 2 ) Trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR) i R j ) An alkylcarbonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, or aryloxycarbonylamino group;
X 2 、X 3 and X 4 Each independently hydrogen, deuterium (D), halogen, or trifluoromethyl;
Y 1 is-CH 2 -、-CHF-、-CF 2 -, or-C (CH) 3 ) 2 -；
Z 1 is-O-, or-CH 2 -；
Rc and Rd are each independently hydrogen;
ri and Rj are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl.
In some more preferred embodiments, n=0, y is absent;
E 1 is-CH-;
e is not equal to G 1 E is hydrogen or halogen when directly linked to form a cyclic compound; g 1 is-CH-, or-C (Rb) -, wherein Rb is alkyl, alkenyl, alkynyl or alkoxy; r is R 4 Hydrogen, alkyl or alkoxy;
e and G 1 Directly linked to form a cyclic compound, E being-OC (RcRd) -, G 1 is-C-, R 4 Is hydrogen, wherein Rc and Rd are each independently hydrogen;
R 1 、R 2 and R is 3 Each independently is hydrogen, halogen, or alkoxy;
R 5 hydrogen, halogen, hydroxy, amino, alkyl or alkoxy;
R 5b hydrogen, halogen, alkyl or alkoxy;
R 7 selected from: alkoxy, hydroxy, alkylsulfonamido, or cycloalkylsulfonamide groups;
Y 1 is-CH 2 -；
Z 1 is-O-;
X 1 selected from: hydrogen, deuterium (D), halogen, nitrile group, amino (NH) 2 ) Trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR) i R j ) An alkylcarbonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, or aryloxycarbonylamino group, wherein Ri and Rj are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl;
X 2 、X 3 and X 4 Each independently is hydrogen, deuterium (D), halogen, or trifluoromethyl.
In some specific embodiments, the compounds of the present invention have a structure selected from the group consisting of:
In another aspect, the invention provides a composition comprising (i) a therapeutically effective amount of at least one compound of formula Ia or IIa, its cis, trans, enantiomer, diastereomer, racemate, tautomer, solvate, hydrate, or pharmaceutically acceptable salt or mixture thereof; and (ii) a pharmaceutically acceptable diluent and/or excipient.
The invention also relates to the use of said compounds or compositions for the preparation of a medicament for the treatment of GPR40 agonists.
The invention also provides a method of treating or preventing diabetes or related metabolic syndrome comprising administering to a patient a therapeutically effective amount of the compound or composition.
The invention also relates to the use of said compounds or compositions for the preparation of a medicament for the treatment or prevention of diabetes or related metabolic syndrome.
In a preferred embodiment, the compounds or compositions of the invention are particularly useful in the treatment of type II diabetes. The compound of the invention can promote insulin secretion only when the blood sugar concentration of the type II diabetes patient is high, so that the risk of hypoglycemia of the patient can be effectively reduced. Meanwhile, compared with the medicines sold on the market, the compound provided by the invention has better GPR40 target selectivity and safety.
The above-described embodiments and other aspects of the invention will be apparent from the following detailed description. For this reason, various references are set forth herein that describe in more detail certain background information, processes, compounds, and/or compositions, and are each incorporated by reference in their entirety.
Detailed Description
In the following description, certain specific details are set forth in order to provide a thorough understanding of embodiments of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. Throughout the specification and claims of this specification, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to be open-ended, i.e. to be "including but not limited to", unless the context requires otherwise.
Reference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
I. Definition of the definition
In the present invention, when not specifically specified, the term "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, which is composed of only carbon and hydrogen atoms. In a preferred embodiment, the alkyl group has one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl) and is attached to the remainder of the molecule by a single bond. Exemplary alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and various isomers thereof, and the like. The alkyl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethylOxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, aryloxy, heteroaryl, heterocycloaryloxy, fused-ring aryl, fused-ring heterocycloaryl, fused-ring oxy, fused-ring aryloxy, fused-ring heterocycloaryloxy, arylureido, or heterocycloarylureido.
In the present invention, unless otherwise specified, "aryl" refers to any stable monocyclic, bicyclic, tricyclic, or tetracyclic ring that may contain up to 7 carbon atoms per ring, wherein at least one ring is an aromatic hydrocarbon ring system. Exemplary aryl groups are hydrocarbon ring system groups containing hydrogen and 6 to 9 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups comprising hydrogen and 9-12 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups comprising hydrogen and 12-15 carbon atoms and at least one aromatic ring; or a hydrocarbon ring system group comprising hydrogen and 15 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from the following constitution: benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene, and the like. "optionally substituted aryl" means: an aryl group or a substituted aryl group. The aryl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyl-sulfonyl-alkoxy, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, aryl, aryloxy, heteroaryl, fused ring aryl, fused ring alkyl, fused ring oxy, benzene or biphenyl optionally containing 1 to 4 of the foregoing optional substituents.
In the invention, there is no special featureWhere otherwise indicated, the term "heteroaryl" means a stable monocyclic, bicyclic or tricyclic ring containing up to 7 atoms per ring, wherein at least one ring is aromatic, and wherein at least one ring contains 1-4 heteroatoms selected from O, N, and/or S. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazole, furanyl, thienyl, benzothiazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl. In addition, "heteroaryl" shall also be understood to include any quaternary ammonium salt or N-oxide derivative of a nitrogen-containing heteroaryl. The heteroaryl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, aryl, aryloxy, heteroaryl, fused-ring aryl, fused-ring alkyl, fused-ring oxy, unsubstituted or benzene or biphenyl containing 1 to 4 of the foregoing optional substituents.
In the present invention, unless otherwise specified, the term "fused ring aryl" means a stable bicyclic or tricyclic ring which may contain up to 7 atoms per ring, wherein at least one ring is aromatic. The fused ring aryl may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, aryl, aryloxy, heteroaryl, fused-ring aryl, fused-ring alkyl, fused-ring oxy, unsubstituted or containing 1 to 4 of the above optional substitutionsBenzene or biphenyl radicals.
In the present invention, unless otherwise specified, the term "fused-ring heteroaryl" means a stable bicyclic or tricyclic ring containing up to 7 atoms per ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N, and/or S. The fused ring heteroaryl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, aryl, aryloxy, heteroaryl, fused-ring aryl, fused-ring alkyl, fused-ring oxy, unsubstituted or benzene or biphenyl containing 1 to 4 of the foregoing optional substituents.
In the present invention, unless otherwise specified, the "alkoxy" represents a resultant group after the alkyl group is bonded to the oxygen atom, that isR is alkyl, which is as defined for alkyl above. Examples of alkoxy groups include, but are not limited to: -O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), -O-isopropyl (isopropoxy), -O-tert-butyl (tert-butoxy) and the like.
In the present invention, unless otherwise specified, "alkenyl" means an unsaturated aliphatic alkenyl group containing 1 to 3 "carbon-carbon double bonds" including branched and straight chains of 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (C 2 -C 10 Alkenyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 Alkenyl) or 2 to 6 carbon atoms (C 2 -C 6 Alkenyl), and their various isomers, etc., which are linked to the remainder of the molecule by single bonds. Examples of alkenyl groups include, but are not limited to: ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. The alkenyl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl Oxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, arylureido, or heterocyclylarylureido.
In the present invention, unless otherwise specified, "alkynyl" means an unsaturated aliphatic alkynyl group containing 1 to 2 "carbon-carbon triple bonds" including branched and straight chains of 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (C 2 -C 10 Alkynyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 Alkynyl) or 2 to 6 carbon atoms (C 2 -C 6 Alkynyl), and their various isomers, etc., which are attached to the remainder of the molecule by single bonds. Examples of alkynyl groups include, but are not limited to: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, arylureido, or heterocyclylarylureido.
In the present invention, unless otherwise specified, the term "alkylthio" means a resultant group after the alkyl group is bonded to the sulfur atom, that isR is alkyl, which is as defined for alkyl above.
In the present invention, unless otherwise specified, the term "aryloxy" means a resultant group after the connection of an aryl group to an oxygen atom, i.eAr is aryl, which is as defined above for aryl.
In the present invention, unless otherwise specified, the term "arylamino" means "NH 3 "an amine group in which one hydrogen is substituted with an aryl group, wherein the definition of the aryl group is the same as that described for the aryl group above.
In the present invention, unless otherwise specified, the "heterocyclic arylamino group" means "NH 3 "an amino group in which one hydrogen is substituted with a heterocyclic aryl group, wherein the heterocyclic aryl group is as defined above for the heterocyclic aryl group.
In the present invention, unless otherwise specified, the term "cycloalkyl" refers to an all-carbon monocyclic or polycyclic group in which each ring does not contain a double bond or a triple bond. Preferably 3-20 carbon atoms, 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, a ring with 4 carbon atoms, or a ring with 3 carbon atoms. Examples of cycloalkyl groups include, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The cycloalkyl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, aryloxy, heteroaryl, heterocycloaryloxy, fused-ring aryl, fused-ring heterocycloaryl, fused-ring oxy, fused-ring aryloxy, fused-ring heterocycloaryloxy, arylureido, or heterocycloarylureido, wherein aryl is as defined above for aryl.
In the present invention, unless otherwise specified, the term "cycloalkenyl" refers to an all-carbon monocyclic or polycyclic group in which the or each ring may contain one or more "carbon-carbon double bonds". Preferably 3-20 carbon atoms, 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, 3 to 8 carbon atoms,3 to 6 carbon atoms, 3 to 5 carbon atoms, a ring having 4 carbon atoms, or a ring having 3 carbon atoms. Examples of cycloalkenyl groups include, for example: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The cycloalkenyl group may be optionally substituted with a group selected from the group consisting of: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH) 2 ) Aminocarbonyl (H) 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, aryloxy, heteroaryl, heterocycloaryloxy, fused-ring aryl, fused-ring heterocycloaryl, fused-ring oxy, fused-ring aryloxy, fused-ring heterocycloaryloxy, arylureido, or heterocycloarylureido. Cycloalkyl groups may be formed when the substituents of the cycloalkenyl group are substituted on a carbon-carbon double bond and saturate the double bond.
In the present invention, unless otherwise specified, the term "cyclic ether group" means a cycloalkyl group having an ether group on the ring.
In the present invention, unless otherwise specified, the "heterocyclic group" is an aromatic or non-aromatic heterocyclic ring containing one or more hetero atoms selected from O, N and S, and includes a bicyclic group. Thus, "heterocyclyl" includes the above-described heteroaryl groups, as well as dihydro or tetrahydro analogs thereof, and includes, but is not limited to, the following "heterocyclyl": benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazole, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuranyl, pyridopyridyl, and heterocyclic groups may be linked to other small organic molecule groups through carbon or heteroatoms to form novel pharmaceutically effective compounds.
In the present invention, unless otherwise specified, the term "fused ring aryl" refers to two or more aryl groups and/or heterocyclic aryl groups, polycyclic organic compounds formed by fused rings, which may also be substituted with alkyl, alkoxy, alkylthio, aryloxy, arylamino, hetero ring as defined in the present inventionA cyclic group, cycloalkyl group, cycloalkoxy group, cycloalkoxycarbonyl group, cycloalkylamino group, cycloalkylaminocarbonyl group, cycloalkenyl group, cyclic ether group, aryl group, halogen, carbonyl group, hydroxy group, heterocyclic aryl group, etc., are substituted in a reasonable manner; wherein-includes but is not limited to naphthalene, anthracene, quinone, phenanthrene, fluorene, benzimidazolyl, furanofuranyl, thiophenothienyl, acenaphthenyl (acenaphthyl),
In the present invention, unless otherwise specified, the term "fused ring alkyl" means a non-aromatic polycyclic system obtained by reduction of one or more double bonds in a fused ring aryl group, wherein the carbon number is "C 10-20 ”。
In the present invention, unless otherwise specified, the term "fused ring alkylaryl" refers to a group in which a hydrogen atom on a carbon in an aryl group is replaced with a fused ring alkyl group, wherein the carbon number is "C 15-20 ”。
In the present invention, unless otherwise specified, the term "fused ring oxy" means a group formed by linking a fused ring aryl group or a fused ring alkyl group to oxygen, i.e Ar is C 10-20 Condensed ring aryl or condensed ring alkyl.
In the present invention, unless otherwise specified, the term "alkoxycarbonyl" means a group formed by linking an alkoxy group to a carbonyl group, i.e.R is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the term "aryloxycarbonyl" means a resultant group after connection of an aryloxy group to a carbonyl group, that isAr is C 6-20 Aryl groups.
In the present invention, unless otherwise specified, the term "heterocyclyloxy" means a group formed by linking a heterocyclic group to oxygen, that isR is C 2-20 A heterocyclic group.
In the present invention, unless otherwise specified, the term "alkylamino" means a group formed by linking an alkyl group to an amino group, i.e.R is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the term "alkylaminocarbonyl" means a group formed by linking an alkylamino group to a carbonyl group, i.e.R is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the term "arylamino" refers to a resultant group after attachment of an aryl group to an amine group, i.eAr is C 6-20 Aryl groups.
In the present invention, unless otherwise specified, the "heterocyclic amine group" means a group formed by linking a heterocyclic group to an amine group, that is R is C 2-20 A heterocyclic group.
In the present invention, unless otherwise specified, the term "arylamino sulfonyl" refers to a group formed by linking an arylamino group to a sulfonyl group, i.e.Ar is C 6-20 Aryl groups.
In the present invention, unless otherwise specified, the term "alkylaminosulfonyl" means a group formed by linking an alkylamino group to a sulfonyl group, i.e.R is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the term "heterocyclic sulfamoyl" means a group formed by linking a heterocyclic amine group to a sulfonyl group, i.e.R is C 2-20 A heterocyclic group.
In the present invention, unless otherwise specified, the term "alkylsulfonamide" means a group formed by linking an alkyl group to a sulfonamide group, i.e.R is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the "heterocyclic sulfonamide group" means a group formed after the heterocyclic group is linked to the sulfonamide group, that isR is C 2-20 A heterocyclic group.
In the present invention, unless otherwise specified, the term "arylsulfonamido" means a group formed by linking an aryl group to a sulfonamide group, i.eAr is C 6-20 Aryl groups.
In the present invention, unless otherwise specified, the term "alkylamino sulfonamide" means a group formed after the alkylamino group is linked to the sulfonamide group, that is R is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the term "alkylcarbonylamino" means a group formed by linking an alkyl group to a carbonyl group and then to an amino group, i.eR is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the term "alkylureido" means a group formed by linking an alkyl group to an ureido group, i.e.R is C 1-20 An alkyl group.
In the present invention, unless otherwise specified, the term "arylureido" means a group formed by linking an aryl group to an ureido group, i.e.Ar is C 6-20 Aryl groups.
In the present invention, unless otherwise specified, the term "alkylthiourea" means a group formed by linking an alkyl group to a thiourea group, i.e.R is C 1-20 An alkyl group.
In the present invention, the term "halogen" means "fluorine, chlorine, bromine, or iodine".
In the present invention, the term "hydroxy" is expressed as
In the present invention, the term "amine group" is expressed as
In the present invention, the term "cyano" is expressed as
In the present invention, the term "carboxyl" is expressed as
In the present invention, the term "sulfonyl" is expressed as
In the present invention, the term "sulfonamide" is expressed as
In the present invention, the term "carbonyl" is expressed as
In the present invention, the "ureido" is represented by
In the present invention, the term "thiourea" is represented by
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
II Compounds of the invention
1) The invention firstly designs and introduces one of the following heterocyclic functional groups containing novel benzo oxygen-containing heterocycles:(wherein R is 8 Is halogen, hydroxy, amino, carboxyl, alkylsulfonyloxy, arylsulfonyloxy or a leaving group which can be substituted), and a novel benzo five-membered oxygen-containing heterocyclic compound which can effectively treat type II diabetes mellitus and is a GPR40 target agonist is synthesized.
The present invention relates generally to compounds encompassed by formula Ia, cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts thereof, or mixtures thereof:
for compounds of formula Ia, n, E 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 5b 、Ra、Rb、Rc、Rd、Re、Rf、Rg、Ri、Rj、X 1 、X 2 、X 3 、X 4 Y and Y 1 And the definition of the subscript "n" is as described in the specification. Specific embodiments of the compounds of formula Ia are also described below.
In one embodiment, n=0, Y is absent, Y 1 And Z is 1 Directly connected by single bond.
In one embodiment, E 1 is-C (Ra) -, wherein Ra is selected from: ra is hydrogen, deuterium (D), alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, or heteroaryl. In a preferred embodiment E 1 is-C (Ra) -, wherein Ra is selected from: hydrogen, deuterium (D), C 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 8 Alkoxy, C 3 -C 8 Cycloalkoxy radicals C 1 -C 8 Alkoxycarbonyl group, C 1 -C 8 Alkylamino, C 3 -C 8 Cycloalkylamino, C 1 -C 8 Alkylaminocarbonyl, C 3 -C 8 Cycloalkyl aminocarbonyl, aryl, or heteroaryl. In a more preferred embodiment, E 1 is-CH-.
In one embodiment, E and G 1 Are linked to form a cyclic compound. In a preferred embodiment, E and G 1 And are connected into five-membered ring compounds. In a preferred embodiment, G 1 is-C-, E is-O-, -C (RcRd) -, -OC (RcRd) -or-C (RcRd) O-. In one embodiment, rc and Rd are independently selected from: hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclyl, heterocyclylaryl, or heterocyclylaryloxy. In another embodiment, rc and Rd may be linked to each other as a cycloalkyl or heterocyclic group. In a preferred embodiment, G 1 is-C-, E is-OC (RcRd) -or-C (RcRd) O-,wherein Rc and Rd are independently selected from: hydrogen, deuterium (D), C 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 1 -C 8 Alkoxy, C 3 -C 8 Cycloalkoxy radicals C 1 -C 8 Alkoxycarbonyl group, C 1 -C 8 Alkylamino, C 3 -C 8 Cycloalkylamino, C 1 -C 8 Alkylaminocarbonyl, C 3 -C 8 Cycloalkyl aminocarbonyl, aryl, aryloxy, heterocyclyl, heteroaryl, or heterocycloaryloxy. In a more preferred embodiment, G 1 is-C-, E is-OC (RcRd) -or-C (RcRd) O-, wherein Rc and Rd are each hydrogen.
In one embodiment, L is-O-.
In one embodiment, R 1 、R 2 And R is 3 Each independently is hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, aminocarbonyl (H) 2 NCO)、C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkoxycarbonyl group, C 1 -C 8 Alkylaminocarbonyl, C 1 -C 8 Alkylcarbonylamino, aryl, aryloxy, or heteroaryl. In a preferred embodiment, R 1 、R 2 And R is 3 Each independently is hydrogen, halogen, or C 1 -C 8 An alkoxy group.
In one embodiment, R 4 And R is 5 Each independently is hydrogen.
In one embodiment, R 6 is-COR 7 . In a preferred embodiment, R 7 is-OH, alkoxy, alkylamino, cycloalkylamino, heterocycloamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryloxy, heterocycloaryloxy, arylamino, or heterocycloarylamino; or R is 7 With substituents R in ortho-position 5 Can be connected with each other to form heterocycle. In a preferred embodiment, R 7 Is C 1 -C 8 Alkoxy, hydroxy, C 1 -C 8 Alkyl sulfonamide group, or C 3 -C 8 Cycloalkyl sulfonamide groups.
In one embodiment, Y 1 is-CH 2 -。
In one embodiment, Z 1 is-O-.
In one embodiment, X 1 、X 2 、X 3 And X 4 Each independently is hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl (H) 2 NCO), alkyl, heterocycloalkyl, alkoxy, heteroatom-substituted alkyloxy, alkylamino (NR) i R j ) Heteroatom substituted alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, aryloxycarbonylamino, heteroaryl, heteroaryloxy, or heteroarylamino; wherein R is i And R is j Each independently is hydrogen, deuterium (D), alkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, aryloxycarbonyl, arylaminocarbonyl, heterocycloaryl, or R i And R is j Are linked to each other to form a 3-8 membered heterocyclic ring containing 1-3 heteroatoms.
In one embodiment, X 1 Selected from: hydrogen, deuterium (D), halogen, nitrile group, amino (NH) 2 ) Trifluoromethyl, trifluoromethoxy, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, C 1 -C 8 Alkylcarbonylamino, C 1 -C 8 Alkyl amino carbonyl amino, C 1 -C 8 Alkoxycarbonylamino, C 3 -C 8 Cycloalkoxycarbonylamino, C 1 -C 8 Alkyl sulfonamide group, C 3 -C 8 Cycloalkyl sulfonamide, aryl, or aryloxycarbonyl amine groups. In a preferred embodiment, X 1 Selected from: hydrogen, deuterium (D), halogen, nitrile group, triFluoromethyl, trifluoromethoxy, C 1 -C 8 An alkoxycarbonylamino group.
In one embodiment, X 2 、X 3 And X 4 Each independently is hydrogen, deuterium (D), halogen, or trifluoromethyl.
The compounds of the present invention may exist in a variety of isomeric forms, as well as in one or more tautomeric forms, including two single tautomers, and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of the compounds of the present invention, including tautomeric forms of the compounds.
Some of the compounds described herein may have asymmetric centers and thus exist in different enantiomeric and diastereomeric forms. The compounds of the present invention may be in the form of optical isomers or diastereomers. Thus, the present invention encompasses the compounds of the present invention and their use as described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including racemic mixtures. The optical isomers of the compounds of the present invention may be obtained by known techniques, such as asymmetric synthesis, chiral chromatography, or by chemical separation of stereoisomers using optically active resolving agents.
Unless otherwise indicated, "stereoisomer" refers to one stereoisomer of a compound that is substantially free of the other stereoisomers of the compound. Thus, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. Stereoisomerically pure compounds having two chiral centers are substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds comprise more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, for example, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
If there is a difference between the described structure and the name given to the structure, the described structure is subject to. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated with, for example, bold or dashed lines, then the structure or portion of a structure is to be interpreted as encompassing all stereoisomers of it. However, in some cases where more than one chiral center is present, structures and names may be represented in the form of single enantiomers to aid in describing the relevant stereochemistry. Those skilled in the art of organic synthesis will be aware of the case of preparing single enantiomers of the compounds by methods of preparing them.
In this specification, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound of the invention. Typical pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble salts and water-insoluble salts such as acetate, aminostilbenesulfonate (4, 4-diaminostilbene-2, 2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, ethanedisulfonate, laurylsulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolylarsenate, hexafluorophosphate, hexylresorcinol, hamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodate, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methanesulfonate, muconate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthalene, oleate, oxalate, palmate, bis (1, 1-bis-hydroxy-3-naphthalene), pamoate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate basic acetate, succinate, sulfate, sulfosalicylate, suramate tannate, tartrate, 8-chlorotheophylline salt, tosylate, triethyliodide and valerate. Pharmaceutically acceptable salts may have more than one charged atom in their structure. In this case, the pharmaceutically acceptable salt may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.
The compounds of the invention may be isotopically-labeled in which one or more atoms are replaced by atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into compounds of formula Ia or IIa include: isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, or iodine. Examples of such isotopes are respectively: 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 36 Cl、 123 i and 125 I. these radiolabeled compounds are useful for detecting biodistribution, tissue concentration, and kinetics of transport and excretion from biological tissue, including subjects administered the labeled compounds. Labeled compounds are also useful in determining the effect, site or pattern of action of a treatment, as well as the binding affinity of a candidate therapeutic to a pharmacologically important target. Thus, certain radiolabeled compounds of formula Ia or IIa are useful in drug and/or tissue distribution studies. Radioisotope tritium, i.e. tritium 3 H, and carbon-14, i.e 14 C is particularly useful for this purpose because they are easy to incorporate and detection means are ready.
By heavy isotopes such as deuterium 2 H substitution can provide certain therapeutic advantages due to higher metabolic stability (e.g., prolonged in vivo half-life of deuterium containing compounds). Substitution of deuterium for hydrogen energy reduces the dosage required to achieve therapeutic effects and thus may be preferred for use in a discovery or clinical setting.
Positron emitting isotopes (e.g 11 C， 18 F， 15 O and 13 substitution energy of N)Labeled analogues of the compounds of the invention are provided which are useful in Positron Emission Tomography (PET) studies, for example, for detecting substance receptor occupancy. Isotopically-labeled compounds of formula Ia or IIa can be prepared generally by conventional techniques known to those skilled in the art or by analogous to those described in the preparations and examples section below, using suitable isotopically-labeling reagents.
The embodiments of the invention described herein are also intended to encompass in vivo metabolites of compounds of formula Ia or IIa. These products may originate, for example, from processes of oxidation, reduction, hydrolysis, amidation, esterification, etc., which are mainly due to the enzymatic activity of the compounds of the present invention after administration. Thus, the present invention includes compounds that are produced as byproducts based on enzymatic or non-enzymatic activity of the compounds of the present invention after administration of the compounds of the present invention to a mammal for a period of time sufficient to produce a metabolite. Metabolites, particularly pharmaceutically active metabolites, are generally identified by the following means: a detectable dose of a radiolabeled compound of the invention is administered to a subject, such as a rat, mouse, guinea pig, monkey or human, for a period of time sufficient for metabolism to occur during the process, and the metabolite is isolated from urine, blood or other biological samples obtained from the subject receiving the radiolabeled compound.
The invention also provides pharmaceutically acceptable salt forms of the compounds of formula Ia or IIa. The scope of the present invention encompasses acid addition salts and base addition salts formed by contacting a pharmaceutically suitable acid or pharmaceutically suitable base with a compound of the present invention.
"pharmaceutically acceptable acid addition salt" means: those salts that retain the properties of the bioavailable and free base, which are not biologically or otherwise undesirable, and whose formation employs inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, tricarboxylic acid, undecene, and the like.
"pharmaceutically acceptable base addition salt" means: those salts that retain the properties of the bioavailable and free acids are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Crystallization generally yields solvates of the compounds of the present invention. The term "solvate" as used herein refers to: an aggregate comprising one or more molecules of a compound of the invention and one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist in hydrated forms, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvate forms. The compounds of the invention may be true solvates, while in other cases the compounds of the invention may retain only adventitious water or a mixture of water plus some adventitious solvent.
"stereoisomer" means: a compound which is formed by identical atoms bonded by identical bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to: the molecules of the two stereoisomers are non-superimposable mirror images of each other.
The compounds of the invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, thereby yielding enantiomers, diastereomers, and other stereoisomeric forms which are determinable in absolute stereochemistry, such as (R) -or (S) -, or, in the case of amino acids, such as (D) -or (L) -. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Traditional techniques for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). When a compound described herein contains an olefinic double bond or other geometric asymmetric center, it is intended to mean that the compound includes both E and Z geometric isomers unless otherwise specified. Also, all tautomeric forms are also intended to be included.
III pharmaceutical composition
In one embodiment, the compound of formula Ia or IIa is formulated in the form of a pharmaceutically acceptable composition comprising an amount of the compound of formula Ia or IIa effective to treat a particular disease or disorder of interest after administration of the pharmaceutical composition to a mammal. The pharmaceutical compositions of the invention may comprise a compound of formula Ia or IIa in combination with a pharmaceutically acceptable carrier, diluent or excipient.
In this regard, a "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent, all of which are approved by the U.S. food and drug administration as acceptable to humans or livestock.
In addition, "mammal" includes humans and domestic animals, e.g., laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-domestic animals, e.g., wild animals, etc.
The pharmaceutical compositions of the invention may be prepared by combining the compounds of the invention with suitable pharmaceutically acceptable carriers, diluents or excipients and may be formulated as solid, semi-solid, liquid or gaseous forms, for example, tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention are formulated to allow the active ingredient contained therein to be bioavailable upon administration of the composition to a patient. The composition to be administered to a subject or patient may be in the form of one or more dosage units, for example, the tablet may be a single dosage unit and the container of the compound of the invention in aerosol form may contain a plurality of dosage units. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, ramington: pharmaceutical Science and practice (Remington: the Science and Practice of Pharmacy), 20 th edition (philadelphia pharmaceutical and Science institute (Philadelphia College of Pharmacy and Science), 2000). In any case, the composition to be administered contains a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to treat the disease or disorder of interest in accordance with the teachings of the present invention.
The pharmaceutical composition of the present invention may be in solid or liquid form. In one aspect, the carrier is a granule, whereby the composition is, for example, in the form of a tablet or powder. The carrier may be a liquid, wherein the composition is, for example, an oral syrup, an injectable liquid, or an aerosol, which may be used, for example, for administration by inhalation. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in the solid or liquid forms contemplated herein.
As a solid composition for oral administration, the pharmaceutical composition may be formulated in the form of powder, granule, compressed tablet, pill, capsule, chewing gum, sheet, or the like. Such solid compositions will typically comprise one or more inert diluents or edible carriers. Furthermore, one or more of the following may be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch, lactose or dextrin, disintegrants, such as alginic acid, sodium alginate, common Li Moer (Primogel), corn starch, etc.; lubricants, such as magnesium stearate or Sterotex (Sterotex); glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate, or orange flavoring; and a colorant.
If the pharmaceutical composition is in the form of a capsule (e.g., a gelatin capsule), it may comprise a liquid carrier, such as polyethylene glycol or an oil, in addition to materials of the type described above.
The pharmaceutical compositions may be in liquid form, such as elixirs, syrups, solutions, emulsions or suspensions. As two examples, the liquid may be for oral administration or for delivery by injection. If intended for oral administration, preferred compositions may contain, in addition to the compounds of the present invention, one or more sweetening agents, preserving agents, dyes/colorings and flavor enhancers. For compositions intended for administration by injection, one or more of surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers and isotonic agents may be included.
The liquid pharmaceutical compositions of the present invention, whether they are solutions, suspensions or other similar forms, may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solutions, preferably physiological saline, ringer's solution, isotonic sodium chloride; fixed oils such as synthetic mono-or diglycerides, polyethylene glycols, glycerol, propylene glycol or other solvents useful as solvents or suspending media; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine tetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for regulating tonicity, such as sodium chloride or dextrose. Parenteral formulations may be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. Saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile.
The pharmaceutical compositions of the present invention may be prepared by any method well known in the pharmaceutical arts. For example, pharmaceutical compositions intended for administration by injection may be prepared by combining a compound of the present invention with sterile, distilled water to form a solution. Surfactants may be added to promote the formation of a uniform solution or suspension. Surfactants are compounds that interact non-covalently with the compounds of the present invention, thereby facilitating dissolution or uniform suspension of the compounds in an aqueous delivery system.
Therapeutic application
A therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, is administered, which varies depending on a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of that compound, the age, weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease or condition of the patient, and the subject undergoing treatment.
An "effective amount" or "therapeutically effective amount" refers to: the amount of the compound of the invention, when administered to a mammal, preferably a human, is sufficient to provide effective treatment of a Mnk-related disorder or disease in the mammal, preferably a human, as described below. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on knowledge and the context of the present invention.
The compounds of the invention, or pharmaceutically acceptable salts thereof, may also be administered prior to, concurrently with, or after the administration of one or more other therapeutic agents. Such combination therapies include the administration of a single pharmaceutical dosage formulation comprising a compound of the invention and one or more other active agents, as well as the administration of the compound of the invention and each active agent in separate pharmaceutical dosage formulations. For example, the compounds of the invention and the other active agents may be administered together to the patient in a single oral dosage composition (e.g., a tablet or capsule), or the agents may be administered in separate oral dosage formulations. When separate dosage formulations are used, the compound of the invention and one or more other active agents may be administered at substantially the same time (i.e., simultaneously), or at separate staggered times (i.e., sequentially); combination therapy is understood to include all of these regimens.
The structure of GPR40 target agonist compounds shown in formulas Ia-IIa is further researched and optimized through a structure-activity relationship (SAR), the risk of hypoglycemia can be effectively reduced, and the type II diabetes can be more safely and effectively treated.
The benzo oxygen-containing heterocyclic compound can stimulate islet beta cells to release insulin to reduce blood sugar level by activating GPR40 targets, and the compounds of the formula Ia-IIa are characterized in that insulin secretion can be promoted only when the blood sugar concentration of type II diabetics is high, so that the risk of hypoglycemia of the patients can be effectively reduced, and better GPR40 target selectivity and safety are achieved.
The specific embodiment is as follows:
the invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental procedures, which are not specifically identified in the examples below, were carried out according to conventional well-known methods and conditions, or according to the commercial specifications.
English abbreviations and comments of chemical reagents and solvents in the process of synthesizing the novel benzo oxygen-containing heterocyclic compounds are summarized in the instrument and raw material description parts in the examples.
The key innovation point of the invention is that according to the synthetic reaction route 1a or 2a shown in the following schemes 1a and 2a, firstly, the target product Ia-IIa or the intermediate RM-2a is respectively prepared by respectively reacting the raw material RM-1a with the raw material SM-1 (such as the reagents with the following SM-1a or RM-1b structures); when R is 7 Is alkoxy (e.g. R) 7 ＝OCH 3 Or OEt), R in the formula IIa according to the invention can be synthesized by hydrolysis of LiOH 7 Each of the target intermediate products being a hydroxyl group.
The general synthetic reaction scheme is as follows:
scheme 1a: schematic of the synthesis of Compounds of formulas Ia-IIa
The operation according to scheme 1a above is as follows:
1. synthesis of RM-2a starting materials RM-Ia (1.0 eq), SM-1b (1.0 eq), and DIAD with PPh were reacted in a round-bottomed flask 3 (1.2 eq) are respectively added into THF (5 x), nitrogen is replaced and protected, the reaction is detected to be finished through TLC and HPLC tracking, and RM-2a (or RM-IIa) is obtained after conventional operations such as post-treatment;
2. synthesis of the target products Ia-IIaRespectively adding RM-Ia (or RM-IIa,1 eq) to LiOH MeOH-H in a round bottom reaction flask 2 The target product Ia-IIa is obtained after the hydrolysis in the O mixed solution (1:1, 10X) and the conventional operations such as post-treatment and purification after TLC detection of the end of the reaction.
The synthesized compound of formula Ia-IIa, wherein n and R 1 、R 2 、R 3 、R 5 、R 5b 、R 7 、Ra、Rb、Rc、Rd、Re、Rf、Rg、Ri、Rj、X 1 、X 2 、X 3 、X 4 Y and Y 1 Respectively with n, R in the invention claims 1-4 1 、R 2 、R 3 、R 5 、R 5b 、R 7 、Ra、Rb、Rc、Rd、Re、Rf、Rg、Ri、Rj、X 1 、X 2 、X 3 、X 4 Y and Y 1 Is the same as defined in the following. The synthetic reaction examples of the compounds in the formulas Ia-IIa are shown in the following scheme 2a, and specifically, the benzo oxygen-containing heterocycle raw materials RM-1a in the following table 1 and table 2 and the raw material SM-1 in the table 3 are adopted for the preparation process of each compound with different structures to be successfully synthesized:
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table 1: starting materials SM-Ia-01 to SM-Ia-23 used in the present invention and structures thereof
Table 2: raw materials SM1-01 to SM1-12 used in the present invention and structures thereof
Using the starting materials RM-1a and SM1 described above, intermediate RM-2a is then prepared via synthetic reaction scheme 2a, below, and each of the specific compounds of formulas Ia-IIa is finally synthesized, respectively, via hydrolysis. Specific reaction examples are as follows:
Scheme 2a: examples of the Synthesis of Compounds of formulas Ia-IIa
In the example of scheme 2a above, scheme 2a:
the first step is carried out by first coupling the starting material RM-Ia-01 with another starting material SM1-01 in a coupling reagent (e.g., DIAD, PPh 3 ) Under the action of a solvent (e.g.: THF) to give the key intermediate compound (RM-2 a-01);
and the second step of reaction: then the intermediate (RM-2 a-01) is hydrolyzed in a solvent (such as MeOH or a mixed solvent of methanol and water) under the action of inorganic base (such as LiOH) to obtain the target product IIa-01.
The intermediate structures of the intermediate compounds RM-IIa obtained by the first-step reactions of the synthetic schemes 1 and 2 are shown in the following RM-IIa structural formula series, respectively; and the second step of hydrolysis reaction to obtain the target product of the formula IIa respectively, wherein the structure of the target product is shown in the following structural formula IIa series:
RM-IIa series of structural formula:
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IIa structural series
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The experimental conditions and product analysis results for each specific reaction step are shown in the examples.
Specifically, the synthesis and analysis results of the novel structural compounds of the formulae Ia-IIa are shown in the final examples of the invention, the chemical and chiral asymmetric purity of each compound is determined by chiral chromatographic column HPLC, and the corresponding chemical structure characterization is respectively carried out by LC-MS and/or hydrogen nuclear magnetic resonance 1 H-NMR) and the like.
The synthesis and effect of various intermediates and compounds of the present invention are illustrated by the following examples.
The instruments and raw materials involved in the examples are described below:
the IR spectrum data was Fourier Transform AVATAR by the company Semoniley (Thermo Nicolet) TM 360E.S.P TM Obtained by analysis with an infrared meter in cm -1 Expressed in units.
The nuclear magnetic resonance hydrogen spectrum is obtained by analysis of a Varian Mercury Plus (400 MHz) nuclear magnetic resonance apparatus. Chemical shifts are reported in ppm (CHCl) as an internal standard for tetramethylsilane 3 : δ=7.26 ppm). The recorded data information is as follows: chemical shiftAnd cleavage and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad; m: multiplet).
Mass spectrometry data were analyzed using a liquid chromatography-mass spectrometer from henika advanced LCQ (Finnigan LCQ Advantage), among other requirements. The molecular weight of the organic carboxylic acid (-COOH) compounds of the formula Ia-IIa of the present invention is predominantly in the anionic mode ESI-MS [ (M-H) + ]However, the molecular weights of the ester intermediate compounds of the formula RM-IIa and some of the compounds of the formula Ia-IIa containing amine groups are cationic ESI-MS [ (M+H) + ]。
In the present invention, the specific raw materials and intermediates involved are provided by custom processing such as Zan nan technology Co., ltd, and all other chemical reagents are purchased from reagent suppliers such as Shanghai reagent Co., aldrich, acros, etc. If the intermediates or products required for the reaction in the synthesis are not sufficient for the next step or the like, the synthesis is repeated a plurality of times until a sufficient number. The GPR40 activity test, pharmacological and toxicological tests and the like of the compound prepared by the invention are completed by CRO service units of Shanghai, beijing and the like.
The English abbreviations related to the chemical raw materials, reagents and solvents in the present invention and examples thereof are as follows:
AIBN: azobisisobutyronitrile
Boc t-Butoxycarbonyl group
(Boc) 2 O: di-tert-butyl dicarbonate
CDI: n, N' -carbonyldiimidazole
DBU:1, 8-diazabicyclo [5.4.0] undec-7-ene
Et: ethyl group
EDCI: N-ethyl-N' -3-dimethylaminopropyl) carbodiimide hydrochloride
HATU:2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
NBS: n-bromosuccinimide
SOCl 2 : thionyl chloride
Pd/C: palladium carbon
DMAP: 4-dimethylaminopyridine
HMTA: hexamethylene tetramine
DIEA: n, N-diisopropylethylamine
Py: pyridine compound
HBr: hydrobromic acid
HCl: hydrochloric acid
HOAc: glacial acetic acid
TFA: trifluoroacetic acid
TsOH: para-toluene sulfonic acid
NaOH: sodium hydroxide
LiOH: lithium hydroxide
ACN: acetonitrile
DCM: dichloromethane (dichloromethane)
DCE: dichloroethane (dichloroethane)
DMF: n, N-dimethylformamide
DMSO: dimethyl sulfoxide
Et 2 O: diethyl ether
EA: acetic acid ethyl ester
PE: petroleum ether
THF: tetrahydrofuran (THF)
TBME: methyl tert-butyl ether
The series of compounds IIa-1 to IIa-48 of formula IIa were synthesized according to the following general synthetic method:
example 1
Synthesis of Compound IIa-1
The first step: raw material RM-Ia-1 (0.052 g,0.24 mmol.), SM1-1 (0.050 g,0.24mmol,1.0 eq.) and PPh3 (0.126 g,0.48mmol,2 eq.) were dissolved in 2L THF, nitrogen protected, cooled in an ice-water bath, DIAD (0.097 g,0.48mmol,2 eq.) was added to the mixture, and after the addition, the mixture was stirred in an ice-water bath for 1h,20-30 degrees, and the reaction was completed overnight. After the reaction is finished, cooling the reaction liquid to room temperature by HPLC, adding water, adding DCM for extraction, merging organic phases, washing with saline solution, drying and concentrating to obtain a crude product; the crude product was isolated by TLC on a scraper to give intermediate RM-IIa-1 (0.029 g);
By mass spectrometryCorroboration, ESI-MS [ (M+H) of RM-IIa-1 + ]M/z theory 405.0, found 405.0.
And a second step of: meOH (2 mL), THF (1 mL) and aqueous LiOH (1N, 1 mL) were added to intermediate RM-IIa-1 (0.029 g), stirred at room temperature for 1h, the reaction was neutralized to pH about 4 with hydrochloric acid (1N) after completion of the reaction by HPLC, water was added, ethyl acetate was added for extraction, the organic phases were combined, washed with brine and dried, and finally column chromatography was separated and purified to give the pale yellow solid product IIa-1 (0.016 g), two-step yield: 21%.
ESI-MS [ (M-H) of IIa-1, confirmed by mass spectrometry + ]M/z theory 389.0, found 389.0.
Example 2
Synthesis of Compound IIa-2
The synthesis procedure for the preparation of compound IIa-2 was the same as in example 1, and the product IIa-2 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-2 (0.23 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-2, and the intermediate was hydrolyzed to obtain pale yellow solid product IIa-2 (0.016 g) in a two-step yield of 17.8%.
ESI-MS [ (M-H) of IIa-2, confirmed by mass spectrometry + ]M/z theory 389.0, found 389.0.
Example 3
Synthesis of Compound IIa-3
The synthesis method for preparing compound IIa-3 was the same as in example 1, and the product IIa-3 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-3 (0.24 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-3, and the intermediate was hydrolyzed to obtain pale yellow solid product IIa-3 (0.030 g), yield in two steps: 32%.
ESI-MS [ (M-H) of IIa-3, confirmed by mass spectrometry + ]M/z theory 389.0, found 389.0.
Example 4
Synthesis of Compound IIa-4
Raw material RM-Ia-4 (0.052 g,0.24 mmol.), SM1-1 (0.050 g,0.24mmol,1.0 eq.) and PPh3 (0.126 g,0.48mmol,2 eq.) were dissolved in 2L THF, nitrogen protected, cooled in an ice-water bath, DIAD (0.097 g,0.48mmol,2 eq.) was added to the mixture, and after the addition, the mixture was stirred in an ice-water bath for 1h,20-30 degrees, and the reaction was completed overnight. After the reaction is finished, cooling the reaction liquid to room temperature by HPLC, adding water, adding DCM for extraction, merging organic phases, washing with saline solution, drying and concentrating to obtain a crude product; separating the crude product by TLC scraping plate to obtain intermediate RM-IIa-4; meOH (2 mL), THF (1 mL) and aqueous LiOH (1N, 1 mL) were added to the intermediate, stirred at room temperature for 1h, the reaction was neutralized to pH about 4 with hydrochloric acid (1N) after the completion of the reaction by HPLC, water was added, ethyl acetate was added for extraction, the organic phases were combined, washed with brine, dried, and finally purified by column chromatography to give the pale yellow solid product IIa-4 (0.024 g), yield in two steps: 25%.
The product IIa-4 was detected 1 H NMR(400MHz,DMSO):δ7.53-7.51(m,1H),7.42-7.40(m,1H),7.13-7.11(m,1H),6.89-6.86(m,1H),6.45-6.41(m,2H),6.09-6.08(m,1H),4.81-4.76(m,1H),4.70-4.65(m,1H),4.56-4.53(m,1H),4.19-4.00(m,1H),3.67-3.64(m,1H),2.64-2.63(m,1H),2.60-2.59(m,1H)。
Mass spectrometry confirmed that ESI-MS [ (M-H) of IIa-4 + ]Theoretical value of m/z 311.1, measured value 311.2.
Example 5
Synthesis of Compound IIa-5
The synthesis procedure for the preparation of compound IIa-5 was the same as in example 1, and the product IIa-5 was obtained by two steps of etherification and hydrolysis, wherein compound SM1-2 (0.55 mmol) was used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIa-5, and the intermediate was hydrolyzed to obtain pale yellow solid product IIa-5 (0.015 g) in 7% yield in two steps.
ESI-MS [ (M-H) of IIa-5, confirmed by mass spectrometry + ]M/z theory 389.0, found 389.1.
Example 6
Synthesis of Compound IIa-6
The synthesis procedure for the preparation of compound IIa-6 was the same as in example 1, and the product IIa-6 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-5 (0.42 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-6, and the intermediate was hydrolyzed to obtain pale yellow solid product IIa-6 (0.050 g) in a two-step yield of 30.6%.
ESI-MS [ (M-H) of IIa-6, confirmed by mass spectrometry + ]M/z theory 389.0, found 388.9.
Example 7
Synthesis of Compound IIa-7
The synthesis procedure for the preparation of compound IIa-7 was the same as in example 1, and the product IIa-7 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-6 (0.55 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-7, and the intermediate was hydrolyzed to obtain pale yellow solid product IIa-7 (0.0023 g) in a two-step yield of 1.2%.
ESI-MS [ (M-H) of IIa-7, confirmed by mass spectrometry + ]M/z theory 345.1, found 345.0.
Example 8
Synthesis of Compound IIa-8
The synthesis procedure for the preparation of compound IIa-8 was the same as in example 1, and the product IIa-8 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-7 (0.32 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-8, which was hydrolyzed to obtain brown solid product IIa-8 (0.038 g) in a two-step yield of 36.3%.
ESI-MS [ (M-H) of IIa-8, confirmed by mass spectrometry + ]M/z theory 329.1, found 329.0.
Example 9
Synthesis of Compound IIa-9
The synthesis procedure for the preparation of compound IIa-9 was the same as in example 1, and the product IIa-9 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-8 (0.39 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-9, and the intermediate was hydrolyzed to obtain brown solid product IIa-9 (0.015 g) in 32% yield in two steps.
ESI-MS [ (M-H) of IIa-9, confirmed by mass spectrometry + ]M/z theory 403.0, found 403.1.
Example 10
Synthesis of Compound IIa-10
The synthesis procedure for the preparation of compound IIa-10 was the same as in example 1, and the product IIa-10 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-9 (0.48 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-10, and the intermediate was hydrolyzed to obtain pale yellow solid product IIa-10 (0.013 g) in a two-step yield of 7.1%.
The product IIa-10 was detected 1 H NMR(400MHz,CDCl 3 ):δ7.54-7.49(m,2H),7.04-6.96(m,2H),6.34(m,2H),5.79-5.78(m,1H),4.72-4.68(m,3H),4.27-4.25(m,1H),3.80-3.75(m,1H),3.00(m,1H),2.75-2.66(m,1H)。 19 F NMR(376MHz,CDCl 3 ):δ-61.92。
Mass spectrometry confirmed that ESI-MS [ (M-H) of IIa-10 + ]M/z theory 379.1, found 379.0.
Example 11
Synthesis of Compound IIa-11
The synthesis procedure for the preparation of compound IIa-11 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-11, wherein compound RM-Ia-10 (0.23 mmol) was used in place of compound RM-Ia-4 and compound SM1-2 (0.23 mmol) was used in the reaction to give intermediate RM-IIa-11, which was hydrolyzed to give product IIa-11 (0.024 g) as a white solid in a two-step yield of 26.6%.
As a result of detection, the product IIa-11 (400 MHz, CDCl 3 ):δ7.48-7.46(m,1H),7.35-7.33(m,1H),7.10-7.08(m,1H),6.85-6.81(m,1H),6.43-6.40(m,2H),5.93-5.91(m,1H),4.82-4.67(m,3H),4.33-4.30(m,1H),3.86-3.81(m,1H),2.86-2.81(m,1H),2.68-2.62(m,1H)。
ESI-MS [ (M-H) of IIa-11, confirmed by mass spectrometry + ]M/z theory 391.0,390.0, found 389.9,390.9.
Example 12
Synthesis of Compound IIa-12
The synthesis method for preparing compound IIa-12 was the same as in example 1, and the product IIa-12 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-11 (0.48 mmol) was used instead of compound RM-Ia-4 in the reaction to obtain intermediate RM-IIa-12, and the intermediate was hydrolyzed to obtain white solid product IIa-12 (0.011 g), the yield in two steps was 6.8%.
ESI-MS [ (M-H) of IIa-12, confirmed by mass spectrometry + ]Theoretical value of m/z336.1, found 336.0.
Example 13
Synthesis of Compound IIa-13
The synthesis procedure for the preparation of compound IIa-13 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-13, wherein compound RM-Ia-7 (0.48 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.48 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-13, which was hydrolyzed to give product IIa-13 (0.020 g) as a white solid in a two-step yield of 10.9%.
ESI-MS [ (M-H) of IIa-13, confirmed by mass spectrometry + ]M/z theory 379.1, found 379.0.
Example 14
Synthesis of Compound IIa-14
The synthesis procedure for the preparation of compound IIa-14 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-14, wherein compound RM-Ia-12 (0.47 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.47 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-14, which was hydrolyzed to give product IIa-14 (0.025 g) as a white solid in a two-step yield of 13.7%.
ESI-MS [ (M-H) of IIa-14, confirmed by mass spectrometry + ]M/z theory 389.0, found 389.1.
Example 15
Synthesis of Compound IIa-15
The synthesis procedure for the preparation of compound IIa-15 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-15, wherein compound RM-Ia-13 (0.26 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.26 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-15, which was hydrolyzed to give product IIa-15 (0.010 g) as a white solid in a two-step yield of 10%.
The product IIa-15 was detected 1 H NMR(400MHz,CDCl 3 ):δ7.53-7.58(m,2H),7.11-7.09(m,1H),7.03-6.99(m,1H),6.43-6.41(m,2H),5.88-5.86(m,1H),4.82-4.71(m,3H),4.34-4.30(m,1H),3.88-3.80(m,1H),2.87-2.81(m,1H),2.69-2.62(m,1H)； 19 F NMR(376MHz,CDCl 3 ):δ-61.90。
ESI-MS [ (M-H) of IIa-15, confirmed by mass spectrometry + ]M/z theory 389.0, found 388.9.
Example 16
Synthesis of Compound IIa-16
The synthesis procedure for the preparation of compound IIa-16 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-16, wherein compound RM-Ia-14 (0.39 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.39 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-16, which was hydrolyzed to give product IIa-16 (0.060 g) as a white solid in a two-step yield of 39.2%.
ESI-MS [ (M-H) of IIa-16, confirmed by mass spectrometry + ]M/z theory 379.1, found 379.2.
Example 17
Synthesis of Compound IIa-17
The synthesis procedure for the preparation of compound IIa-17 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-17, wherein compound RM-Ia-10 (0.37 mmol) was used instead of compound RM-Ia-4 and compound SM1-3 (0.37 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-17, which was hydrolyzed to give product IIa-17 (0.052 g) as a white solid in a two-step yield of 30%.
ESI-MS [ (M-H) of IIa-17, confirmed by mass spectrometry + ]M/z theory 468.9, found 469.0.
Example 18
Synthesis of Compound IIa-18
The synthesis procedure for the preparation of compound IIa-18 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-18, wherein compound RM-Ia-10 (0.37 mmol) was used instead of compound RM-Ia-4 and compound SM1-1 (0.37 mmol) was used in the reaction to give intermediate RM-IIa-18, which was hydrolyzed to give product IIa-18 (0.076 g) as a white solid in a two-step yield of 37%.
ESI-MS [ (M-H) of IIa-18, confirmed by mass spectrometry + ]M/z theory 546.8, found 546.7.
Example 19
Synthesis of Compound IIa-19
The synthesis procedure for the preparation of compound IIa-19 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-19, wherein compound RM-Ia-10 (0.37 mmol) was used instead of compound RM-Ia-4 and compound SM1-5 (0.37 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-19, which was hydrolyzed to give product IIa-19 (0.057 g) as a white solid in a two-step yield of 36%.
ESI-MS [ (M-H) of IIa-19, confirmed by mass spectrometry + ]M/z theory 423.0, found 423.0.
Example 20
Synthesis of Compound IIa-20
The synthesis procedure for the preparation of compound IIa-20 was the same as in example 1, and the product IIa-20 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-10 (0.46 mmol) was used instead of compound RM-Ia-4 and compound SM1-6 (0.46 mmol) was used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIa-20, which was hydrolyzed to obtain white solid product IIa-20 (0.018 g) in 9% two steps yield.
ESI-MS [ (M-H) of IIa-20, confirmed by mass spectrometry + ]M/z theory 407.0, found 407.1.
Example 21
Synthesis of Compound IIa-21
The synthesis procedure for the preparation of compound IIa-21 was the same as in example 1, and the product IIa-21 was obtained by a two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-10 (0.21 mmol) was used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-21, and hydrolysis of the intermediate gave the product IIa-21 (0.020 g) as a white solid in a two-step yield of 24%.
ESI-MS [ (M-H) of IIa-21, confirmed by mass spectrometry + ]M/z theory 389.0, found 388.9.
Example 22
Synthesis of Compound IIa-22
Raw material IIa-21 (0.250 g,0.64 mmol.) was dissolved in 2mL THF and 2mL MTBE, cooled to-78 ℃ in a bath of dry ice acetone under nitrogen protection, liHMDS (1 m,1.7mL,1.7 mmol.) was added dropwise, stirred for 0.5h, tmcl (0.173 g,1.6 mmol) was added dropwise, stirred for 0.5h, NBS (0.137 g,0,77 mmol) was added, slowly warmed to room temperature, and the reaction was completed for 3 h. HPLC shows that after the reaction is completed, water is added to the reaction solution, hydrochloric acid (1N) is added to neutralize the pH to about 2, ethyl acetate is added to extract the reaction solution, then the organic phases are combined, washed with saline solution and dried, and finally, the light yellow solid product IIa-22 (0.055 g) is obtained through column chromatography separation and purification, and the yield of one step is 18%.
ESI-MS [ (M-H) of IIa-22, confirmed by mass spectrometry + ]M/z theory 468.9, found 469.1.
Example 23
Synthesis of Compound IIa-23
Raw material IIa-22 (0.030 g,0.064 mmol.) was added to concentrated aqueous ammonia (3 mL) and the reaction was heated in a 100 degree oil bath for 1.5h to complete the reaction. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and dried to give a pale yellow solid product IIa-23 (0.020 g), yield in one step: 18%.
ESI-MS [ (M+H) of IIa-23, confirmed by mass spectrometry + ]M/z theory 404.0, found 404.0.
Example 24
Synthesis of Compound IIa-24
Raw material RM-IIa-21 (0.1 g,0.24 mmol.) was dissolved in 2mL THF, cooled to-70 ℃ in a dry ice acetone bath under nitrogen protection, liHMDS (1 m,0.37mL,0.37 mmol.) was added dropwise, stirred for 0.5h, 3-phenyl-2 (benzenesulfonyl) oxaziridine/THF (0.1 g,0.37 mmol) solution was added dropwise, the reaction was warmed slowly to room temperature, and the reaction was completed for 2 h. After the reaction, the reaction solution was neutralized to pH of about 2 by adding hydrochloric acid (1N) to the reaction solution, extracted by adding ethyl acetate, combined with the organic phase, washed with brine and dried, and finally separated and purified by column chromatography to obtain intermediate RM-IIa-22 (0.10 g), meOH (2 mL), THF (1 mL) and aqueous LiOH (1N, 1 mL) were sequentially added to the intermediate, stirred at room temperature for 1h, and after the reaction was completed, the reaction solution was neutralized to pH of about 4 by hydrochloric acid (1N) to the reaction solution by HPLC to the reaction solution, extracted by adding water to the reaction solution, combined with the ethyl acetate to the organic phase, washed with brine and dried, and finally separated and purified by column chromatography to obtain pale yellow solid product IIa-24 (0.020 g) with a two-step yield of 20%.
ESI-MS [ (M-H) of IIa-24, confirmed by mass spectrometry + ]M/z theory 405.0, found 405.0.
Example 25
Synthesis of Compound IIa-25
Raw material RM-IIa-21 (0.2 g,0.49 mmol.) was dissolved in 2mL of THF, cooled to-70℃in a bath of dry ice acetone under nitrogen protection, liHMDS (1M, 0.8mL,0.8 mmol.) was added dropwise, stirred for 0.5h, and (PhSO 2 ) NF/THF (0.2 g,0.64 mmol) solution was slowly warmed to room temperature and reacted for 2h, the reaction was completed. After the reaction, the reaction solution was neutralized to pH of about 2 by adding hydrochloric acid (1N) to the reaction solution, extracted by adding ethyl acetate, combined with the organic phase, washed with brine and dried, and finally separated and purified by column chromatography to obtain intermediates RM-IIa-23 and RM-IIa-24 (0.035 g), meOH (2 mL), THF (1 mL) and aqueous LiOH solution (1N, 1 mL) were sequentially added to the intermediates, stirred at room temperature for 1h, after the reaction was completed, the reaction solution was neutralized to pH of about 4 by hydrochloric acid (1N) to the reaction solution, water was added to the reaction solution, extracted by adding ethyl acetate to the reaction solution, the organic phase was combined with the brine to the reaction solution, washed with the organic phase and dried, and finally separated and purified by column chromatography to obtain pale yellow solid products IIa-25 and IIa-26 (60%: 30%,0.015 g) in two steps, the yield was 7%.
ESI-MS [ (M-H) of IIa-25, confirmed by mass spectrometry + ]M/z theory 407.0, found 407.0.
Example 26
Synthesis of Compound IIa-26
The synthesis procedure for the preparation of compound IIa-26 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-26, wherein compound RM-Ia-10 (0.29 mmol) was used instead of compound RM-Ia-4 and compound SM1-7 (0.29 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-24, which was hydrolyzed to give product IIa-26 (0.045 g) as a white solid in a two-step yield of 36%.
ESI-MS [ (M-H) of IIa-26 as confirmed by mass spectrometry + ]M/z theory 425.0, found 425.0.
Example 27
Synthesis of Compound IIa-27
The synthesis procedure for the preparation of compound IIa-27 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-27, wherein compound SM1-8 (0.29 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-25, and the intermediate was hydrolyzed to give product IIa-27 (0.045 g) as a white solid in a two-step yield of 36%.
The product IIa-27 was detected 1 H NMR(400MHz,CDCl 3 ):δ7.48-7.46(m,1H),7.33-7.31(m,1H),7.15-7.13(m,3H),6.85-6.72(m,3H),5.95-5.93(m,1H),4.77-4.69(m,2H),3.60-3.54(m,1H),2.90-2.77(m,3H),2.53-2.47(m,2H),1.78-1.63(m,1H)。
ESI-MS [ (M-H) of IIa-27, confirmed by mass spectrometry + ]M/z theory 387.0, found 386.9.
Example 28
Synthesis of Compound IIa-28
The synthesis procedure for the preparation of compound IIa-28 was the same as in example 1, and the product IIa-28 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-10 (0.30 mmol) was used instead of compound RM-Ia-4 and compound SM1-8 (0.30 mmol) was used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIa-26, which was hydrolyzed to obtain white solid product IIa-28 (0.040 g) in two steps of yield: 34%.
ESI-MS [ (M-H) of IIa-28 as confirmed by mass spectrometry + ]M/z theory 387.0, found 386.8.
Example 29
Synthesis of Compounds IIa-29
The synthesis procedure for the preparation of compound IIa-29 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-29, wherein compound RM-Ia-9 (0.29 mmol) was used instead of compound RM-Ia-4 and compound SM1-7 (0.29 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-27, which was hydrolyzed to give product IIa-29 (0.050 g) as a white solid in a two-step yield of 41%.
ESI-MS [ (M-H) of IIa-29, confirmed by mass spectrometry + ]M/z theory 415.0, found 415.0.
Example 30
Synthesis of Compound IIa-30
Raw material IIa-15 (0.020g, 0.052 mmol.) was dissolved in 5mL of DCE, CDI (0.017 g,0.105 mmol.) was added, reacted for 0.5h at 50℃and cyclopropanesulfonamide (0.095 g,0.078 mmol.) and DBU (0.020g, 0.13 mmol.) were added, reacted overnight at 50℃and the reaction was completed. HPLC shows that after the reaction is completed, the reaction solution is added with water, added with hydrochloric acid (1N) to neutralize to pH of about 2, added with ethyl acetate for extraction, combined with an organic phase, washed with saline solution and dried, and finally separated and purified by column chromatography to obtain a pale yellow solid product IIa-30 (0.010 g), and the yield of one step is 40%.
ESI-MS [ (M-H) of IIa-30, confirmed by mass spectrometry + ]Theoretical value of m/z 482.1, actual measurement 482.2.
Example 31
Synthesis of Compound IIa-31
The synthesis procedure for the preparation of compound IIa-31 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-31, wherein compound RM-Ia-9 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-11 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-28, which was hydrolyzed to give product IIa-31 (0.028 g) as a white solid in two steps in 29%.
ESI-MS [ (M-H) of IIa-31, confirmed by mass spectrometry + ]M/z theory 397.1, found 397.2.
Example 32
Synthesis of Compound IIa-32
The synthesis procedure for the preparation of compound IIa-32 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-32, wherein compound RM-Ia-15 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-29, which was hydrolyzed to give product IIa-32 (0.024 g) as a white solid in a two-step yield of 30%.
ESI-MS [ (M-H) of IIa-32, confirmed by mass spectrometry + ]M/z theory 426.2, found 426.1.
Example 33
Synthesis of Compound IIa-33
Compound IIa-32 (0.020g, 0.06 mmol) was added to HCl/MeOH (6N, 2 mL), stirred at room temperature for 1h, the reaction was checked, and concentrated to give the product IIa-33 (0.017 g) as a white solid in 78% one-step yield.
Is confirmed by mass spectrometryESI-MS [ (M+H) of IIa-33, syndrome + ]M/z theory 328.1, found 328.2.
Example 34
Synthesis of Compounds IIa-34
The synthesis procedure for the preparation of compound IIa-34 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-34, wherein compound RM-Ia-16 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-30, which was hydrolyzed to give product IIa-34 (0.032 g) as a white solid in two steps in 34% yield.
ESI-MS [ (M+H) of IIa-34, confirmed by mass spectrometry + ]M/z theory 356.2, found 356.3.
Example 35
Synthesis of Compound IIa-35
Compound RM-IIa-29 (0.6 g,1.36 mmol) was added to HCl/MeOH (6N, 12 mL), stirred overnight at room temperature, and concentrated to give intermediate RM-IIa-31 (0.5 g) as a white solid.
Raw material RM-IIa-31 (0.050 g,0.13 mmol.) was dissolved in 2mL DCM, DMAP (0.039 g,0.32 mmol) was added, methyl chloroformate (0.015 g,0.15 mmol) was added with ice-water bath cooling, and the reaction was stirred at room temperature overnight and completed. After the reaction is finished, the reaction solution is subjected to post-treatment column chromatography separation and purification to obtain an intermediate RM-IIa-32 (0.045 g), meOH (2 mL), THF (1 mL) and an aqueous LiOH solution (1N, 1 mL) are sequentially added into the intermediate, stirring is carried out for 1h at room temperature, the reaction solution is neutralized to pH of about 4 by hydrochloric acid (1N) after the reaction is finished, water is added, ethyl acetate is added for extraction, an organic phase is combined, the organic phase is washed by saline solution and then dried, and finally column chromatography separation and purification are carried out to obtain a white solid product IIa-35 (0.040 g), and the yield of the two steps is 80%.
ESI-MS [ (M-H) of IIa-35, confirmed by mass spectrometry + ]M/z theory 384.1, found 384.1.
Example 36
Synthesis of Compound IIa-36
Raw material RM-IIa-31 (0.050 g,0.13 mmol.) was dissolved in 2mL of DCM, DMAP (0.039 g,0.32 mmol) was added, and cyclopentylchloroformate (0.023 g,0.15 mmol) was added with ice-water bath cooling and the reaction stirred at room temperature overnight and completed. After the reaction is finished, the reaction solution is subjected to column chromatography separation and purification to obtain an intermediate RM-IIa-33 (0.052 g), meOH (2 mL), THF (1 mL) and an aqueous LiOH solution (1N, 1 mL) are sequentially added into the intermediate, stirring is carried out at room temperature for 1h, the reaction solution is neutralized to pH of about 4 by hydrochloric acid (1N) after the reaction is finished, water is added, ethyl acetate is added for extraction, an organic phase is combined, the organic phase is washed by saline solution and then dried, and finally column chromatography separation and purification are carried out to obtain a white solid product IIa-36 (0.042 g), and the two-step yield is 73%.
ESI-MS [ (M-H) of IIa-36, confirmed by mass spectrometry + ]M/z theory 438.2, found 438.1.
Example 37
Synthesis of Compound IIa-37
Raw material RM-IIa-31 (0.050 g,0.13 mmol.) was dissolved in 2mL of DCM, DMAP (0.039 g,0.32 mmol) was added, phenyl chloroformate (0.024 g,0.15 mmol) was added with cooling in an ice-water bath, and the reaction was stirred at room temperature overnight and completed. After the reaction was completed, the reaction mixture was separated and purified by column chromatography to give an intermediate (0.050 g), which was dissolved in 2mL of DMF, and DMAP (0.025 g,0.2 mmol) and tert-butylamine (0.015 g,0.2 mmol) were added thereto, followed by stirring at room temperature for 3 hours to complete the reaction. After the reaction is finished, the reaction solution is subjected to post-treatment column chromatography separation and purification to obtain an intermediate RM-IIa-34 (0.043 g), meOH (2 mL), THF (1 mL) and an aqueous LiOH solution (1N, 1 mL) are sequentially added into the intermediate, stirring is carried out for 1h at room temperature, the reaction solution is neutralized to pH of about 4 by hydrochloric acid (1N) after the reaction is finished, water is added, ethyl acetate is added for extraction, an organic phase is combined, the organic phase is washed by saline solution and then dried, and finally column chromatography separation and purification are carried out to obtain a white solid product IIa-37 (0.025 g), and the two-step yield is 45%.
ESI-MS [ (M-H) of IIa-37, confirmed by mass spectrometry + ]M/z theory 425.2, found 425.1.
Example 38
Synthesis of Compounds IIa-38
Raw material RM-IIa-31 (0.050 g,0.13 mmol.) was dissolved in 2mL of DCM, DMAP (0.039 g,0.32 mmol) was added, and cyclopentylchloroformate (0.023 g,0.15 mmol) was added with ice-water bath cooling and the reaction stirred at room temperature overnight and completed. After the reaction is finished, the reaction solution is subjected to post-treatment column chromatography separation and purification to obtain an intermediate RM-IIa-35 (0.042 g), meOH (2 mL), THF (1 mL) and an aqueous LiOH solution (1N, 1 mL) are sequentially added into the intermediate, stirring is carried out for 1h at room temperature, the reaction solution is neutralized to pH of about 4 by hydrochloric acid (1N) after the reaction is finished, water is added, ethyl acetate is added for extraction, an organic phase is combined, the organic phase is washed by saline solution and then dried, and finally column chromatography separation and purification are carried out to obtain a white solid product IIa-38 (0.024 g), and the two-step yield is 45%.
ESI-MS [ (M-H) of IIa-38, confirmed by mass spectrometry + ]M/z theory 410.2, found 410.1.
Example 39
Synthesis of Compound IIa-39
Raw material RM-IIa-31 (0.050 g,0.13 mmol.) was dissolved in 2mL of DCM, DMAP (0.039 g,0.32 mmol) was added, and under ice-water bath cooling, isopropyl chloride (0.022 g,0.15 mmol) was added and the reaction was stirred at room temperature overnight and completed. After the reaction was completed, the reaction mixture was subjected to column chromatography to obtain intermediate RM-IIa-36 (0.013 g), meOH (2 mL), THF (1 mL) and an aqueous LiOH solution (1N, 1 mL) were sequentially added to the intermediate, stirred at room temperature for 1h, after the completion of the reaction, the reaction mixture was neutralized to pH of about 4 with hydrochloric acid (1N), water was added, ethyl acetate was added to extract, the organic phases were combined, washed with brine and dried, and finally column chromatography was separated and purified to obtain a white solid product IIa-39 (0.010 g), yield in two steps: 18%.
ESI-MS [ (M-H) of IIa-39 as confirmed by mass spectrometry + ]M/z theory 432.1, found 432.2.
Example 40
Synthesis of Compound IIa-40
The synthesis procedure for the preparation of compound IIa-40 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-40, wherein compound RM-Ia-17 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-37, which was hydrolyzed to give product IIa-40 (0.034 g) as a white solid in two steps in a yield of 33%.
ESI-MS [ (M-H) of IIa-40 as confirmed by mass spectrometry + ]M/z theory 426.2, found 426.3.
Example 41
Synthesis of Compound IIa-41
The synthesis procedure for the preparation of compound IIa-41 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-41, wherein compound RM-Ia-18 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-38, which was hydrolyzed to give product IIa-41 (0.026 g) as a white solid in 27% yield in two steps.
ESI-MS [ (M-H) of IIa-41, confirmed by mass spectrometry + ]M/z theory 395.1, found 395.2.
Example 42
Synthesis of Compound IIa-42
The synthesis procedure for the preparation of compound IIa-42 was the same as in example 1, and the product IIa-42 was obtained by two steps of etherification and hydrolysis, wherein compound RM-Ia-19 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIa-39, and the intermediate was hydrolyzed to obtain the white solid product IIa-42 (0.022 g) in a two-step yield of 23%.
ESI-MS [ (M-H) of IIa-42, confirmed by mass spectrometry + ]M/z theory 395.1, found 395.2.
Example 43
Synthesis of Compound IIa-43
The synthesis procedure for the preparation of compound IIa-43 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-43, wherein compound RM-Ia-20 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-40, which was hydrolyzed to give product IIa-43 (0.035 g) as a white solid in a two-step yield of 30%.
ESI-MS [ (M+H) of IIa-43, confirmed by mass spectrometry + ]M/z theory 480.2, found 480.3.
Example 44
Synthesis of Compound IIa-44
The synthesis procedure for the preparation of compound IIa-44 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-44, wherein compound RM-Ia-21 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-41, which was hydrolyzed to give product IIa-44 (0.032 g) as a white solid in 32% yield in two steps.
ESI-MS [ (M-H) of IIa-44 as confirmed by mass spectrometry + ]M/z theory 415.2, found 415.1.
Example 45
Synthesis of Compound IIa-45
The synthesis procedure for the preparation of compound IIa-45 was the same as in example 1, and the product IIa-45 was obtained by two steps of etherification and hydrolysis, wherein compound SM1-9 (0.42 mmol) was used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIa-42, and hydrolysis of the intermediate gave the product IIa-45 (0.030 g) as a white solid in 18% yield in two steps.
ESI-MS [ (M-H) of IIa-45 as confirmed by mass spectrometry + ]M/z theory 389.0, found 388.9.
Example 46
Synthesis of Compound IIa-46
The synthesis procedure for the preparation of compound IIa-46 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-46, wherein compound RM-Ia-13 (0.24 mmol) was used instead of compound RM-Ia-4 and compound SM1-12 (0.24 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-43, which was hydrolyzed to give product IIa-46 (0.038 g) as a white solid in a two-step yield of 40%.
ESI-MS [ (M-H) of IIa-46 as confirmed by mass spectrometry + ]M/z theory 389.1, found 389.2.
Example 47
Synthesis of Compounds IIa-47
The synthesis procedure for the preparation of compound IIa-47 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-47, wherein compound RM-Ia-22 (0.38 mmol) was used instead of compound RM-Ia-1 and compound SM1-2 (0.38 mmol) was used instead of compound SM1-1 in the reaction to give intermediate RM-IIa-44, which was hydrolyzed to give product IIa-47 (0.110 g) as a white solid in 66% yield in two steps.
ESI-MS [ (M-H) of IIa-47 as confirmed by mass spectrometry + ]M/z theory 434.0, found 434.1.
Example 48
Synthesis of Compounds IIa-48
The synthesis procedure for the preparation of compound IIa-48 was the same as in example 1, and the etherification and hydrolysis were carried out in two steps to give product IIa-48, wherein compound RM-Ia-23 (0.35 mmol) was used in place of compound RM-Ia-1 and compound SM1-2 (0.35 mmol) was used in the reaction to give intermediate RM-IIa-45, which was hydrolyzed to give product IIa-48 (0.075 g) as a white solid in a two-step yield of 46%.
ESI-MS [ (M-H) of IIa-48 as confirmed by mass spectrometry + ]M/z theory 459.0, found 459.1.
Example 49
Method for detecting GPR40 activity of compound:
the compound prepared by the invention can be initially determined and screened for the effect on GPR40 by the following preclinical in vitro inhibition activity test experiments, and then the curative effect and safety can be further confirmed by clinical experiments. Other methods will be apparent to those of ordinary skill in the art. The GPR40 agonist TAK-875 previously developed by the Japanese Wuta-tsai company was shown to have consistency in the results of the ex vivo assay with those of the related in vivo activity assay in preclinical and clinical assay results studies.
The compounds of the present invention, or stereoisomers, tautomers, esterified or amidated prodrugs thereof, or pharmaceutically acceptable salts thereof, and mixtures thereof, are tested by evaluation experiments of the activity of the compounds IIa-01 to IIa-48 and a reference compound Ref-1 (TAK-875) on GPR40, and the comparison of the test results reveals that there are a number of inhibitory activities (EC 50 ) Is superior to the reference compound.
CHO-K1/GPR40 cells were seeded in 384 well plates at a density of 10000 cells/well. Cells were cultured at 37℃under 5% CO2 incubator conditions for 24 hours. After the experiment, the fines were discardedCell culture medium, 30. Mu.l of 1 Xcontaining 2.5mM Probenecid was added rapidly to each wellCaltium 6 dye and incubated at 37℃for 2 hours in the dark. For the measurement, different concentrations of drug (15. Mu.l/well) were added to the wells and fluorescence values were read. The fluorescence excitation wavelength is 494nm, and the emission wavelength is 516nm. FLIPR instrument data, EC was derived according to the formula Y=bottom+ (Top-Bottom)/(1+ (EC 50/X)/(HillSlope) 50 。/>
The results of the GPR40 agonist activity test for each of the novel structural compounds of formula IIa are set forth in table 3 below; wherein the range of the active effect of the GPR40 agonist of the compounds of the invention (EC 50 ) At the position of<10nM is labeled "A"; the activity range is 10-100nM, denoted "B"; active range >100nM is indicated as "C".
Table 3: GPR40 agonist activity assay for Compounds of formula IIa
/>
Example 50
Compound toxicity screening assay
To test for higher activity of some of the novel compounds (IIa-01 to IIa-48) (EC 50 <10 nM) toxicity of the compounds (IIa-11, IIa-15, IIa-40 and IIa-48), the invention adopts 18-22g healthy mice, each of which is administered by single dose of 600mg/kg and 1 infusion, and the toxicity of the test animal is observed for 5 consecutive days to evaluate the toxicity of the test animal to the body, and the acute toxicity (Acute Toxocity Study, MTD) test is carried out, which shows that the total toxicity of the compounds is very small (LD 50 :>600 The survival rate of the mice after administration is 100 percent, no abnormality occurs in the body weight and in vitro and in vivo observation during administration and recovery period of 5 days, no abnormality is found in various organs such as heart, liver, lung, kidney, intestine and the like in vivo as a result of dissection,the compounds tested are generally recognized as safe and nontoxic within the appropriate dosage. Therefore, the in vitro experiments prove that the high-activity compounds of the invention not only have better curative effect on the type II diabetes, but also are safe and reliable.
Example 51
The BSEP (Bile Salt Export Pump) bile salt transport effect detection method of the compound comprises the following steps:
In the experiment, whether a candidate compound has an inhibition effect in the transportation process of the BSEP transporter or not is initially studied by a method for detecting the absorption capacity of the BSEP bile salt transporter to a substrate Taurocholic Acid (TCA) by using LC/MS/MS. BSEP protein micro-membrane capsule with reverse absorption capacity is obtained by transfecting BSEP gene through Hi5 cells, and the micro-membrane capsule can absorb and ingest taurocholate TCA. The principle of the experiment is that under the condition that energy ATP, a substrate taurocholate TCA and a candidate compound to be detected coexist, a substrate absorption experiment of a BSEP protein microcapsule is carried out, after a certain transfer action time, residual energy outside the microcapsule, the substrate and the candidate compound are completely washed off, and then the microcapsule is subjected to cleavage to release the absorbed substrate taurocholate TCA, so that LC/MS/MS is used for detecting the taurocholate TCA to determine whether the candidate compound inhibits the TCA transfer process.
Sample treatment:
1. compounds were dissolved to 100mM using 100% dmso, respectively, stored in a-20 degree refrigerator and all compounds were completely dissolved.
2. The initial concentration of the sample was 100mM, diluted 2-fold with a Bravo apparatus, 11 concentration gradients total; the nadir concentration was 97.65 μm.
3. Control compound (Glyburide) initial concentration 20mM, 2-fold gradient dilution with Bravo apparatus, total 11 concentration gradients; the nadir concentration was 19.53 μm.
4. Transfer 300nl of compound to the intermediate plate using an ECHO automated loading machine.
5. Positive control (HPE) wells and negative control (ZPE) wells were also each transformed with 300nl DMSO.
The experimental operation steps are as follows:
1. 14.7. Mu.l of ATP buffer was added to the corresponding wells of the compound and ZPE, respectively.
2. Add 14.7. Mu.l of AMP buffer to the corresponding wells of HPE, respectively.
Plates were shaken at 3.25 degrees celsius for 10 minutes.
4. To all wells, 15ul of BSEP-Hi5-VT Vesicle solution was added separately and plates were shaken at 25℃for 40 minutes.
5. Immediately, 5ul of 0.5M EDTA solution was added to all wells, and 65. Mu.l of buffer B was added, and the reaction was completed.
6. Transfer 95 μl of liquid from the end-of-reaction compound plate to the filter plate using a loading instrument.
7. After the liquid receiving plate is placed under the filter plate, the liquid is removed using a centrifuge, and the liquid received in the receiving plate is discarded.
8. Add 90. Mu.l buffer B to the filter plate, repeat step 7, repeat steps 7 and 8, wash the filter plate three times.
9. The filter plates were dried overnight.
10. The next day 81 μl of 80% methanol/water solution was added to the filter plate.
11. The filter plate was shaken for 15 minutes after film lamination.
12. A new liquid receiving plate was placed under the filter plate and centrifuged for 5 minutes, and all liquid in the filter plate was filtered into the receiving plate.
13. 13.5. Mu.l of the internal standard solution was added to each well in the liquid-receiving plate and sealed with a sealing membrane.
14. The content of taurine in the receiving plate was detected using LC/MS.
Table 4: comparison of optimized GPR40 agonist Activity and potential side effects thereof
Note that: the compounds shown in table 4 have an inhibition result (IC 50) of BSEP below 25 μm [ e.g.: ref-1 (TAK-875) has a value of 7.1, which is significantly lower than 25, the BSEP-inhibiting side effects of this compound would potentially lead to a risk of liver damage in vivo.
The activity measurements in tables 3 and 4 above show that:(1) The activity (EC 50) of the five-membered heterocyclic compound containing 1-2 oxygen atoms in the novel benzo heterocyclic compounds is obviously better than that of a six-membered heterocyclic compound containing 1-2 oxygen atoms in the similar structure; (2) Z in the compounds of the formula IIa according to the invention 1 The activity of the benzo oxygen-containing five-membered heterocyclic compound is better than Z in the similar structure when the compound is oxygen (O) 1 Is "CH 2 "activity of the corresponding compound; (3) The benzo-oxygen-containing five-membered heterocyclic compounds IIa-05, IIa-10, IIa-11, IIa-13, IIa-15, IIa-21, IIa-32, IIa-40, IIa-41, IIa-42 and IIa-48 of the present invention show very good activity against the GPR40 target (EC) 50 ：<10 nM), is superior to the similar control compound TAK-875, and is a novel GPR40 agonist with better activity, safety and other advantages.
The benzo oxygen-containing five-membered heterocyclic compounds listed in the above Table 4 not only show better activity, but also have a BSEP side effect result of more than 25, which may cause liver damage, which is significantly superior to TAK-875 new drugs of Japanese Wuta-tsu corporation which terminate clinical three-phase test because of liver toxicity problem, and the completed acute toxicity (MTD) test result shows that the safety of the active compounds IIa-11, IIa-15, IIa-40 and IIa-48 listed in Table 4 is better, the survival rate of mice after administration of 600mg/kg of the new compound for 5 days is 100%, no abnormality occurs during administration and recovery period of 5 days, and no abnormality is found in the anatomical result. Therefore, the novel benzo oxygen-containing five-membered heterocyclic compound IIa designed and synthesized by the invention has a plurality of high-activity compounds and has the value of further carrying out animal and clinical tests and popularization and application.
In the innovative research of GPR40 target agonists, several compounds (such as IIa-11, IIa-15, IIa-40 and IIa-48) with better activity effects are discovered, the toxicity of a TMD high-dose (600 mg/kg/day) acute toxicity test is very low, detection results of BSEP (> 25 uM), hERG (> 30 uM) and Ames and the like show no related side effects, and the related results are superior to those of the currently known reference compound TAK-875, so that a novel GPR40 target agonist medicament with better GPR40 target selectivity and capable of safely and efficiently treating type II diabetes patients is provided.
These and other changes can be made to the embodiments in light of the above-detailed description. In general, the terms used in the claims should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments following the full scope of equivalents to which the claims are entitled. Accordingly, the claims are not limited by the present disclosure.

Claims (5)

1. A compound of formula IIa:
or a pharmaceutically acceptable salt thereof,
wherein:
n=0, Y is absent, Y 1 Oxygen at the ortho position of Y is directly connected with a single bond to form five-membered heterocycle;
Y 1 is-CH 2 -；
E 1 is-CH-;
e and G 1 Directly linked to form cyclic compounds, G 1 is-C-, E is-OC (RcRd) -, rc and Rd are each independently hydrogen;
R 1 、R 2 and R is 3 Each independently is hydrogen, halogen, alkyl or alkoxy;
R 4 is hydrogen;
R 5 hydrogen, halogen, hydroxy, amino, alkylamino, alkyl or alkoxy;
R 5b hydrogen, halogen, alkyl or alkoxy;
R 7 is hydroxy, alkoxy, or cycloalkyl sulfonamide;
X 1 is hydrogen, deuterium (D), halogen, nitrile group, amino (NH) 2 ) Trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR) i R j ) Alkyl amino carbonyl amino group, alkoxy carbonyl amino group, ring alkoxy carbonyl amino group, alkyl sulfonamide group and cycloalkyl sulfonamide A group, aryl, or aryloxycarbonylamino group;
X 2 、X 3 and X 4 Each independently hydrogen, deuterium (D), halogen, or trifluoromethyl;
ri and Rj are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl.
2. The compound of claim 1, wherein the compound has a structure selected from the group consisting of:
3. a composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or excipient.
4. Use of a compound according to claim 1 or 2 or a composition according to claim 3 in the manufacture of a medicament for use as a GPR40 agonist.
5. Use of a compound according to claim 1 or 2 or a composition according to claim 3 in the manufacture of a medicament for the treatment or prophylaxis of type II diabetes.
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Citations (6)

* Cited by examiner, † Cited by third party
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CN1735408A (en) * 2002-11-08 2006-02-15 武田药品工业株式会社 Receptor function controlling agent
CN102076650A (en) * 2008-06-25 2011-05-25 第一三共株式会社 Carboxylic acid compound
JP2011148774A (en) * 2009-12-21 2011-08-04 Daiichi Sankyo Co Ltd Medicine containing carboxylic acid compound
JP2013147443A (en) * 2012-01-18 2013-08-01 Daiichi Sankyo Co Ltd β-SUBSTITUTED CARBOXYLIC ACID DERIVATIVE
WO2015044073A1 (en) * 2013-09-26 2015-04-02 Boehringer Ingelheim International Gmbh Process and intermediates for preparing indanyloxydihydrobenzofuranyl acetic acid derivatives as gpr40 agonists
CN105001212A (en) * 2014-04-16 2015-10-28 江苏柯菲平医药股份有限公司 Fused ring compound, preparation method and applications thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1735408A (en) * 2002-11-08 2006-02-15 武田药品工业株式会社 Receptor function controlling agent
CN102076650A (en) * 2008-06-25 2011-05-25 第一三共株式会社 Carboxylic acid compound
JP2011148774A (en) * 2009-12-21 2011-08-04 Daiichi Sankyo Co Ltd Medicine containing carboxylic acid compound
JP2013147443A (en) * 2012-01-18 2013-08-01 Daiichi Sankyo Co Ltd β-SUBSTITUTED CARBOXYLIC ACID DERIVATIVE
WO2015044073A1 (en) * 2013-09-26 2015-04-02 Boehringer Ingelheim International Gmbh Process and intermediates for preparing indanyloxydihydrobenzofuranyl acetic acid derivatives as gpr40 agonists
CN105001212A (en) * 2014-04-16 2015-10-28 江苏柯菲平医药股份有限公司 Fused ring compound, preparation method and applications thereof

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