PPARG modulators

Abstract

The invention discloses a PPARG regulator as shown in a general formula (I), a pharmaceutical composition and a preparation method of the PPARG regulator and application of the PPARG regulator to preparation of medicines for preventing and / or treating indications related to PPARG. The compound provided by the invention is an ideal PPARG inverse agonist, and can be used for treating and / or preventing various diseases related to PPARG, especially for treating cancers.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a PPARG regulator, a pharmaceutical composition, a preparation method and use thereof in preparing, preventing and / or treating drugs for PPARG-related indications. Background Art

[0002] PPARs (peroxisome proliferator-activated receptors) are ligand-activated receptors in the nuclear hormone receptor family and are ligand-activated transcription factors that regulate the expression of specific target genes. PPARs include three subtypes: PPARα, PPARγ (PPARG), and PPARβ.

[0003] PPARG and retinoid X receptors (RXRs) form heterodimers to play a role. The formed PPARG / RXR heterodimer binds to the PPAR response element (PPRE) upstream of the target gene promoter, thereby regulating the transcriptional expression of the target gene. PPARG regulates the body's glucose and lipid metabolism and the expression of cell differentiation transcription factors. PPARγ1 is expressed in a variety of cells including immune cells and adipocytes and regulates energy metabolism and immunity, while PPARγ2 is particularly abundant in BAT and white adipose tissue and plays a role in controlling adipocyte differentiation and lipid metabolism.

[0004] Mutations related to the PPARG gene and its partner protein RXRs. Overactivation of the PPARG gene is carcinogenic, such as high expression of PPARG, gene amplification, and mutations in RXRs, which is consistent with the increased risk of bladder cancer in patients with long-term use of PPARG agonists, including pioglitazone, in clinical practice. In vitro pharmacological antagonism of PPARG has been shown to have anti-proliferative effects on cancer cells and promote osteoblast formation. Genetic experiments have shown that PPARG agonists may induce pro-inflammatory effects in the tumor environment. The key role of PPARG in regulating energy metabolism may also affect the occurrence and development of tumors. Studies have found that PPARG is often overexpressed and genetically altered in luminal urothelial carcinoma, and PPARG activation has also become an important molecular feature of the luminal subtype of advanced urothelial carcinoma.

[0005] Urothelial carcinoma can be divided into non-muscle invasive urothelial carcinoma (NMIUC, 70%), muscle invasive urothelial carcinoma (MIUC, 25%), or metastatic urothelial carcinoma. MIUC is a heterogeneous, aggressive disease with a five-year survival rate of 60% for patients and less than 10% for patients with localized disease. First-line treatment for urothelial carcinoma includes platinum-based chemotherapy, and PD-1 immunotherapy can be considered for patients who are not suitable for platinum. In the case of stable disease after platinum-based chemotherapy, maintenance therapy with PD-1 immunotherapy is recommended, and it is recommended to determine the FGFR mutation status before deciding on second-line treatment. Patients with FGFR3 mutations are suitable for treatment with FGFR inhibitors. Enfortumab vedotin is a new standard of care for progression after platinum-based chemotherapy and immunotherapy. In general, the treatment of urothelial carcinoma is very limited, the overall prognosis is poor, and the clinical treatment demand is high.

[0006] Based on the important role of PPARG in diseases such as urothelial carcinoma and the huge unmet clinical needs of urothelial carcinoma, compounds targeting PPARG and / or RXRα signaling pathways can be developed. Summary of the invention

[0007] In order to solve the defects of the prior art, the object of the present invention is to provide a PPARG modulator, a pharmaceutical composition, a preparation method and use of the same in the preparation, prevention and / or treatment of drugs for PPARG-related indications.

[0008] In one aspect, the present invention provides a compound of formula (I):

[0009]

[0010] or a deuterated substance, a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof;

[0011] in,

[0012] Ring A is a benzene ring or a 5-10 membered heterocyclic group, preferably a benzene ring, a 5-7 membered monocyclic heteroaryl containing 1-3 N, O, S atoms, or a 9-10 membered bicyclic heterocyclic group containing 1-5 heteroatoms selected from N, O, and S atoms;

[0013] X is The “*” end is connected to R1, and the “**” end is connected to ring A;

[0014] R1 is R 1a or R 1b ;

[0015] R 1a Select any 1-3 R a Substituted C 1-6 Alkyl, optionally substituted with 1-3 Ra Substituted C 2-6 Alkenyl, optionally substituted with 1-3 R a Substituted C 2-6 Alkynyl, optionally substituted with 1-2 R a Substituted amino groups;

[0016] The R a is selected from halogen, hydroxy, cyano, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy, optionally halogenated C 1-6 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2, optionally C 1-3 Alkyl or halogenated C 1-3 Alkyl-substituted amino, optionally substituted 4-8 membered heterocyclic group;

[0017] R 1b Select any 1-3 R b substituted 3-9 membered cycloalkyl, optionally substituted with 1-3 R b Substituted 3-9 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S;

[0018] The R b is selected from halogen, hydroxy, cyano, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy;

[0019] R2 is selected from halogen, hydroxy, cyano, nitro, oxo, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy;

[0020] r is 0, 1, 2, or 3;

[0021] R3, R4, R5, R6, and R7 are each independently selected from H, halogen, hydroxy, cyano, nitro, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2.

[0022] In some specific embodiments, the above compound has a structure shown in Formula II:

[0023]

[0024] The ring A is selected from a benzene ring or a 5-7 membered monocyclic heteroaryl containing 1-3 N, O, S;

[0025] The ring A and R2 form the following structure:

[0026] As a preference:

[0027] X is The “*” end is connected to R1, and the “**” end is connected to ring A;

[0028] R1 is R 1a or R 1b ;

[0029] R 1a Select from 1-3 R a Substituted C 1-6 Alkyl, optionally substituted with 1-3 R a Substituted C 2-6 Alkenyl, optionally substituted with 1-3 R a Substituted C 2-6 Alkynyl, optionally substituted with 1-2 R a The amino group is preferably substituted with 1 to 3 R a Substituted C 1-3 Alkyl, optionally substituted with 1-3 R a Substituted C 2-4 Alkenyl, optionally substituted with 1-2 R a Substituted amino groups;

[0030] The R a is selected from hydroxy, cyano, optionally halogenated C 1-6 Alkoxy, optionally halogenated C 1-6 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 alkyl)2, an optionally substituted 4-8 membered heterocyclic group, more preferably a hydroxyl group, a cyano group, an optionally halogenated C 1-3 Alkoxy, optionally halogenated C 1-3 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 alkyl)2, optionally substituted 4-8 membered heterocyclic group;

[0031] R 1b Select any 1-3 R b substituted 3-9 membered cycloalkyl, optionally substituted with 1-3 R b Substituted 3-9 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S;

[0032] The R b is selected from halogen, hydroxy, cyano, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy;

[0033] R3, R4, R5, R6, and R7 are each independently selected from H, halogen, hydroxy, cyano, nitro, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2.

[0034] Further preferred:

[0035] R1 is R 1a or R 1b ;

[0036] R 1a Select from 1-3 R a Substituted methyl, ethyl, optionally substituted with 1-3 R a Substituted vinyl, optionally with 1-3 R a substituted ethynyl or optionally substituted with 1-2 R a Substituted amino groups;

[0037] R a is selected from hydroxy, cyano, methoxy, difluoromethoxy, trifluoromethoxy, -S(=O)2-Me, -S(=O)(=NH)-Me, -N=S(=O)-Me2, dimethylamino,

[0038] Furthermore, the R 1a Selected from

[0039] R 1b Selected from

[0040] The R b is selected from F, hydroxy, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy;

[0041] Furthermore, the R 1b Selected from

[0042]

[0043] R3, R4, R5, R6, and R7 are each independently selected from H, F, hydroxy, cyano, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -S(=O)(=NH)-Me, and -N=S(=O)-Me2.

[0044] In some specific embodiments, X is One end of “*” is connected to R1, and one end of “**” is connected to ring A.

[0045] In some specific embodiments, Ring A is selected from a 9-10 membered bicyclic heterocyclic group containing 1-5 heteroatoms selected from N, O, and S;

[0046] R2 is selected from halogen, hydroxy, oxo, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy.

[0047] In some specific embodiments, ring A is selected from

[0048] More preferably, the ring A and R2 form the following structure:

[0049] As a preference:

[0050] R 1a Select any 1-3 R a Substituted C 1-3 Alkyl, optionally substituted with 1-3 R a Substituted C 2-4 Alkenyl, optionally substituted with 1-3 R a Substituted C 2-4 Alkynyl, optionally substituted with 1-2 R a Substituted amino group; R 1a Preferably, 1 to 3 R a substituted methyl, ethyl, vinyl or optionally substituted with 1-2 R a Substituted amino groups;

[0051] The R a is selected from F, hydroxy, cyano, optionally halogenated C 1-3 Alkyl, optionally halogenated C 1-3 Alkoxy, optionally halogenated C 1-3 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2, optionally C 1-3 Alkyl or halogenated C 1-3 Alkyl-substituted amino, optionally substituted 4-8 membered heterocyclic group; Ra Preferred are F, hydroxy, cyano, methoxy, difluoromethoxy, trifluoromethoxy, -S(=O)2-Me, -S(=O)(=NH)-Me, -N=S(=O)-Me2, dimethylamino,

[0052] Furthermore, the R 1a Selected from

[0053] R 1b Select any 1-3 R b substituted 3-9 membered cycloalkyl, optionally substituted with 1-3 R b Substituted 3-9 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S, including

[0054] The R b is selected from F, hydroxy, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy;

[0055] Furthermore, the R 1b Selected from

[0056] As a preference:

[0057] R3, R4, R5, R6, and R7 are each independently selected from H, F, hydroxy, cyano, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -S(=O)(=NH)-Me, and -N=S(=O)-Me2.

[0058] As a preference:

[0059] R3 and R7 are H;

[0060] R4 and R6 are F;

[0061] R5 is selected from H, F, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -S(=O)(=NH)-Me, -N=S(=O)-Me2.

[0062] Such compounds include:

[0063]

[0064]

[0065]

[0066]

[0067] The second aspect of the present invention also provides a pharmaceutical composition, which contains any one of the above-mentioned compounds, deuterated substances, stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier thereof.

[0068] The third aspect of the present invention also provides the use of the above-mentioned compound, its deuterated product, stereoisomer or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing PPARG-related diseases.

[0069] Preferably, the drug for treating and / or preventing PPARG-related diseases is an immune checkpoint inhibitor used alone or in combination; the combined immune checkpoint inhibitor includes PD-1 antibody or PD-L1 antibody.

[0070] Preferably, the PPARG-related disease is selected from diseases caused by changes in PPARG activity (such as mutation, amplification or overexpression, etc.) or changes in RXRA activity.

[0071] Preferably, the PPARG-related diseases include tumors, metabolic diseases, autoimmune diseases, and inflammatory diseases.

[0072] Preferably, the PPARG-related disease is selected from bladder cancer, urothelial carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, skin cancer, melanoma, colon cancer, renal cancer, brain cancer and blood cancer.

[0073] Preferably, the PPARG-related cancer is selected from urothelial carcinoma.

[0074] Beneficial effects:

[0075] The compounds provided by the present invention have strong efficacy, good pharmacokinetic properties, and low toxic and side effects, and are ideal PPARG regulators or PPARG inverse agonists. The compounds provided by the present invention have good PPARG inhibitory activity. The compounds of the present invention are ideal high-activity PPARG inverse agonists and can be used to treat and / or prevent diseases including bladder cancer, urothelial cancer, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, skin cancer, melanoma, colon cancer, kidney cancer, brain cancer and blood cancer. DETAILED DESCRIPTION

[0076] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0077] definition

[0078] "Optional" or "optionally" used herein means that any optional item can be selected or not selected. For example, "group A is optionally replaced by 1-3 groups B" comprises that group A is not replaced by group B, group A is replaced by 1 group B, group A is replaced by 2 groups B, and group A is replaced by 3 groups B. These four situations.

[0079] As used herein, "substituted" or "substituted" means that any one or more hydrogen atoms on any atom in a group or fragment are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is "oxo" (i.e., =O), it means that two hydrogen atoms are replaced by oxygen, and when the atom replaced by oxygen is a carbon atom, a carbonyl group (C=O) is formed. Oxygen substitution does not occur on aromatic groups.

[0080] As used herein, "optionally substituted" means that it may be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents may be any on the basis of chemical feasibility. For example, "optionally substituted 5-6 membered heterocyclic group" means a 5-6 membered heterocyclic group substituted or unsubstituted by any group. For another example, "optionally substituted by 1-3 R a Substituted C 1-6 "Alkyl" refers to an alkyl group which is unsubstituted or substituted with 1 to 3 R a Substituted C 1-6 alkyl.

[0081] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0082] The "chemical bond" used herein generally refers to a covalent bond between two atoms in a compound molecule formed by sharing a pair of electrons.

[0083] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0084] When the listed linking groups do not specify their connection direction, their connection direction is arbitrary. For example, in the ring A-L1-R1, the linking group L1 is -MW-. In this case, -MW- can connect the rings A and R1 in the same direction as the reading order from left to right to form the ring AMW-R1, or can connect the rings A and R1 in the opposite direction to the reading order from left to right to form the ring AWM-R1. Combinations of the linking groups, substituents and / or their variants are permitted only if such combinations will produce stable compounds.

[0085] If there is no special description, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds and become a group with corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid line bond straight line. Dotted key For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the carbon atom in the group are connected to other groups; The dotted lines in the figure indicate that the 1- and 4-carbon atoms in the phenyl group are connected to other groups; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0086] Unless otherwise specified, in a cyclic group, the attachment site of the group or fragment is located on the ring connected by the dotted line. Any connection site on the benzene ring of the group can be connected to other groups through one chemical bond, including at least These are 4 connection methods.

[0087] Generally, in aromatic or heteroaromatic rings, double bonds and single bonds have no limiting meaning. For example, All refer to a benzene ring or a phenyl group, wherein the double bond or Specifically refers to the large π bond delocalized in the plane of the benzene ring; When ring C is limited to a 5-membered aryl or heteroaryl group, ring B and ring C form a conjugated cyclic aryl or cyclic heteroaryl group, and its non-limiting examples include even though The left ring in the Still includes In this group, the double bond represents a large π bond delocalized on the annular aromatic ring.

[0088] The numerical intervals used herein include the endpoint values ​​and any values ​​between the endpoint values. For example, "0-3" may include 0, 1, 2 or 3, and "1-3" may include 1, 2 or 3.

[0089] The “C 1-n "Including C 1-2 , C 1-3 , ...C 1-n For example, “C 1-6 " means that the moiety has 1-6 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. Thus, for example, "C 1-4 "Alkyl" refers to an alkyl group containing 1-4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The numerical ranges in this article, such as "1-6", refer to each integer in the given range.

[0090] The annular atom refers to the non-hydrogen atom in the ring group that is used to form the ring. The linking atoms in are 3 carbon atoms; The atoms in the middle ring are three carbon atoms and one oxygen atom; The atoms in the middle chain are 1 N atom and 5 carbon atoms; The atoms in the middle chain are 8 carbon atoms and 1 nitrogen atom.

[0091] As used herein, "nm members" refers to the number of annular atoms in a cyclic group. For example, a "3-8 member" group refers to a group having 3-8 annular atoms in the moiety, i.e., the group contains 3 annular atoms, 4 annular atoms, 5 annular atoms, 6 annular atoms, 7 annular atoms, or 8 annular atoms. Thus, for example, a "3-8 membered cycloalkyl" refers to a saturated cyclic alkyl group containing 3-8 carbon atoms, i.e., the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0092] The term "alkyl" used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein preferably has 1-6 carbon atoms, for example 1-5 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like. In the definitions of radicals herein, when the term “alkyl” appears in a numerical range, for example, “C 1-6 The term "alkyl" refers to an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also includes the case where no numerical range is specified. The alkyl group may be optionally substituted or unsubstituted.

[0093]

[0046] "Alkyl" as used herein in combination refers to an alkyl group attached to another group, for example, an alkyl group in an alkoxy group, and has the same definition as when used alone.

[0094] The term "alkoxy" or "-O-alkyl" as used herein, alone or in combination, is represented as "alkyl-O-". Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted.

[0095] The term "cycloalkyl" as used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic carbocyclic ring. Preferably, it is a 3-12-membered cycloalkyl, more preferably a 3-10-membered cycloalkyl, and most preferably a 3-8-membered cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like cycloalkyls, which may be optionally substituted or unsubstituted.

[0096] The term "aryl" used herein, alone or in combination, refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic condensed ring (and ring) aromatic hydrocarbons, wherein all condensed ring systems (excluding any ring system that is a part of an optional substituent or formed by an optional substituent) are aromatic. Examples of aryl groups / parts include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".

[0097] The term "heterocyclyl" used herein alone or in combination includes alicyclic and heteroaryl groups, wherein one or more (such as one, two, three or four) of the annular atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, condensed, bridged and spirocyclic rings. Examples of heterocyclic groups include heterocycloalkyl, heterocycloalkenyl and heteroaryl groups as discussed below. Preferred herein are 3-10 membered monocyclic, bicyclic or tricyclic heterocyclic groups, which may contain 1, 2 or 3 annular atoms selected from nitrogen, oxygen and / or sulfur. Non-limiting examples of "heterocyclyl" include azetidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, etc. The heterocyclyl group may be optionally substituted or unsubstituted.

[0098] In the definition of "heterocyclic group", "heterocyclic group" refers to a polycyclic group containing heteroatoms, which contains two or more cyclic structures and shares a pair of atoms with each other. Among them, one or more rings may contain several unsaturated bonds, or one ring may have a completely conjugated π-electron aromatic system, and the atoms in the rings are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2) heteroatoms, and the remaining link atoms are carbon. It is preferably 6-12 members, more preferably 8-9 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic cyclic ring group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic cyclic ring group.

[0099] The term "heterocycloalkyl" used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic, wherein one or more (such as one, two, three or four) ring atoms are saturated heterocyclic groups of heteroatoms, which can be spirocyclic or bridged rings.Preferred herein are 3-12 cycloalkyls, more preferably 3-10 cycloalkyls, most preferably 3-8 cycloalkyls.Non-limiting examples of monocyclic heterocycloalkyls include but are not limited to propylene oxide, thiirane, aziridine, azetidine, oxetane, thiamine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.

[0100] The term "heteroaryl" as used herein, alone or in combination, refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule. Non-limiting examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like; and also include, but are not limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, indazole, 1,8-naphthyridine, benzo[d]isoxazole, benzo[ d]thiazole, pyrrolo[3,2-b]pyridine, furano[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, thiazolo[4,5-c]pyridine, thieno[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, 2,3-dihydrobenzofuran, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]oxazol-2(3H)-one, etc. The heteroaryl group may be optionally substituted or unsubstituted.

[0101] The term "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[0102] The term "hydroxy," as used herein, alone or in combination, refers to -OH.

[0103] The term "cyano," as used herein, alone or in combination, refers to -CN.

[0104] As used herein, the term "substituted" or "substituted by" means that one or more hydrogens on a particular atom are replaced by a specified group (such as halogen, alkyl, etc.), and if the normal valence of the specified atom is not exceeded under the existing circumstances, the substitution results in a stable compound.

[0105] The term "pharmaceutically acceptable salt" used herein is well known to those skilled in the art.

[0106] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0107] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient.

[0108] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0109] The term "stereoisomer" as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.

[0110] The term "enantiomer" as used herein refers to the isomerism caused by the different spatial configuration of atoms or atomic groups (groups) in compounds with the same molecular formula, and two compounds that are enantiomers are mirror images of each other and cannot overlap. The term "cis-trans isomer" as used herein generally refers to the stereoisomerism of diastereoisomers that occur in compound molecules due to the restriction factor of free rotation, which makes each group arranged in space differently. Organic molecules containing such isomers such as olefins, azo compounds, alicyclic hydrocarbons, etc. are regarded as cis-trans isomers. In the present application, cis-trans isomerism is mainly embodied in the form of alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism will occur when cyclohexane is replaced by two substituents, and when the two substituents are replaced on the same side of the ring, they are "cis" isomers, and on different sides, they are "trans" isomers.

[0111] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, hindered isomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0112] Unless otherwise indicated, the structure described in the present invention also includes all isomers of the structure (e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformation) isomer forms), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, steric isomers of biphenyl structures (see "Basic Organic Chemistry" (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers. Therefore, single stereoisomers of the compounds of the present invention as well as enantiomeric mixtures, diastereomeric mixtures, steric isomers and geometric (conformation) isomer mixtures are all within the scope of the present invention.

[0113] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0114] Some of the preparation conditions used in the examples are as follows:

[0115] Prep-HPLC conditions: instrument: GILSON-GX281; wavelength: 220nm & 254nm; column model: Waters X-bridge (30×100mm, 10μm) or Luna C18 (30×75mm, 3μm) or Luna C18 (30×75mm, 3μm); mobile phase: A: 10mM ammonium bicarbonate or H2O (0.1% formic acid) or H2O (0.1% trifluoroacetic acid), B: acetonitrile; running time: 15min; flow rate: 25mL / min.

[0116] Reverse phase column purification used a C18 reverse phase silica gel column (Spherical C18, 40-60 μm, 40 g-120 g) with water / acetonitrile (95 / 5 to 30 / 70) as the mobile phase.

[0117] Example 1

[0118] 4-(Cyclopropylsulfonyl)-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile

[0119]

[0120] (1) 2-Chloro-5-cyanobenzoic acid

[0121] Dissolve 2-chloro-5-iodobenzoic acid (20g, 71mmol), potassium carbonate (10g, 71mmol), potassium ferrocyanide trihydrate (15g, 35.5mmol) in tert-butyl alcohol / water solution (90mL / 120mL) and stir at room temperature for 1 hour. Then add tri(dibenzylideneacetone)dipalladium (650mg, 0.71mmol) and 1,4-bis(diphenylphosphine)butane (606mg, 1.42mmol), and heat the mixture to 80℃ and stir for 37 hours under nitrogen protection. Add pyrrolidine dithiocarboxylic acid ammonium salt (6g, 35.5mmol) and water (100mL) to the reaction solution, stir and react at 45℃ for 2 hours. The reaction solution is cooled to room temperature, concentrated to remove tert-butyl alcohol, and filtered to remove insoluble matter. The filtrate was extracted with ethyl acetate (100 mL x 3), and the pH of the aqueous phase was adjusted to acidic with 1 M hydrochloric acid. A solid product precipitated, and the solid was filtered and dried to obtain the title compound (12 g, brown solid), yield: 92%. MS (ESI): m / z 181.9 [M+H] + .

[0122] (2) 1-(2-amino-4,6-difluorophenyl)ethane-1-one

[0123] Dissolve 3,5-difluoroaniline (11g, 8.5mmol) in acetonitrile (100mL), slowly add 1M boron trichloride dichloromethane solution (90mL, 90mmol) at 0℃, then add aluminum chloride (11g, 8.5mmol) in four portions, and heat to 80℃ and stir for 16 hours after the addition is complete. Cool to 0℃, add 4M hydrochloric acid (100mL, 400mmol), and stir at 80℃ for 2 hours. Concentrate the reaction solution to remove acetonitrile and extract with ethyl acetate (60mL x 3). Combine the organic phases, wash with saturated sodium bicarbonate solution (100mL x 2), dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate to obtain the title compound (3.77g, yellow solid), yield: 26%. MS (ESI): m / z 172.0[M+H] + .

[0124] (3) N-(2-acetyl-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide

[0125] Dissolve 2-chloro-5-cyanobenzoic acid (1.6 g, 8.8 mmol), 1-(2-amino-4,6-difluorophenyl)ethane-1-one (1.5 g, 8.8 mmol), and pyridine (3.5 g, 44 mmol) in dichloromethane (30 mL), add phosphorus oxychloride (2.7 g, 17.6 mmol) three times, and then stir at room temperature for 1 hour. Add water (50 mL) to the reaction solution, and extract the aqueous phase with dichloromethane (30 mL x 3). The organic phases are combined, washed with 1M hydrochloric acid (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to obtain the title compound (1.8 g, white solid), yield: 62%. MS (ESI): m / z 334.9 [M+H] + .

[0126] (4) 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile

[0127] N-(2-acetyl-3,5-difluorophenyl)-2-chloro-5-cyanobenzamide (1.8 g, 5.4 mmol) and sodium hydroxide (2.2 g, 54 mmol) were dissolved in 1,4-dioxane (20 mL) and stirred at 110°C for 1.5 hours. The reaction solution was adjusted to acidic pH with 1M hydrochloric acid, diluted with water (80 mL), and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (750 mg, light yellow solid), yield: 44%. MS (ESI): m / z 316.9 [M+H] + .

[0128] (5) 4-(Cyclopropylsulfonyl)-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile

[0129] 4-Chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (50 mg, 0.16 mmol), sodium cyclopropylsulfinate (27 mg, 0.21 mmol), potassium phosphate (34 mg, 0.16 mmol), cuprous iodide (3 mg, 0.016 mmol) and 8-hydroxyquinoline (2 mg, 0.016 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the mixture was heated to 120 ° C and stirred for 24 hours under nitrogen protection. Water (30 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain a crude product. The crude product was further purified by Prep-HPLC to obtain the title compound (11.2 mg, white solid), yield: 18%. MS (ESI): m / z 386.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.33-8.26(m,3H),7.16-7.06(m,2H),6.09(s,1H),2.89-2.84(m,1H),1.13-1.09(m,4H).

[0130] Example 2 to Example 17

[0131] The preparation of Examples 2 to 17 refers to the method of Example 1, using corresponding raw materials and synthesized through similar steps.

[0132]

[0133] Embodiment 18

[0134] 3-(5,7-Difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2-hydroxyethyl)sulfonyl)benzonitrile

[0135]

[0136] (1) 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2-hydroxyethyl)thio)benzonitrile

[0137] 2-Mercaptoethane-1-ol (25 mg, 0.32 mmol) and potassium carbonate (44 mg, 0.32 mmol) were dissolved in N, N-dimethylformamide (5 mL), nitrogen was replaced, and the mixture was stirred at room temperature for 0.5 hours. Then, a solution of 4-chloro-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)benzonitrile (50 mg, 0.16 mmol, step 4 of Example 1) in N, N-dimethylformamide (2 mL) was slowly added dropwise, and the mixture was heated to 78°C and stirred for 16 hours. The reaction solution was directly purified by reverse phase column to obtain the title compound (25 mg, light yellow solid), with a yield of 44%. MS (ESI): m / z 358.9 [M+H] + .

[0138] (2) 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2-hydroxyethyl)sulfonyl)benzonitrile

[0139] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2-hydroxyethyl)thio)benzonitrile (25 mg, 0.07 mmol) and m-chloroperbenzoic acid (31 mg, 0.18 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated, diluted with N,N-dimethylformamide, and purified by Prep-HPLC to obtain the title compound (1.9 mg, white solid), yield: 7%. MS (ESI): m / z 391.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.29-8.23 (m, 3H), 7.16-7.11 (m, 2H), 6.25 (s, 1H), 3.74 (t, J = 5.6 Hz, 2H), 3.68-3.57 (m, 2H). Example 19 to Example 30

[0140] The preparation of Examples 19 to 30 refers to the method of Example 18, using corresponding raw materials and synthesized through similar steps.

[0141]

[0142]

[0143] Embodiment 31

[0144] 5,7-Difluoro-2-(6-(methylsulfonyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)quinolin-4(1H)-one

[0145]

[0146] (1) (E)-5-bromo-2-(((dimethylamino)methylene)amino)isonicotinic acid methyl ester

[0147] Dissolve 2-amino-5-bromoisonicotinic acid methyl ester (508 g, 2.2 mmol) and N,N-dimethylformamide dimethyl acetal (2 mL) in isopropanol (2 mL) and stir at 80°C for 16 hours. The reaction solution was concentrated to obtain the title compound (629 mg, yellow solid), yield: 100%. MS (ESI): m / z 285.9 [M+H] + .

[0148] (2) (E)-5-bromo-2-(N'-hydroxycarboxamido)isonicotinic acid methyl ester

[0149] (E)-5-bromo-2-(((dimethylamino)methylene)amino)isonicotinic acid methyl ester (629 mg, 2.2 mmol) and hydroxylamine hydrochloride (306 mg, 4.4 mmol) were dissolved in isopropanol (7 mL) and stirred at 50°C for 16 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give the title compound (460 mg, light yellow solid) in a yield of 76%. MS (ESI): m / z 273.8 [M+H] + .

[0150] (3) 6-Bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid methyl ester

[0151] (E)-5-bromo-2-(N'-hydroxycarboxamido)isonicotinic acid methyl ester (304 mg, 1.1 mmol) and trifluoroacetic anhydride (462 mg, 2.2 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred at 40°C for 5 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (200 mg, white solid) in a yield of 71%. MS (ESI): m / z 255.8 [M+H] + .

[0152] (4) 6-Bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid

[0153] Dissolve 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid methyl ester (100 mg, 0.39 mmol) and sodium hydroxide (47 mg, 1.17 mmol) in methanol / water (10 mL / 2 mL) and stir at room temperature for 1 hour. The reaction solution was concentrated to remove methanol, diluted with water (30 mL), and the pH was adjusted to acidic with 1M hydrochloric acid. The title compound (70 mg, white solid) was purified by reverse phase column, with a yield of 74%. MS (ESI): m / z 241.8 [M+H] + .

[0154] (5) N-(2-acetyl-3,5-difluorophenyl)-6-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide

[0155] 6-Bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (70 mg, 0.3 mmol), 1-(2-amino-4,6-difluorophenyl)ethane-1-one (103 mg, 0.6 mmol, step 2 of Example 1) and pyridine (107 mg, 1.5 mmol) were dissolved in dichloromethane (5 mL), and phosphorus oxychloride (92 mg, 0.6 mmol) was added and stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with 1M hydrochloric acid (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to obtain the title compound (90 mg, yellow solid), yield: 79%. MS (ESI): m / z 394.7 [M+H] + .

[0156] (6) 2-(6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-5,7-difluoroquinolin-4(1H)-one

[0157] N-(2-acetyl-3,5-difluorophenyl)-6-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (90 mg, 0.23 mmol) and sodium hydroxide (92 mg, 2.3 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 110°C for 1.5 hours. The reaction solution was adjusted to acidic pH with 1M hydrochloric acid, diluted with water (40 mL), and extracted with dichloromethane / methanol (v / v=10 / 1, 25 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=94 / 6) to obtain the title compound (36 mg, light yellow solid), yield: 42%. MS (ESI): m / z 376.7 [M+H]+ .

[0158] (7) 5,7-difluoro-2-(6-(methylsulfonyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)quinolin-4(1H)-one

[0159] 2-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-5,7-difluoroquinolin-4(1H)-one (36 mg, 0.1 mmol), sodium methanesulfinate (20 mg, 0.2 mmol), potassium phosphate (21 mg, 0.1 mmol), cuprous iodide (4 mg, 0.02 mmol) and 8-hydroxyquinoline (3 mg, 0.02 mmol) were dissolved in dimethyl sulfoxide (5 mL) and stirred at 120 ° C under nitrogen protection for 16 hours. Water (80 mL) was added to the reaction solution, and extracted with dichloromethane / methanol (v / v=10 / 1, 40 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=92 / 8) to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (5.3 mg, white solid), yield: 14%. MS (ESI): m / z 376.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),8.86(s,1H),8.22(s,1H),7.20-7.11(m,2H),6.36(s,1H),3.51(s,3H).

[0160] Example 32 to Example 37

[0161] The preparation of Examples 32 to 37 refers to the method of Example 31, using corresponding raw materials and synthesized through similar steps.

[0162]

[0163] Embodiment 38

[0164] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(ethylenesulfonyl)benzonitrile

[0165]

[0166] 3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-((2-hydroxyethyl)sulfonyl)benzonitrile (15 mg, 0.04 mmol) and Burgess reagent (14 mg, 0.06 mmol) were dissolved in tetrahydrofuran solution (10 mL), heated to 60°C in a sealed tube under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain the title compound (1 mg, white solid), yield: 7%. MS (ESI): m / z 373.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 8.32-8.26 (m, 3H), 7.17-7.06 (m, 3H), 6.29 (d, J = 10.0Hz, 1H), 6.20 (d, J = 16.4Hz, 1H), 5.96-5.93 (m, 1H).

[0167] FX-909 was prepared according to Example 1 of patent WO2023078252, and its structure is shown below:

[0168]

[0169] Test Example 1: PPARG inverse agonist activity test

[0170] Using LanthaScreen TM TR-FRET detection of peroxisome proliferator-activated gamma receptor coactivator. First, 100 nL of compound with a final concentration of 1% DMSO was transferred to a 384 reaction plate (Corning) using an Echo 655 automatic pipette device, 5 μL of PPARγ-LBD (Thermo Fisher, Cat# PV4545) was added to the ligand test compound, and then 5 μL of agonist GW1929, fluorescein coactivator peptide Fluorescein TRAP220 / DRIP-2peptide (Thermo Fisher) and terbium-labeled anti-GST antibody Tb-anti-GST Ab (ThermoFisher) were added. The final concentrations of PPARγ-LBD, GW1929, Fluorescein TRAP220 / DRIP-2peptide and Tb-anti-GSTAb were 5 nM, 10 nM, 125 nM and 5 nM, respectively. After incubation at room temperature for 2 h, the TR-FRET signal (Ratio: 520 / 495 nm) was read using BMG (PHERAstar FSX), and the IC was obtained using GraphPad Prism software. 50The results of each compound are shown in Table 1, where A represents <100 nM, B represents 100-1000 nM, and C represents >1000 nM.

[0171] Table 1

[0172]

[0173] Test Example 2: Liver microsome stability test

[0174] 1. Preparation of mother solution: Prepare the mother solution used in the experiment according to the table below.

[0175] Table 2

[0176]

[0177] 2. Add the stock solution to the culture plate. Diclofenac was used as a positive control in this study, and the final concentrations of the test substance and diclofenac were both 1 μM. Preheat the mixture at 37°C for 5 minutes.

[0178] 3. Add NADPH regeneration solution to start the reaction. The test sample without NADPH is used as a negative control. Incubate the incubation solution in a 37°C water bath.

[0179] 4. At 0, 5, 15, 30, and 60 min, add 200 μL of cold methanol and acetonitrile solution (methanol:acetonitrile=1:1) containing IS (50 ng / mL labetalol, 50 ng / mL tolbutamide) to stop the reaction. Centrifuge the sample at 4000 rpm for 10 min, take 60 μL of the supernatant and mix with 120 μL of H2O for LC-MS / MS analysis.

[0180] 5. Data analysis. All calculations were performed using Microsoft Excel, and peak areas were determined from the extracted ion chromatograms. The slope value k was determined by the natural logarithm linear regression of the remaining parent drug percentage versus the incubation time curve. The in vitro half-life (in vitro t 1 / 2 ), the in vitro t 1 / 2 The results were converted to in vitro intrinsic clearance according to the specified formula.

[0181] Table 3

[0182]

[0183] According to the data in Table 3, the liver microsome metabolic stability of the compound in Example 1 of this patent is significantly improved compared with the compound FX-909. The compound in Example 1 of this application has a long half-life and a low clearance rate in the mouse and human liver microsome stability tests. The data suggest that the compound in Example 1 of this application improves the metabolic stability of the drug compared with the compound FX-909, and may have pharmacokinetic advantages and improve drug administration compliance.

[0184] Test Example 3: HT1197 cell clone formation inhibition test

[0185] 1. Take HT1197 cells in the logarithmic growth phase, digest them with 0.25% trypsin and blow them into single cells, and suspend the cells in complete culture medium containing 10% fetal bovine serum for later use.

[0186] 2. Dilute the cell suspension to the required concentration, inoculate 5 mL / well into a 6-well plate containing 20-30% FBS medium, 5000 cells / plate. On the second day, add a certain working concentration of drugs to each well, and replicate each concentration three times. Shake the cells by cross-shaking method to disperse them evenly, and place them in a cell culture incubator at 37°C, 5% CO2 and saturated humidity for 2-3 weeks.

[0187] 3. Observe regularly. When visible clones appear in the culture dish, terminate the culture. Discard the supernatant and carefully rinse twice with PBS. Add 4% paraformaldehyde to fix the cells at room temperature for 15 minutes (or fix overnight at 4°C). Then slowly wash away the staining solution with running water and air dry.

[0188] 4. Count the colonies directly with the naked eye, or count the number of colonies with more than 50 cells under a microscope (low power). The test results are recorded in Table 4.

[0189] Table 4. Results of clone formation assay

[0190]

[0191] According to the results of the clone formation experiment, FX-909 and compound 1 had a significant dose-effect relationship in the HT1197 cell inhibitory activity in the clone formation experiment, and compound 1 had a better inhibitory effect at a higher dose.

Claims

1. A compound of formula (I): or a deuterated substance, a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof; in, Ring A is a benzene ring or a 5-10 membered heterocyclic group, preferably a benzene ring, a 5-7 membered monocyclic heteroaryl containing 1-3 N, O, S atoms, or a 9-10 membered bicyclic heterocyclic group containing 1-5 heteroatoms selected from N, O, and S atoms; X is The "*" end is connected to R1, and the "**" end is connected to ring A; R1 is R 1a or R 1b ; R 1a Select any 1-3 R a Substituted C 1-6 Alkyl, optionally substituted with 1-3 R a Substituted C 2-6 Alkenyl, optionally substituted with 1-3 R a Substituted C 2-6 Alkynyl, optionally substituted with 1-2 R a Substituted amino groups; The R a is selected from halogen, hydroxy, cyano, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy, optionally halogenated C 1-6 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2, optionally C 1-3 Alkyl or halogenated C 1-3 Alkyl-substituted amino, optionally substituted 4-8 membered heterocyclic group; R 1b Select any 1-3 R b substituted 3-9 membered cycloalkyl, optionally substituted with 1-3 R b Substituted 3-9 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S; The R b is selected from halogen, hydroxy, cyano, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy; R2 is selected from halogen, hydroxy, cyano, nitro, oxo, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy; r is 0, 1, 2, or 3; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, hydroxy, cyano, nitro, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2.

2. The compound according to claim 1, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: It has the structure shown in formula II: The ring A is selected from a benzene ring or a 5-7 membered monocyclic heteroaryl containing 1-3 N, O, S; The ring A and R2 form the following structure:

3. The compound according to claim 2, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: X is The "*" end is connected to R1, and the "**" end is connected to ring A; R1 is R 1a or R 1b ; R 1a Selected from 1-3 R a Substituted C 1-6 Alkyl, optionally substituted with 1-3 R a Substituted C 2-6 Alkenyl, optionally substituted with 1-3 R a Substituted C 2-6 Alkynyl, optionally substituted with 1-2 R a The amino group is preferably substituted with 1 to 3 R a Substituted C 1-3 Alkyl, optionally substituted with 1-3 R a Substituted C 2-4 Alkenyl, optionally substituted with 1-2 R a Substituted amino groups; The R a is selected from hydroxy, cyano, optionally halogenated C 1-6 Alkoxy, optionally halogenated C 1-6 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 alkyl) 2, an optionally substituted 4-8 membered heterocyclic group, more preferably a hydroxyl group, a cyano group, an optionally halogenated C 1-3 Alkoxy, optionally halogenated C 1-3 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 alkyl)2, optionally substituted 4-8 membered heterocyclic group; R 1b Select any 1-3 R b substituted 3-9 membered cycloalkyl, optionally substituted with 1-3 R b Substituted 3-9 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S; The R b is selected from halogen, hydroxy, cyano, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, hydroxy, cyano, nitro, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2.

4. The compound according to claim 3, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: R1 is R 1a or R 1b ; R 1a Selected from 1-3 R a Substituted methyl, ethyl, optionally substituted with 1-3 R a Substituted vinyl, optionally with 1-3 R a substituted ethynyl or optionally substituted with 1-2 R a Substituted amino groups; R a is selected from hydroxy, cyano, methoxy, difluoromethoxy, trifluoromethoxy, -S(=O)2-Me, -S(=O)(=NH)-Me, -N=S(=O)-Me2, dimethylamino, Furthermore, the R 1a Selected from R 1b Selected from The R b is selected from F, hydroxy, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy; Furthermore, the R 1b Selected from R3, R4, R5, R6, and R7 are each independently selected from H, F, hydroxy, cyano, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -S(=O)(=NH)-Me, and -N=S(=O)-Me2.

5. The compound according to claim 2, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: X is The "*" end is connected to R1, and the "**" end is connected to ring A.

6. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: Ring A is selected from a 9-10 membered bicyclic heterocyclic group containing 1-5 heteroatoms selected from N, O, and S; R2 is selected from halogen, hydroxy, oxo, optionally halogenated C 1-6 Alkyl, optionally halogenated C 1-6 Alkoxy.

7. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: Ring A is selected from More preferably, the ring A and R2 form the following structure:

8. The compound according to any one of claims 1, 2, 5, 6, and 7, or a deuterated substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof, characterized in that: R 1a Select any 1-3 R a Substituted C 1-3 Alkyl, optionally substituted with 1-3 R a Substituted C 2-4 Alkenyl, optionally substituted with 1-3 R a Substituted C 2-4 Alkynyl, optionally substituted with 1-2 R a Substituted amino group; R 1a Preferably, 1 to 3 R a substituted methyl, ethyl, vinyl or optionally substituted with 1-2 R a Substituted amino groups; The R a is selected from F, hydroxy, cyano, optionally halogenated C 1-3 Alkyl, optionally halogenated C 1-3 Alkoxy, optionally halogenated C 1-3 Alkylsulfonyl, aminosulfonyl, -S(=O)(=NH)C 1-3 Alkyl, -N=S(=O)(C 1-3 Alkyl)2, optionally C 1-3 Alkyl or halogenated C 1-3 Alkyl-substituted amino, optionally substituted 4-8 membered heterocyclic group; R a Preferred are F, hydroxy, cyano, methoxy, difluoromethoxy, trifluoromethoxy, -S(=O)2-Me, -S(=O)(=NH)-Me, -N=S(=O)-Me2, dimethylamino, Furthermore, the R 1a Selected from R 1b Select any 1-3 R b substituted 3-9 membered cycloalkyl, optionally substituted with 1-3 R b Substituted 3-9 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S, including The R b is selected from F, hydroxy, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy; Furthermore, the R 1b Selected from 9. The compound according to any one of claims 1, 2, 5, 6, and 7, or a deuterated substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof, characterized in that: R3, R4, R5, R6, and R7 are each independently selected from H, F, hydroxy, cyano, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -S(=O)(=NH)-Me, and -N=S(=O)-Me2.

10. The compound according to any one of claims 1, 2, 5, 6, and 7, or a deuterated substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof, characterized in that: R3 and R7 are H; R4 and R6 are F; R5 is selected from H, F, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -S(=O)(=NH)-Me, -N=S(=O)-Me2.

11. The compound according to claim 1, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: Includes the following compounds:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, its deuterated substance, stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier thereof.

13. Use of the compound according to any one of claims 1 to 11, its deuterated product, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating and / or preventing PPARG-related diseases.

14. The use according to claim 13, characterized in that: The drug for treating and / or preventing PPARG-related diseases is a single or combined immune checkpoint inhibitor; the combined immune checkpoint inhibitor includes PD-1 antibody or PD-L1 antibody.

15. The use according to claim 13, characterized in that: The PPARG-related disease refers to a disease caused by changes in PPARG activity or RXRA activity; the activity change includes mutation, amplification or overexpression; Preferably, the PPARG-related disease is selected from tumors, metabolic diseases, autoimmune diseases, and inflammatory diseases; Further preferably, the PPARG-related disease is selected from bladder cancer, urothelial carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, skin cancer, melanoma, colon cancer, renal cancer, brain cancer and blood cancer; Still more preferably, the PPARG-related cancer is selected from urothelial carcinoma.

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