Imidazopyridine derivative and use thereof

Abstract

Provided are a compound represented by the following formula (I), or a pharmaceutically acceptable salt, eutectic, stereoisomer, solvate, prodrug or metabolite thereof, and a use thereof for treating obesity or obesity complications.

Description

Imidazopyridine derivatives and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to an imidazopyridine derivative and uses thereof for treating or preventing obesity or obesity complications. BACKGROUND

[0002] The endocannabinoid system (ECS) is composed of cannabinoid receptors (CB1 and CB2), their ligands (Anandamide and 2-AG), and enzymes that regulate their synthesis and breakdown (monoacylglycerol lipase and fatty acid amide hydrolase). ECS plays an important role in regulating a variety of physiological functions, such as food intake, energy metabolism, emotional behavior, pain, cell division, and inflammation.

[0003] CB1 and CB2 are both members of the G protein-coupled receptor superfamily. CB1 receptors are widely expressed in central tissues such as cortex, hippocampus, tonsil, pituitary, and hypothalamus, and are also distributed in peripheral organs and tissues including thyroid, adrenal gland, reproductive organs, bone, fat, liver, muscle, pancreas, kidney, and gastrointestinal tract. CB1 receptors bind to cannabinoids and their derivatives, activate intracellular signals, and mediate the ECS to exert a wide range of biological functions, such as increasing appetite, promoting lipogenesis, inducing insulin resistance, and triggering dyslipidemia. Studies have shown that over-activated CB1 receptors are closely related to the development of visceral obesity, type 2 diabetes mellitus (T2DM), and its related complications. Therefore, inhibiting the over-activation of CB1 is considered a potential method for treating obesity, T2DM, and non-alcoholic fatty liver disease (NAFLD). Rimonabant, the first CB1 inhibitor for weight loss, was approved for marketing in the European Union in 2006. Later studies showed that rimonabant had a risk of increasing depression, anxiety, and suicide, and was withdrawn from the market worldwide in October 2008. The central side effects of rimonabant are caused by its ability to penetrate the blood-brain barrier and block CB1 receptors in the brain. Therefore, developing CB1 receptor antagonists with high peripheral selectivity will reduce or eliminate central nervous system side effects, providing safer and more effective medication options for patients with obesity, diabetes, dyslipidemia, cardiovascular disease, and other diseases. SUMMARY

[0004] The purpose of the present application is to provide a CB1 inhibitor, a pharmaceutical composition comprising the same, and uses thereof in treating or preventing obesity or obesity complications.

[0005] In one aspect, the present application relates to a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug, or metabolite thereof:

[0006] in,

[0007] Ring A and ring B each represent an aryl group or a five- or six-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and S, preferably selected from phenyl, naphthyl, thiophene, pyridyl, pyrimidinyl, pyrroleyl, imidazolyl, and thiazolyl.

[0008] The ring C represents a 5-7 membered monocyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, preferably selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, heptyl, homopiperazinyl, tetrahydrothiophenyl, tetrahydrothioranyl, morpholinyl, thiazolinyl and oxazolinyl;

[0009] X is O or NR 5 , where R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 Alkylamino C 1-3 Alkyl groups, preferably selected from C 1-6 alkyl;

[0010] R 1 -(CH2) q -(CR 1a R 1b )-Y, where q is 0, 1, 2 or 3, Y is a functional group selected from hydroxyl, amino, cyano and halogen, and R 1a and R 1b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 Alkylamino C 1-3 Alkyl; preferably, q is 1 or 2, Y is hydroxyl, R 1a and R 1b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0011] p is 1 or 2, R 2 Each is independently selected from aminoacyl, aminosulfonyl, alkylsulfinyl, carboxyl, C2-6 alkylcarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylaminocarbonyl, C 1-3 alkyl, preferably R 2 each independently selected from the group consisting of aminoacyl and C 1-6 alkyl;

[0012] m and n are each independently 0, 1, 2 or 3, each preferably 0 or 1;

[0013] R 3 and R 4 each independently selected from the group consisting of halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylaminocarbonyl, C 1-3 alkyl, more preferably independently selected from the group consisting of halogen and C 1-6 alkyl.

[0014] In a preferred embodiment, ring A and ring B are different and represent aryl and a five- or six-membered monocyclic heteroaryl containing one or two heteroatoms independently selected from N and S, respectively.

[0015] In another preferred embodiment, ring C represents a 5-7 membered monocyclic nitrogen heterocyclyl, preferably selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, and homopiperazinyl; further preferably, ring C is attached to the imidazopyridine moiety via a N atom.

[0016] In other preferred embodiments, p is 2 and R 2 are each different, wherein one R 2 is selected from the group consisting of aminoacyl, sulfamoyl, alkylsulfinyl, carboxyl, C 2-6 alkylcarbonyl, and C 1-6 alkylaminocarbonyl, and the other R 2 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C1-6 haloalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylamino C 1-3 alkyl; further preferably, R 2 are each independently selected from the group consisting of aminoacyl and C 1-6 alkyl, and both R 2 are attached to the same carbon atom of ring C.

[0017] Further preferably, the present application relates to a compound of formula (II), or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof

[0018] wherein,

[0019] ring A represents aryl or a five- or six-membered monocyclic heteroaryl containing one or two heteroatoms independently selected from N and S, preferably selected from the group consisting of phenyl, thienyl, pyridyl and thiazolyl, more preferably selected from the group consisting of phenyl, thien-2-yl, and pyrid-2-yl;

[0020] X is O or NR 5 wherein R 5 is selected from the group consisting of hydrogen and C 1-6 alkyl, preferably selected from the group consisting of C 1-3 alkyl, more preferably methyl;

[0021] R 1a and R 1b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, preferably selected from the group consisting of C 1-3 alkyl, more preferably methyl;

[0022] R 2a is selected from the group consisting of hydrogen and C 1-6 alkyl, preferably selected from the group consisting of C 1-3 alkyl, more preferably methyl;

[0023] m and n are each independently 0, 1, 2 or 3, each preferably 0 or 1;

[0024] R 3 and R 4 are each independently selected from the group consisting of halogen and C 1-6 alkyl, more preferably independently selected from the group consisting of fluorine, chlorine and C 1-3 alkyl, more preferably chlorine or methyl.

[0025] In a preferred aspect, m is 1 and R 3 is located in ortho position on the phenyl ring.

[0026] In preferred aspects, n is 1 and R 4 is meta or para on the A ring.

[0027] Preferably, the compound of formula (I) or (II) is selected from:

[0028] In another aspect, the present application also relates to a pharmaceutical composition comprising:

[0029] (1) a compound as described above, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof;

[0030] (2) optionally one or more other active ingredients; and

[0031] (3) a pharmaceutically acceptable carrier and / or excipient.

[0032] In yet another aspect, the present application also relates to the use of a compound as described above, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, for the manufacture of a medicament for the treatment or prevention of obesity or obesity comorbidities.

[0033] In preferred embodiments, the obesity comorbidities are selected from one or more of diabetes, dyslipidemia, metabolic syndrome, dementia, inflammatory disease, cardiovascular disease, liver disease, or cancer.

[0034] Further preferably, the diabetes is selected from one or more of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, or insulin resistance; the dyslipidemia is selected from one or more of poor lipid profile, low levels of high-density lipoprotein, high levels of low-density lipoprotein, or high levels of triglycerides; the inflammatory disease is selected from one or more of osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, or obesity-related inflammation; the cardiovascular disease is selected from one or more of atherosclerosis, hypertension, stroke, or heart attack; the liver disease is selected from one or more of liver inflammation, liver fibrosis, non-alcoholic steatohepatitis, fatty liver, liver enlargement, alcoholic liver disease, jaundice, cirrhosis, or hepatitis; and the cancer is selected from one or more of colon cancer, breast cancer, thyroid cancer, alveolar rhabdomyosarcoma, or hepatocellular carcinoma.

[0035] Additionally preferably, the obesity complication is selected from one or more of high blood pressure; gallbladder disease; gastrointestinal disease; menstrual irregularities; degenerative arthritis; venous stasis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arteriosclerotic disease; pseudotumor cerebri; accident proneness; increased risk of surgery; osteoarthritis; high cholesterol; or increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies.

[0036] In other aspects, the present application also relates to uses and methods of the compounds, or pharmaceutically acceptable salts, co-crystals, stereoisomers, solvates, prodrugs, or metabolites thereof, as described above, for the treatment or prevention of obesity or obesity complications. DETAILED DESCRIPTION

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0038] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be straight-chain or branched. Depending on the structure, alkyl can be a monovalent group or a divalent group (i.e., alkylene). In the present application, alkyl is preferably an alkyl group having 1-8 carbon atoms, more preferably a "lower alkyl" group having 1-6 carbon atoms, and even more preferably an alkyl group having 1-4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like. It is to be understood that "alkyl" as referred to herein includes all possible configurations and conformation of such alkyl groups that can exist, e.g., "propyl" as referred to herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl, and t-butyl, "pentyl" includes n-pentyl, isopentyl, neopentyl, t-pentyl, and pent-3-yl, and the like.

[0039] The term "alkoxy" refers to -O-alkyl, wherein alkyl is as defined herein. Typical alkoxyl groups include, but are not limited to, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, and the like.

[0040] The term "alkoxyalkyl" refers to an alkyl group as defined herein substituted with an alkoxy group as defined herein.

[0041] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having from 3 to 12 ring atoms. Depending on the structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylene). In the present application, cycloalkyl is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl" group having 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0042] The term "alkyl(cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl group as defined herein substituted with a cycloalkyl group as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0043] The term "aryl" as used herein refers to an aromatic group in which each of the constituent atoms of the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and indenyl. Depending on the structure, the aryl group can be a monovalent radical or a divalent radical (i.e., an arylene group).

[0044] The term "aryl" as used herein refers to an aromatic group in which each of the constituent atoms of the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and indenyl. Depending on the structure, the aryl group can be a monovalent radical or a divalent radical (i.e., an arylene group).

[0045] The term "aryloxy" refers to -O-aryl, wherein aryl is as defined herein.

[0046] The term "heteroaryl" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. N-containing "heteroaryl" moieties refer to aromatic groups in which at least one of the ring-forming atoms is a nitrogen atom. Depending on the structure, the heteroaryl group can be a monovalent radical or a divalent radical (i.e., a heteroarylene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, furopyridinyl, and the like.

[0047] The term "alkyl(aryl)" or "arylalkyl" refers to an alkyl group as defined herein substituted with an aryl group as defined herein. Non-limiting alkyl(aryl) groups include benzyl, phenethyl, and the like.

[0048] The term "alkyl(heteroaryl)" or "heteroarylalkyl" refers to an alkyl group as defined herein substituted with a heteroaryl group as defined herein.

[0049] The term "heteroalkyl," as used herein, means an alkyl radical, as defined herein, in which one or more of the skeletal chain atoms are heteroatoms, for example, oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom(s) can be located at any position of the heteroalkyl group, including the position wherein the heteroalkyl group is attached to the rest of the molecule.

[0050] The term "heterocycloalkyl" or "heterocyclyl," as used herein, means a non-aromatic ring in which one or more of the atoms constituting the ring is a heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be a monocyclic or a polycyclic ring composed of three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxine, 1,3-dioxane, 1,4-dioxine, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiine, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolin, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group can be a monovalent radical or a divalent radical (i.e., a heterocycloalkylene group).

[0051] The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0052] The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means an alkoxy group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0053] The term "halo" or "halogen" means fluorine, chlorine, bromine, and iodine.

[0054] The terms "haloalkyl," "haloalkoxy," and "haloheteroalkyl" include structures in which at least one hydrogen of an alkyl, alkoxy, or heteroalkyl group is replaced with a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are the same or different from each other.

[0055] The term "hydroxyl" means an -OH group.

[0056] The term "cyano" means a -CN group.

[0057] The term "ester" refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heterocycloalkyl (attached through a ring carbon).

[0058] The term "amino" refers to a -NH2 group.

[0059] The term "amino" refers to a -NH2 group.

[0060] The term "amino" refers to a -NH2 group.

[0061] The term "amido" or "carboxamido" refers to -NR-CO-R', wherein R and R' are each independently hydrogen or alkyl.

[0062] The term "alkylamino" refers to an amino substituent which is further substituted with one or two alkyl groups, specifically the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, with the proviso that -NRR' is not -NH2. "Alkylamino" includes groups wherein the nitrogen of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes groups wherein the nitrogen of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

[0063] The terms "arylaminos" and "diarylaminos" refer to amino substituents which are further substituted with one or two aryl groups, specifically the group -NRR', wherein R and R' are each independently selected from hydrogen, lower alkyl, or aryl, wherein N is attached to at least one or two aryl groups, respectively.

[0064] The term "cycloalkylamino" refers to an amino substituent which is further substituted with one or two cycloalkyl groups as defined herein.

[0065] The term "heteroalkylamino" refers to an amino substituent which is further substituted with one or two heteroalkyl groups as defined herein.

[0066] The term "heteroalkylamino" refers to an amino substituent which is further substituted with one or two heteroalkyl groups as defined herein.

[0067] The term "heteroalkylamino" refers to an amino substituent which is further substituted with one or two heteroalkyl groups as defined herein.

[0068] The term "heteroalkylamino" refers to an amino substituent which is further substituted with one or two heteroalkyl groups as defined herein.

[0069] The term "alkylaminoalkyl" means an alkyl group substituted with an alkylamino group, as defined herein.

[0070] The term "aminoalkyl" means an alkyl substituent further substituted with one or more amino groups.

[0071] The term "aminoalkoxy" means an alkoxy substituent further substituted with one or more amino groups.

[0072] The term "hydroxyalkyl" or "hydroxyalkyl" means an alkyl substituent further substituted with one or more hydroxy groups.

[0073] The term "cyanoalkyl" means an alkyl substituent further substituted with one or more cyano groups.

[0074] The term "acyl" means a monovalent radical of an organic or inorganic oxygen- acid from which a hydroxyl group has been removed, of the general formula R-M(O)-, where M is typically C.

[0075] The term "carbonyl" is an organic functional group (C=0) consisting of a carbon and oxygen atom connected by a double bond.

[0076] The term "alkanoyl" or "alkylcarbonyl" means a carbonyl group further substituted with one alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeroyl, hexanoyl, and the like.

[0077] The term "arylcarbonyl" means a carbonyl group as defined herein substituted with an aryl group as defined herein.

[0078] The term "alkoxycarbonyl" means a carbonyl group further substituted with one alkoxy group.

[0079] The term "heterocycloalkylcarbonyl" means a carbonyl group further substituted with one heterocycloalkyl group.

[0080] The terms "alkylaminocarbonyl", "cycloalkylaminocarbonyl", "arylaminocarbonyl", "aralkylaminocarbonyl", "heteroarylaminocarbonyl" mean a carbonyl group as defined herein substituted with an alkylamino, cycloalkylamino, arylamino, aralkylamino, or heteroarylamino group, respectively, as defined herein.

[0081] The term "alkylcarbonylalkyl" or "alkanoylalkyl" means an alkyl group further substituted with one alkylcarbonyl group.

[0082] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" means an alkoxy group further substituted with one alkylcarbonyl group.

[0083] The term "heterocycloalkylcarbonylalkyl" means an alkyl group further substituted with one heterocycloalkylcarbonyl group.

[0084] The term "mercapto" refers to the -SH group. The term "alkylthio" refers to a mercapto group as defined herein substituted with an alkyl group as defined herein.

[0085] The term "sulfone" or "sulfonyl" refers to the functional group that results from the loss of a hydroxyl group from a sulfonic acid, specifically -S(=O)2-.

[0086] The term "sulfoxide" or "sulfoxyl" refers to -S(=O)-.

[0087] The term "aminosulfonyl" refers to the -S(=O)2-NH2group.

[0088] The term "alkylsulfoxide" or "alkylsulfoxyl" refers to alkyl-S(=O)-.

[0089] The term "alkylsulfone" or "alkylsulfonyl" refers to -S(=O)2-R, wherein R is alkyl.

[0090] The term "alkylaminosulfonyl" refers to a sulfonyl group as defined herein substituted with an alkylamino group as defined herein.

[0091] The term "alkylsulfonamido" or "cycloalkylsulfonamido" refers to an amino group as defined herein substituted with an alkylsulfonyl group or a cycloalkylsulfonyl group as defined herein, i.e., -NH-S(=O)2-R, wherein R is alkyl and cycloalkyl, respectively.

[0092] The term "cycloalkylsulfone" and "cycloalkylsulfonyl" refers to -S(=O)2-R, wherein R is cycloalkyl.

[0093] The term "quaternary ammonium" refers to -N + RR' R", wherein R, R' and R" are each independently selected from alkyl groups having 1-8 carbon atoms.

[0094] The term "optionally" means that one or more of the events described thereafter can or can not occur and includes both the event occurring and the event not occurring. The terms "optionally substituted" or "substituted" mean that the referenced group can be substituted with one or more additional groups, each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, cyano, halo, amido, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminocarbonyl, an amino protecting group, and the like. Preferably, the amino protecting group is selected from pivaloyl, t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.

[0095] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, esters, acids, isomers, metabolites, prodrugs, and isotopically-labeled derivatives of the disclosed compounds.

[0096] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or free bases, and which is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0097] In another aspect, the term "pharmaceutically acceptable salt" herein refers to those salts which retain the desired biological activity of the subject compounds and exhibit minimal undesired toxicological effects, i.e., those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without excessive toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio, and include the salts herein. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid or base form with a suitable inorganic or organic acid or base, respectively. Pharmaceutically acceptable salts are detailed, e.g., in Berge et al. J. Pharmaceutical Sciences (1977) 66:1-19. The pharmaceutically acceptable salts of the compounds provided herein include those derived from the appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0098] "Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of the API and the CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are a kind of multi-component crystals, including binary co-crystals formed between two neutral solids, and multi-component co-crystals formed by neutral solids and salts or solvates.

[0099] "Stereoisomers" refer to isomers that have the same molecular formula but different structures due to having a different spatial arrangement of their atoms. This occurs naturally in some compounds having a carbon atom bonded to four different groups. Stereoisomers include enantiomeric pairs and diastereomeric pairs. Enantiomers are non-superimposable mirror images of each other. Diastereomers are non-conformational isomers that are not mirror images of each other.

[0100] "Solvate" or "solvates" refers to a solvent addition form of a compound. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in their crystal lattice. The solvent can be water, ethanol, or isopropanol, among others. If the solvent is water, the solvate is a hydrate. If the solvent is alcohol, the solvate is an alcoholate. Hydrates are formed by the combination of water molecules with molecules of the substance, in which the water retains its molecular state as H2O.

[0101] "Prodrugs" refer to compounds of the present application which, upon in vivo delivery, are metabolized by the patient into the compounds of the present application. Prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application in such a way that the modifications can be cleaved in any mammalian species in vivo to provide the parent compound. Upon administration of a prodrug of the present application to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups. Non-limiting examples of prodrugs include esters, carbonates, hemiesters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketals, among others.

[0102] A "metabolite" of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolized" as used herein refers to the sum of the processes by which a particular substance is changed by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, enzymes can produce a particular structural transformation of a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while glucuronyl transferases catalyze the conjugation of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free thiols. Further information on metabolism can be found in The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill (1996). Metabolites of compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatic cells in vitro and analyzing the resultant compounds. Both of these methods are known in the art. In some embodiments, a metabolite of a compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound. In some embodiments, a compound is metabolized to a pharmaceutically active metabolite.

[0103] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as carriers, excipients, and / or one or more other therapeutic or active agents.

[0104] A "carrier" refers to a material, not itself active, with which the compound is administered, such that it does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0105] An "excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose and its derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, and disintegrating agents.

[0106] An "effective amount" refers to an amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician. In addition, the term "therapeutically effective amount" refers to any amount which, when administered to a subject in need thereof, results in treatment, healing, prevention, or amelioration of a disease, disorder, or side-effect, or a decrease in the rate of advancement of a disease or disorder, or improvement in physiological function, compared with that subject who does not receive the amount. Also included within the scope of this term is an amount effective to enhance normal physiological function.

[0107] The term "treatment" as used herein refers to alleviating at least one symptom of a disease, disorder, or condition. The term includes administration and / or application of one or more compounds described herein to a subject to provide management or treatment of a condition. "Treatment" for purposes of the present disclosure can but need not provide cure; rather, "treatment" can be palliative in that it can provide management of a condition. When the compounds described herein are used to address unwanted proliferative cells, including cancer, "treatment" includes partial or complete destruction of the unwanted proliferative cells, but with minimal damage to normal cells. The desired mechanism of treatment of unwanted rapidly proliferating cells, including cancer cells, is apoptosis at the cellular level.

[0108] The term "prevention" as used herein includes co-prevention or slowing the onset of clinically significant disease or prevention or slowing the onset of pre-clinically significant disease stage in an at-risk individual. This includes prophylactic treatment of individuals at risk of developing a disease.

[0109] The term "subject" or "patient" includes an organism, such as a human or non-human animal, that can have a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or that can otherwise benefit from administration of a compound of the application. Preferred humans include human patients that have or are predisposed to a disorder or associated condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, e.g., non-human primates, sheep, cows, dogs, cats, and rodents such as mice, and non-mammals, such as chickens, amphibians, reptiles, etc.

[0110] GI 50 refers to the concentration of a drug required to inhibit the growth of 50% of cells, i.e., the concentration of a drug at which 50% of cells, such as cancer cells, have their growth inhibited or controlled.

[0111] IC 50 as used herein refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay that measures the effect.

[0112] EC 50 as used herein refers to the dose, concentration, or amount of a compound that elicits 50% of the maximal expression of a particular response that a particular compound induces, stimulates, or potentiates in a dose-dependent response.

[0113] Unless otherwise indicated, the present application employs conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques described in the specification are those known to one of ordinary skill in the art. In general, the techniques and procedures are carried out in accordance with the methods well known in the art and as described in various general and more specific references which are cited throughout this specification.

[0114] Active compound

[0115] The present disclosure relates to a CB1 inhibitor, in particular to a compound of formula (I), or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof:

[0116] wherein,

[0117] Ring A and Ring B each represent aryl or a five- or six-membered monocyclic heteroaryl containing one or two heteroatoms independently selected from N and S, preferably selected from the group consisting of phenyl, naphthyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl and thiazolyl;

[0118] Ring C represents a 5-7 membered monocyclic heterocyclyl containing one or two heteroatoms independently selected from N, O and S, preferably selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, azepanyl, homopiperazinyl, tetrahydrothienyl, tetrahydrothiopyranyl, morpholinyl, thiazolinyl, and oxazolinyl;

[0119] X is O or NR 5 wherein R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylamino C 1-3 alkyl, preferably selected from the group consisting of C 1-6 alkyl;

[0120] R 1 is -(CH2) q -(CR 1a R 1b )-Y, wherein q is 0, 1, 2 or 3, Y is a functional group selected from the group consisting of hydroxyl, amino, cyano and halogen, R1a and R 1b each independently is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylamino C 1-3 alkyl; preferably, q is 1 or 2, Y is hydroxy, R 1a and R 1b each independently is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0121] p is 1 or 2, R 2 each independently is selected from the group consisting of aminoacyl, sulfamoyl, alkylsulfinyl, carboxy, C 2-6 alkanoyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylamino C 1-3 alkyl, preferably R 2 each independently is selected from the group consisting of aminoacyl and C 1-6 alkyl;

[0122] m and n are each independently 0, 1, 2, or 3, each preferably 0 or 1;

[0123] R 3 and R 4 each independently is selected from the group consisting of halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylamino C 1-3 alkyl, more preferably independently selected from the group consisting of halogen and C 1-6 alkyl.

[0124] In preferred embodiments, ring A and ring B are different and represent aryl and a five- or six-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and S, respectively.

[0125] In another preferred embodiment, ring C represents a 5-7 membered monocyclic nitrogen heterocyclyl group, preferably selected from pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, and homopiperazinyl; further preferably, ring C is attached to the imidazopyridine moiety via a N atom.

[0126] In other preferred embodiments, p is 2, and R 2 are different from each other, one R 2 is selected from aminoacyl, sulfamoyl, alkylsulfinyl, carboxyl, C 2-6 alkanoyl, and C 1-6 alkylaminocarbonyl, the other R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylaminoC 1-3 alkyl; further preferably, R 2 are selected from aminoacyl and C 1-6 alkyl, respectively, and both R 2 are attached to the same carbon atom of ring C.

[0127] Further preferably, the present disclosure relates to a CB1 inhibitor, in particular to a compound of formula (II), or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof:

[0128] wherein,

[0129] ring A represents aryl or a five- or six-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and S, preferably selected from phenyl, thienyl, pyridyl and thiazolyl, more preferably selected from phenyl, thien-2-yl, and pyrid-2-yl;

[0130] X is O or NR 5 , wherein R 5 is selected from hydrogen and C 1-6 alkyl, preferably selected from C 1-3 alkyl, more preferably methyl;

[0131] R 1a and R 1beach independently selected from the group consisting of hydrogen and C 1-6 alkyl, preferably selected from the group consisting of C 1-3 alkyl, more preferably methyl;

[0132] R 2a selected from the group consisting of hydrogen and C 1-6 alkyl, preferably selected from the group consisting of C 1-3 alkyl, more preferably methyl;

[0133] each of m and n is independently 0, 1, 2, or 3, each preferably 0 or 1;

[0134] R 3 and R 4 each independently selected from the group consisting of halogen and C 1-6 alkyl, more preferably independently selected from the group consisting of fluorine, chlorine and C 1-3 alkyl, more preferably chlorine or methyl.

[0135] In a preferred aspect, m is 1 and R 3 is located in ortho position on the phenyl ring.

[0136] In a preferred aspect, n is 1 and R 4 is located in meta or para position on the A ring.

[0137] Preferably, the compound of formula (I) or (II) is selected from the group consisting of:

[0138] Also described herein are pharmaceutically acceptable salts, co-crystals, stereoisomers, solvates, prodrugs or metabolites of such compounds.

[0139] In particular, the compounds described herein can be made and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts formed with free bases by reaction of the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, 2-naphthalenesulfonic acid, t-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfic acid, gluconic acid, glutamic acid, salicylic acid, hydroxy-naphthoic acid, stearic acid, muconic acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion; or coordinates with an organic or inorganic base, acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0140] The corresponding counterion of a pharmaceutically acceptable salt can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectroscopy, or any combination thereof.

[0141] The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or, in the case of an aqueous solution, lyophilization.

[0142] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy methods, elemental analysis. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0143] Pharmaceutical uses

[0144] CB1 inhibitors of the present disclosure are useful for treating or preventing obesity or obesity comorbidities.

[0145] In preferred embodiments, the obesity complication is selected from one or more of diabetes, dyslipidemia, metabolic syndrome, dementia, inflammatory disease, cardiovascular disease, liver disease, or cancer.

[0146] Further preferably, the diabetes is selected from one or more of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, or insulin resistance; the dyslipidemia is selected from one or more of poor lipid profile, low levels of high-density lipoprotein, high levels of low-density lipoprotein, or high levels of triglycerides; the inflammatory disease is selected from one or more of osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, or obesity-related inflammation; the cardiovascular disease is selected from one or more of atherosclerosis, hypertension, stroke, or heart attack; the liver disease is selected from one or more of liver inflammation, liver fibrosis, nonalcoholic steatohepatitis, fatty liver, hepatomegaly, alcoholic liver disease, jaundice, cirrhosis, or hepatitis; and the cancer is selected from one or more of colon cancer, breast cancer, thyroid cancer, alveolar rhabdomyosarcoma, or hepatocellular carcinoma.

[0147] Additionally preferably, the obesity complication is selected from one or more of hypertension; gallbladder disease; gastrointestinal disease; menstrual irregularities; degenerative arthritis; venous stasis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arteriosclerotic disease; pseudotumor cerebri; accident proneness; increased risk of surgery; osteoarthritis; high cholesterol; or increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies.

[0148] In embodiments of the application, the medicament comprising a compound of the application can be administered to a patient by at least one of injection, orally, inhalation, rectally, and transdermally. The amount of a given medicament to be administered when treating a patient in accordance with the present application will depend on a number of factors, such as the particular dosing regimen, the type and severity of the disease or condition, the unique characteristics of the subject or host in need of treatment, such as weight, but, depending on the particular circumstances, including, for example, the specific medicament employed, the route of administration, the condition being treated, and the subject or host being treated, the dosages can routinely be adjusted by those skilled in the art. Typically, in terms of the dosages used in adult human therapy, the dosage employed will typically be in the range of 0.02-5000 mg / day, such as about 1-1500 mg / day. The desired dose can conveniently be presented in a dosage unit or a single administration, or in divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, such as two, three, or four doses per day or more. It will be appreciated by those skilled in the art that the actual

[0149] In some embodiments of the methods or uses disclosed herein, a compound, such as any of the compounds described herein, is administered to a subject at a dose (e.g., a therapeutically effective dose) of about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, or 0.1-50 mg. In some embodiments, the dose (e.g., a therapeutically effective dose) is about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, 0.1-50 mg, 0.1-75 mg, 0.5-75 mg, 1-75 mg, 0.1-100 mg, 0.5-100 mg, or 1-100 mg. In some embodiments, the dose is about 1-10 mg. In some embodiments, the dose is about 1-50 mg. In some embodiments, the dose is about 1-100 mg.

[0150] Pharmaceutical compositions

[0151] Another aspect of the present application relates to a pharmaceutical composition comprising (1) a compound as described above, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug, or metabolite thereof; (2) optionally one or more other active ingredients; and (3) a pharmaceutically acceptable carrier and / or excipient.

[0152] Preparation of compounds

[0153] The compounds of the present application can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. Additionally, the solvents, temperatures, and other reaction

[0154] The reactions can be carried out in sequential order to provide the compounds described herein; or they can be used to synthesize fragments which are subsequently incorporated by the methods described herein and / or methods known in the art.

[0155] The starting materials used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques known to those skilled in the art and starting materials. The general methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to incorporate the various moieties in the molecules provided herein.

[0156] If desired, the reaction products can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. The products can be characterized using conventional methods, including physical constants and spectral data.

[0157] Non-limiting examples of synthetic schemes for preparing compounds of the present application are described below.

[0158] Preparation Example 1. Compound Q1 was synthesized by the following synthetic route

[0159] Preparation Examples 2-14

[0160] Compounds Q2-Q8 were synthesized according to a similar method to that of compound Q1.

[0161] Example 1. In vitro CB1 activity detection experiment

[0162] The inhibitory effect of the compounds of the present application on CB1 receptor was analyzed by measuring the change of intracellular cAMP level using HTRF (homogeneous time-resolved fluorescence)-cAMP detection method. The CHO cells with high expression of hCB1 were cultured in DMEM medium containing 10% FBS. At the beginning of the test, the cells with a confluence rate of about 90% were selected, digested and resuspended in HBSS buffer (containing 20mM HEPES, pH=7.4) and inoculated in 384-well plates at 7.5x10 3 cells per well, and different concentrations of test compounds were added at the same time, and incubated at room temperature for 30 minutes. Then EC80 of CP55940 and Forskolin were added, and incubated at 37°C for 20 minutes. The cAMP content was detected using cAMP HTRF detection kit. The excitation light was 337nm, and the emission light was 620nm and 665nm. Finally, the IC 50 value was fitted using DoseResp function.

[0163] Example 2. High-fat diet induced pharmacodynamic test experiment in mice

[0164] 6-week-old C57BL / b male mice were purchased from Vantianlihua. After the mice were induced by high-fat diet for 12 weeks, they were grouped according to body weight. After grouping, the animals were given corresponding doses of compounds or vehicle by gavage every day. The body weight and food intake of the animals were measured every day.

[0165] Industrial applicability

[0166] The present application provides a CB1 inhibitor, which can be used for treating or preventing obesity or obesity complications. Thus, the present application is suitable for industrial application.

[0167] Although the present application has been described in detail, it should be understood that various modifications can be made to the application without departing from the spirit and scope thereof. Accordingly, all such modifications are intended to be included within the scope of the application as defined in the following claims.

Claims

1. A compound, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug, or metabolite thereof, wherein the compound has the structure of Formula (I): Formula (I). wherein each of Ring A and Ring B represents aryl or a five- or six-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and S; Ring C represents a 5-7 membered monocyclic heterocyclyl group containing one or two heteroatoms independently selected from N, O and S; X is O or NR 5 wherein R 5 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylaminoC 1-3 alkyl; R 1 is -(CH2) q -(CR 1a R 1b )-Y, wherein q is 0, 1, 2 or 3, Y is a functional group selected from the group consisting of hydroxy, amino, cyano and halogen, R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylamino C 1-3 alkyl; p is 1 or 2, R 2 each independently selected from aminoacyl, sulfamoyl, alkylsulfinyl, carboxy, C 2-6 alkanoyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylaminoC 1-3 alkyl; each of m and n is independently 0, 1, 2 or 3; R 3 and R 4 each independently is selected from the group consisting of halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylaminoC 1-3 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: each of said Ring A and said Ring B is independently selected from phenyl, naphthyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl and thiazolyl; and / or said Ring C is selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, azepanyl, homopiperazinyl, tetrahydrothienyl, tetrahydrothiopyranyl, morpholinyl, thiazolinyl, and oxazolinyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: q is 1 or 2, Y is hydroxy, R 1a and R 1b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 2 each independently selected from aminoacyl and C 1-6 alkyl; each of m and n is independently 0 or 1; R 3 and R 4 each independently is selected from the group consisting of halogen and C 1-6 alkyl; and / or R 5 selected from C 1-6 alkyl.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: each of said Ring A and said Ring B is different and represents aryl and a five- or six-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and S.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: said Ring C represents a 5-7 membered monocyclic nitrogen heterocyclyl group, preferably selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, and homopiperazinyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: said Ring C is attached to the imidazopyridine moiety through a N atom.

7. The compound of claim 3, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: p is 2 and R 2 each different, one R 2 is selected from aminoacyl, sulfamoyl, alkylsulfinyl, carboxy, C 2-6 alkanoyl, and C 1-6 alkylaminocarbonyl, the other R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, and C 1-4 alkylaminoC 1-3 alkyl 8. The compound of claim 7, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: R 2 are independently selected from the group consisting of aminoacyl and C 1-6 alkyl, and both R 2 are attached to the same carbon atom of ring C.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug, or metabolite thereof, wherein the compound has a structure according to Formula (II): wherein Ring A represents aryl or a five- or six-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and S; X is O or NR 5 wherein R 5 is selected from hydrogen and C 1-6 alkyl; R 1a and R 1b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 2a selected from hydrogen and C 1-6 alkyl; each of m and n is independently 0, 1, 2 or 3; R 3 and R 4 are each independently selected from the group consisting of halogen and C 1-6 alkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: said Ring A is selected from phenyl, thienyl, pyridyl and thiazolyl, more preferably from phenyl, thien-2-yl, and pyrid-2-yl; R 5 selected from C 1-3 alkyl, more preferably methyl; R 1a and R 1b each independently is selected from C 1-3 alkyl, more preferably methyl; R 2a selected from C 1-3 alkyl, more preferably methyl; each of m and n is 0 or 1; and / or R 3 and R 4 are each independently selected from the group consisting of fluorine, chlorine and C 1-3 alkyl, more preferably chlorine or methyl.

11. The compound of claim 9 or 10, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof, wherein: m is 1 and R is hydrogen; and R 3 on the phenyl ring in the ortho position; and / or n is 1 and R is hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, relative to the point of attachment to the imidazopyridine moiety 4 meta or para on the A ring.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug, or metabolite thereof, wherein, The compound is selected from:

13. A pharmaceutical composition comprising: (1) a compound of any one of claims 1-12, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug or metabolite thereof; and (2) a pharmaceutically acceptable carrier. (2) optionally one or more other active ingredients; and (3) a pharmaceutically acceptable carrier and / or excipient.

14. Use of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt, co-crystal, stereoisomer, solvate, prodrug, or metabolite thereof, in the manufacture of a medicament for the treatment or prevention of obesity or an obesity comorbidity.

15. The use of claim 14, wherein the obesity comorbidity is selected from one or more of diabetes, dyslipidemia, metabolic syndrome, dementia, an inflammatory disease, a cardiovascular disease, a liver disease, or a cancer.

16. The use of claim 15, wherein: the diabetes is selected from one or more of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, or insulin resistance; the dyslipidemia is selected from one or more of poor lipid levels, low levels of high-density lipoprotein, high levels of low-density lipoprotein, or high levels of triglycerides; the inflammatory disease is selected from one or more of osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, or obesity-related inflammation; the cardiovascular disease is selected from one or more of atherosclerosis, hypertension, stroke, or heart attack; the liver disease is selected from one or more of liver inflammation, liver fibrosis, nonalcoholic steatohepatitis, fatty liver, hepatomegaly, alcoholic liver disease, jaundice, cirrhosis, or hepatitis; and / or the cancer is selected from one or more of colon cancer, breast cancer, thyroid cancer, alveolar rhabdomyosarcoma, or hepatocellular carcinoma.

17. The use of claim 14 or 15, wherein: the obesity comorbidity is selected from one or more of hypertension; gallbladder disease; gastrointestinal disease; menstrual irregularities; degenerative arthritis; venous stasis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arteriosclerotic disease; pseudotumor cerebri; accident proneness; increased risk of surgery; osteoarthritis; high cholesterol; or increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies.

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