Formulation comprising glp-1r agonist and process for preparing the same

Abstract

A long-acting injection preparation and a preparation method therefor. The preparation contains an active compound such as the compound as shown in formula (I) or formula (II), or compound 6, or a stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof, and at least one pharmaceutically acceptable carrier.

Description

Preparation of GLP-1R agonist and preparation method thereof

[0001] Citation of Related Applications

[0002] This disclosure claims the rights of Chinese invention patent application No. 202410644340.1, filed with the State Intellectual Property Office of the People's Republic of China on May 22, 2024, entitled “A Formulation of a GLP-1R Agonist and a Method for Preparing the Same,” Chinese invention patent application No. 202410544932.6, filed with the State Intellectual Property Office of the People's Republic of China on May 1, 2024, entitled “A Formulation of a GLP-1R Agonist and a Method for Preparing the Same,” Chinese invention patent application No. 202310856937.8, filed with the State Intellectual Property Office of the People's Republic of China on July 12, 2023, entitled “A Formulation of a GLP-1R Agonist and a Method for Preparing the Same,” and U.S. Patent and Trademark Office No. 63 / 531,417, filed with the U.S. Patent and Trademark Office on August 8, 2023, entitled “Formulation Comprising of GLP-1R Agonist and Use thereof.” The entire disclosure is hereby incorporated by reference into this disclosure.

[0003] field

[0004] The present disclosure relates generally to the field of medicine, and more particularly to a long-acting formulation of a long-acting GLP-1R agonist, a method for preparing the same, and uses thereof.

[0005] background

[0006] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enteroendocrine cells in the intestine in response to a meal. GLP-1 is thought to play a role in the regulation of postprandial blood glucose, both by directly increasing meal-induced insulin secretion from pancreatic beta cells and by promoting satiety by delaying the transit of food through the intestine. GLP-1 mediates intracellular signaling through the GLP-1 receptor (GLP-1R), which belongs to a family of G protein-coupled receptors present on cell membranes and, upon activation, leads to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP). Non-alcoholic steatohepatitis (NASH) can be associated with features of the metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease.

[0007] GLP-1R agonists are currently being extensively studied for conditions associated with diabetes, obesity, and NASH. GLP-1R agonists include peptides such as exenatide, liraglutide, and dulaglutide, which are approved for the treatment of type 2 diabetes. These peptides are primarily administered by subcutaneous injection. Oral GLP-1 agonists are also being studied for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, dulaglutide, and exenatide, are resistant to rapid degradation by dipeptidyl peptidase 4, resulting in a longer half-life than endogenous GLP-1.

[0008] There remains a need for compounds with desirable therapeutic properties, metabolic properties, and / or ease of administration for the treatment of GLP-1R mediated diseases and conditions.

[0009] The present invention relates to a long-acting GLP-1R agonist composition and therapeutic drug delivery to reduce the treatment schedule from daily to weekly or monthly, or even less frequent dosing, provide greater patient privacy and satisfaction, and improve treatment regimen compliance.

[0010] Compared with oral preparations, long-acting injections have the characteristics of stable blood drug concentration, effective drug effect lasting for weeks or even months, and reduced dosing frequency. The targeted development of such preparations will not only bring convenience to patients' treatment, but also bring huge social effects.

[0011] Overview

[0012] The long-acting injection preparation provided in the present application has the characteristics of stable blood drug concentration, effective drug action time of up to several weeks or even months, and reduced drug administration frequency.

[0013] The present application provides a long-acting injection preparation, which comprises an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof:

[0014] in

[0015] X is selected from -N= or -CR a ; R a Selected from hydrogen atoms, halogen or C 1-6 alkyl;

[0016] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 , Z 11 , Z 12 , Z 13 Selected from -N= or -C=;

[0017] Q1 is selected from C 6-10Aryl or 5- to 10-membered heteroaryl, wherein C 6-10 Aryl or 5 to 10 membered heteroaryl is optionally substituted by one to five independently selected halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Substitution of alkoxy groups;

[0018] Q2 is selected from 3 to 12-membered heterocyclic groups or 5 to 10-membered heteroaryl groups, wherein the 3 to 12-membered heterocyclic groups and the 5 to 10-membered heteroaryl groups are optionally substituted by 1 to 3 independently selected halogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6-alkoxy and -NR Qa R Qb The substituents are substituted, and the two C 1-6 The alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbon ring; and R Qa and R Qb are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and (C 1- 6-alkyl)carbonyl;

[0019] R1, R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected halogen atoms, C 1-6 Substitution of alkoxy and hydroxy groups;

[0020] R4, R5 and R6 are each independently selected from hydrogen, halogen and C 1-6 alkyl;

[0021] R7 and R8 are independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 3-15 The substituent of the cycloalkyl group is substituted, or R7 and R8 together with the carbon atom to which they are attached form a C 3-15 Carbocyclic ring; wherein R7 and R8 together form a C 3-15 The carbocyclic ring is optionally substituted by one to three C 1-6 Alkyl substituted, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR 7a R 7b , C 1-6 substituted with an alkoxy group and a 3- to 12-membered heterocyclic group, and R 7a and R 7b are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6alkyl)carbonyl;

[0022] n1 is 0, 1, 2, or 3;

[0023] n2 is 0, 1, 2, 3, 4, or 5;

[0024] R9 is selected from the following groups:

[0025] -CO2R 9f and -C(=O)-NR 9g R 9h ; and R 9a , R 9b , R 9c , R 9d and R 9g are each independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 1-6 Alkoxy substituents substituted; R 9e is hydrogen or C optionally substituted by one or more halogen atoms 1-6 Alkyl; R 9f is hydrogen or C 1-6 Alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 alkyl)carbonyl, cyano or -S(=O) n3 -R 9i ; n3 is 0, 1 or 2; R 9i It is C 1-6 alkyl;

[0026] Z1 is selected from the following groups:

[0027] where R za Selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, R zb and R zc Independent hydrogen or C 1-6 alkyl;

[0028] n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10;

[0029] Z2 is selected from C 1-6 Alkyl, C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10Aryl and 5- to 10-membered heteroaryl are independently optionally substituted with one to five Gs; G is selected from the following groups:

[0030] a. Oxo;

[0031] b. Halogen;

[0032] c. cyano;

[0033] d.-NR zd R ze , where R zd and R ze are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0034] e.-C(=O)-NR zf R zg , where R zf and R zg are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0035] f.-S(=O) n7 -R zh , where n7 is 0, 1 or 2; R zh is hydrogen or C 1-6 alkyl;

[0036] C 1-6 Alkyl, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR zi R zj 、C 1-6 substituted with an alkoxy group and a 3 to 12-membered heterocyclic group; wherein R zi and R zj are each independently selected from hydrogen or C 1-6 alkyl, and the 3 to 12 membered heterocyclic group is optionally substituted by one or more cyano groups, C 1-6 Alkyl and 3- to 12-membered heterocyclic substituents;

[0037] hC 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl groups, halogen groups and C 1-6 Substitution of alkoxy groups;

[0038] i. 3 to 12 membered heterocyclic group, wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 alkyl)carbonyl substituted with a substituent;

[0039] JC 6-10 Aryl, where C 6-10 Aryl is optionally substituted with one or more (C 1-6 alkyl)carbonyl substituted, and

[0040] k. 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted by one or more independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl and substituted with a 3- to 12-membered heterocyclic group; wherein R zk and R zl are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, and wherein the 3 to 12 membered heterocyclic group is optionally replaced by one or more independently selected C 1-6 Alkyl and (C 1-6 The substituent of the (alkyl)carbonyl group is substituted.

[0041] The present application provides a long-acting injection, which comprises an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (II) and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds and at least one pharmaceutically acceptable carrier:

[0042] in

[0043] X is selected from -N= or -CR a ; R a Selected from hydrogen atoms, halogen or C 1-6 alkyl;

[0044] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 , Z 11 , Z 12 , Z 13 Selected from -N= or -C=;

[0045] Z 14 Selected from N or C

[0046] Q1 is selected from C 6-10 Aryl or 5- to 10-membered heteroaryl, wherein C 6-10 Aryl or 5 to 10 membered heteroaryl is optionally substituted by one to five independently selected halogen, C1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Substitution of alkoxy groups;

[0047] Q2 is selected from 3 to 12-membered heterocyclic groups or 5 to 10-membered heteroaryl groups, wherein the 3 to 12-membered heterocyclic groups and the 5 to 10-membered heteroaryl groups are optionally substituted by 1 to 3 independently selected halogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy and -NR Qa R Qb The substituents are substituted, and the two C 1-6 The alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbon ring; and R Qa and R Qb are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and (C 1- 6-alkyl)carbonyl;

[0048] R1, R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected halogen atoms, C 1-6 Substitution of alkoxy and hydroxy groups;

[0049] R4, R5 and R6 are each independently selected from hydrogen, halogen and C 1-6 alkyl;

[0050] R7 and R8 are independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 3-15 The substituent of the cycloalkyl group is substituted, or R7 and R8 together with the carbon atom to which they are attached form a C 3-15 Carbocyclic ring; wherein R7 and R8 together form a C 3-15 The carbocyclic ring is optionally substituted by one to three C 1-6 Alkyl substituted, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR 7a R 7b , C 1-6 substituted with an alkoxy group and a 3- to 12-membered heterocyclic group, and R 7a and R 7b are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0051] n1 is 0, 1, 2, or 3;

[0052] n2 is 0, 1, 2, 3, 4, or 5;

[0053] R9 is selected from the following groups:

[0054] -CO2R 9f and -C(=O)-NR 9g R 9h ; and R 9a , R 9b , R 9c , R 9d and R 9g are each independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 1-6 Alkoxy substituents substituted; R 9e is hydrogen or C optionally substituted by one or more halogen atoms 1-6 Alkyl; R 9f is hydrogen or C 1-6 Alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 alkyl)carbonyl, cyano or -S(=O) n3 -R 9i ; n3 is 0, 1 or 2; R 9i It is C 1-6 alkyl;

[0055] Z1 is selected from the following groups:

[0056] where R za Selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, R zb and R zc Independent hydrogen or C 1-6 alkyl;

[0057] n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10;

[0058] Z2 is selected from C 1-6 Alkyl, C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently optionally substituted with one to five Gs; G is selected from the following groups:

[0059] a. Oxo;

[0060] b. Halogen;

[0061] c. cyano;

[0062] d.-NR zd R ze , where R zd and R ze are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0063] e.-C(=O)-NR zf R zg , where R zf and R zg are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0064] f.-S(=O) n7 -R zh , where n7 is 0, 1 or 2; R zh is hydrogen or C 1-6 alkyl;

[0065] C 1-6 Alkyl, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR zi R zj 、C 1-6 substituted with an alkoxy group and a 3 to 12-membered heterocyclic group; wherein R zi and R zj are each independently selected from hydrogen or C 1-6 alkyl, and the 3 to 12 membered heterocyclic group is optionally substituted by one or more cyano groups, C 1-6 Alkyl and 3- to 12-membered heterocyclic substituents;

[0066] hC 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl groups, halogen groups and C 1-6 Substitution of alkoxy groups;

[0067] i. 3 to 12 membered heterocyclic group, wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 alkyl)carbonyl substituted with a substituent;

[0068] JC 6-10 Aryl, where C 6-10 Aryl is optionally substituted by one or more (C 1-6 alkyl)carbonyl substituted, and

[0069] k. 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted by one or more independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl and substituted with a 3- to 12-membered heterocyclic group; wherein R zk and R zl are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, and wherein the 3 to 12 membered heterocyclic group is optionally replaced by one or more independently selected C 1-6 Alkyl and (C 1-6 The substituent of the (alkyl)carbonyl group is substituted.

[0070] l.-P(O)R g1 R g2 , where R g1 or R g2 Independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl.

[0071] The present application provides a long-acting injection preparation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound 6 or its stereoisomer, pharmaceutically acceptable salt or deuterated compound and at least one pharmaceutically acceptable carrier:

[0072] Preferably, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, calcium salt and magnesium salt.

[0073] Another aspect of the present invention provides a method for treating a GLP-1-mediated disease or symptom, comprising administering a therapeutically effective amount of the formulation disclosed herein to an individual in need thereof;

[0074] I. Detailed Description

[0075] In the following description, certain specific details are included to provide a thorough understanding of the various disclosed embodiments. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0076] Unless otherwise required by this disclosure, throughout this specification and the claims that follow, the words "include" and "comprising" should be construed in an open, inclusive sense, ie, "including, but not limited to."

[0077] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0078] Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that the specific referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0079] It should be understood that the singular articles "a," "an," and "the" used in the specification and appended claims of this disclosure include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a sustained-release tablet containing "a pharmaceutically acceptable excipient" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0080] II. Definition

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the beginning or end of a chemical group is used for convenience to indicate the point of attachment to the parent molecule; a chemical group may be described with or without one or more dashes without losing its ordinary meaning. A prefix such as "C u-v ″ or ″C u -C v " means that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" means that the alkyl group has 1 to 6 carbon atoms.

[0082] "Alkyl" is a monovalent or divalent linear or branched saturated hydrocarbon radical. For example, an alkyl group may have 1 to 10 carbon atoms (i.e., C 1-10Alkyl) or 1 to 8 carbon atoms (ie C 1-8 Alkyl) or 1 to 6 carbon atoms (ie C 1-6 Alkyl) or 1 to 4 carbon atoms (ie C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH3), 2-propyl (i-Pr, i-Propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH3), 3-pentyl (-CH(CH2CH3) )2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2C H3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2). 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3). The alkyl group may be unsubstituted or substituted.

[0083] "Alkenyl" is a monovalent or divalent linear or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0084] "Alkynyl" is a monovalent or divalent linear or branched hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkynyl groups can be unsubstituted or substituted.

[0085] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, making the alkyl group divalent. For example, C2-6 alkoxyalkyl includes -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. Alkoxyalkyl groups can be unsubstituted or substituted.

[0086] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).

[0087] "Haloalkyl" is an alkyl group as defined herein wherein one or more hydrogen atoms of the alkyl group are independently replaced by a halogen, which may be the same or different, such that the alkyl group is divalent. The alkyl group and the halogen group may be any of those described above. In some embodiments, the haloalkyl group specifies the number of carbon atoms in the alkyl portion, for example, C 1-4 Haloalkyl groups include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups may be unsubstituted or substituted.

[0088] "Aryl" refers to a monovalent or divalent single all-carbon aromatic ring or a polycondensed all-carbon ring system, wherein the rings are aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl group. Aryl also includes multiple condensed ring systems (e.g., ring systems composed of 2, 3, or 4 rings) having about 9 to 20 carbon atoms, wherein multiple rings are aromatic. Where valence requirements permit, the rings of multiple condensed ring systems may be interconnected by fusion bonds. It is also understood that when referring to a range of atoms in an aryl group (e.g., a 6-10 member aryl group), the range of atoms refers to the total number of ring atoms in the aryl group. For example, a 6-member aryl group includes phenyl, and a 10-member aryl group includes naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Aryl groups can be unsubstituted or substituted.

[0089] "5-10 membered aromatic heterocycle" or "heteroaryl ring" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, as long as the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems consisting of 2, 3, or 4 rings) in which a heteroaryl as defined above is condensed with one or more rings selected from heteroaryl (forming, for example, 1,8-naphthyridinyl) and aryl (forming, for example, benzimidazolyl or indazolyl) to form multiple condensed ring systems. Thus, a heteroaryl group (single aromatic ring or multiple condensed ring systems) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring. Where valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fusion bonds. It should be understood that the individual rings of multiple condensed ring systems can be interconnected in any order. It should be understood that the point of attachment of a heteroaryl or heteroaryl multiple condensed ring system can be any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when a heteroaryl group is referred to as having a range of atoms (e.g., a 5 to 10 member heteroaryl group), that range is for the total ring atoms of the heteroaryl group, including carbon atoms and heteroatoms. It is also understood that the rings of the multiple condensed ring systems may include an aryl ring fused to a heterocyclic ring having saturated or partially unsaturated bonds (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxazolyl, quinazolyl, benzofuranyl, benzimidazolyl, thiophenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group can be unsubstituted or substituted.

[0090] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or multiple condensed all-carbon ring systems, wherein the ring in each instance is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyls also include multiple condensed ring systems (e.g., ring systems comprising 2 rings) having about 7 to 12 carbon atoms. Where valence requirements permit, the rings of multiple condensed ring systems can be interconnected by fusion bonds, spiral bonds, or bridge bonds. Exemplary polycyclic cycloalkyls include octahydropentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2ene, and spiro[2.5]octane.Cycloalkyl groups can be unsubstituted or substituted.

[0091] As used herein, "heterocycle" or "heterocyclic ring" or "heterocyclyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom in the ring (i.e., at least one cyclic (i.e., annular) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has 3 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 4 to 12 ring atoms, 4 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms, wherein the heteroatoms in the rings are selected from the group consisting of oxygen, nitrogen, and sulfur. Where valence requirements permit, the rings of multiple condensed ring systems (e.g., bicyclic heterocycles) may be interconnected by fusion bonds, spiral bonds, and bridge bonds. Heterocycles include, but are not limited to, nitrogen heterocycles, aziridines, imidazolidines, morpholine, oxirane, oxygen heterocycles, sulfur heterocycles, piperazine, and piperidine. Pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxo-6-azaspiro[3.3]heptane-6-yl, 6-oxa-1-azaspiro[3.3]heptane-1-yl, 2-thia-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.0]hexan-2-yl, 2-azabicyclo[2.1.1]hexan-2-yl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptan-6-yl, 5-azaspiro[2.4]heptan-6-yl, and the like. The heterocyclyl group can be unsubstituted or substituted.

[0092] As used herein, "substituted" refers to a group wherein one or more hydrogen atoms of the group are independently replaced with one or more substituents (eg, 1, 2, 3, or 4 or more), as indicated.

[0093] "Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of formula (I), including the compounds of the Examples. In some embodiments, "compounds of the present disclosure" include compounds of formula (I).

[0094] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or veterinary animals.

[0095] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including an amount of a compound that, when administered to a subject being treated for a disease, is sufficient to affect the treatment of the disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, and other factors of the subject being treated. An effective amount may include a range of amounts. As is understood in the art, an effective amount may be one or more doses, i.e., one dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, when used in conjunction with one or more other agents, a desired or beneficial result may or has been achieved. The appropriate dosage of any co-administered compound may be selectively reduced due to the combined action of the compounds (e.g., additive or synergistic).

[0096] As used herein, "co-administration" refers to administering a unit dose of a compound of the present disclosure before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound of the present disclosure within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents a few hours later (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure a few hours later (e.g., 1-12 hours). Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the body of the subject.

[0097] Also provided are pharmaceutically acceptable salts, hydrates, solubilized forms, isomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0098] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0099] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound that possess the pharmacological activity required of the free base. These salts can be extracted from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared into pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, disulfates, sulfites, disulfates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, and pyrophosphates. Chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propanolates, oxalates, malonates, ferrites, sebacates, and fumarates.

[0065] Pharmaceutically acceptable salts include maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propanesulfonates. Benzenesulfonates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0100] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from appropriate bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1-C4 alkyl) salts. 4+ Also included are base addition salts such as sodium, potassium or calcium salts.

[0101] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and, therefore, may be used to increase the half-life of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, when administered to a mammal. See "Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984)". Such compounds are synthesized by methods well known in the art, for example, using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0102] Examples of isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Using positron-emitting isotopes, such as 11 C. 18 F. 15 O and 13 N substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (IA-1) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0103] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, for amino acids, as (D)- or (L)-. This statement is meant to include all such possible isomers, as well as their racemates and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L)-isomers can be prepared using chiral syntheses or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolving racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all isomeric forms are also included. When a compound is indicated in its chiral form, it is understood that the embodiment includes, but is not limited to, the specific diastereomer or enantiomerically enriched form. If chirality is not specified but is present, it is understood that the embodiment is directed to the specific diastereomer or enantiomerically enriched form; or a racemic or scalar mixture of such a compound. As used herein, "scalar mixture" refers to a mixture of stereoisomers in a ratio other than 1:1.

[0104] As used herein, "stereoisomers" refer to compounds that are bound by the same atoms but have different three-dimensional structures and are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0105] As used herein, "tautomer" refers to a proton transfer from one atom of one molecule to another atom of the same molecule. In some embodiments, the present disclosure includes tautomers of the compounds.

[0106] As used herein, "solvate" refers to the result of the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0107] As used herein, "hydrate" refers to a compound of the present invention chemically bound to one or more water molecules.

[0108] "Prevention" or "prevention" refers to any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compound can be administered to a subject (including a human) at risk for or with a family history of the disease or condition.

[0109] As used herein, "prodrug" refers to a derivative of a drug that is converted to the parent drug according to some chemical or enzymatic pathway after administration to the human body. In some embodiments, a prodrug is a biologically active derivative of a drug that is converted to the biologically active parent drug according to some chemical or enzymatic pathway after administration to the human body.

[0110] As used herein, "treat" or "treatment" or "treatment" refers to an approach to obtaining beneficial or desired results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the extent of symptoms and / or preventing worsening of symptoms associated with a disease or condition. In one embodiment, "treat" or "treatment" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the disease state, delaying disease progression, improving quality of life, and / or prolonging survival. As used herein, an "at-risk individual" refers to an individual who is at risk of developing a disease for which treatment is desired. An individual who is "at risk" may or may not have a detectable disease or condition and may or may not have exhibited detectable disease prior to the treatment methods described herein. "At risk" means that the individual has one or more so-called risk factors, which are measurable parameters that are associated with the development of a disease or condition and are known in the art to increase the probability of individuals with one or more of these risk factors developing the disease or condition compared to individuals without these risk factors.

[0111] III. Preparations

[0112] The present application provides a long-acting injection preparation, which comprises an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof:

[0113] in

[0114] X is selected from -N= or -CR a ; R a Selected from hydrogen atoms, halogen or C 1-6 alkyl;

[0115] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 , Z 11 , Z 12 , Z 13 Selected from -N= or -C=;

[0116] Q1 is selected from C 6-10 Aryl or 5- to 10-membered heteroaryl, wherein C 6-10 Aryl or 5 to 10 membered heteroaryl is optionally substituted by one to five independently selected halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Substitution of alkoxy groups;

[0117] Q2 is selected from 3 to 12-membered heterocyclic groups or 5 to 10-membered heteroaryl groups, wherein the 3 to 12-membered heterocyclic groups and the 5 to 10-membered heteroaryl groups are optionally substituted by 1 to 3 independently selected halogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy and -NR Qa R Qb The substituents are substituted, and the two C 1-6 The alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbon ring; and R Qa and R Qb are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and (C 1- 6-alkyl)carbonyl;

[0118] R1, R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected halogen atoms, C 1-6 Substitution of alkoxy and hydroxy groups;

[0119] R4, R5 and R6 are each independently selected from hydrogen, halogen and C 1-6 alkyl;

[0120] R7 and R8 are independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 3-15 The substituent of the cycloalkyl group is substituted, or R7 and R8 together with the carbon atom to which they are attached form a C 3-15 Carbocyclic ring; wherein R7 and R8 together form a C 3-15 The carbocyclic ring is optionally substituted by one to three C 1-6 Alkyl substituted, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR 7a R 7b , C 1-6 substituted with an alkoxy group and a 3- to 12-membered heterocyclic group, and R 7a and R 7b are independently selected from hydrogen, C1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0121] n1 is 0, 1, 2, or 3;

[0122] n2 is 0, 1, 2, 3, 4, or 5;

[0123] R9 is selected from the following groups:

[0124] -CO2R 9f and -C(=O)-NR 9g R 9h ; and R 9a , R 9b , R 9c , R 9d and R 9g are each independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 1-6 Alkoxy substituents substituted; R 9e is hydrogen or C optionally substituted by one or more halogen atoms 1-6 Alkyl; R 9f is hydrogen or C 1-6 Alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 alkyl)carbonyl, cyano or -S(=O) n3 -R 9i ; n3 is 0, 1 or 2; R 9i It is C 1-6 alkyl;

[0125] Z1 is selected from the following groups:

[0126] where R za Selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, R zb and R zc Independent hydrogen or C 1-6 alkyl;

[0127] n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10;

[0128] Z2 is selected from C 1-6 Alkyl, C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein C 3-15Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently optionally substituted with one to five Gs; G is selected from the following groups:

[0129] a. Oxo;

[0130] b. Halogen;

[0131] c. cyano;

[0132] d.-NR zd R ze , where R zd and R ze are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0133] e.-C(=O)-NR zf R zg , where R zf and R zg are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0134] f.-S(=O) n7 -R zh , where n7 is 0, 1 or 2; R zh is hydrogen or C 1-6 alkyl;

[0135] C 1-6 Alkyl, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR zi R zj 、C 1-6 substituted with an alkoxy group and a 3 to 12-membered heterocyclic group; wherein R zi and R zj are each independently selected from hydrogen or C 1-6 alkyl, and the 3 to 12 membered heterocyclic group is optionally substituted by one or more cyano groups, C 1-6 Alkyl and 3- to 12-membered heterocyclic substituents;

[0136] hC 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl groups, halogen groups and C1-6 Substitution of alkoxy groups;

[0137] i. 3 to 12 membered heterocyclic group, wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 alkyl)carbonyl substituted with a substituent;

[0138] JC 6-10 Aryl, where C 6-10 Aryl is optionally substituted by one or more (C 1-6 alkyl)carbonyl substituted, and

[0139] k. 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted by one or more independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl and substituted with a 3- to 12-membered heterocyclic group; wherein R zk and R zl are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, and wherein the 3 to 12 membered heterocyclic group is optionally replaced by one or more independently selected C 1-6 Alkyl and (C 1-6 The substituent of the (alkyl)carbonyl group is substituted.

[0140] On the other hand, the present invention provides a long-acting injection preparation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (II) and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds and at least one pharmaceutically acceptable carrier:

[0141] in

[0142] X is selected from -N= or -CR a ; R a Selected from hydrogen atoms, halogen or C 1-6 alkyl;

[0143] Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 , Z 11 , Z 12 , Z 13 Selected from -N= or -C=;

[0144] Z 14 Selected from N or C

[0145] Q1 is selected from C 6-10 Aryl or 5- to 10-membered heteroaryl, wherein C 6-10Aryl or 5 to 10 membered heteroaryl is optionally substituted by one to five independently selected halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Substitution of alkoxy groups;

[0146] Q2 is selected from 3 to 12-membered heterocyclic groups or 5 to 10-membered heteroaryl groups, wherein the 3 to 12-membered heterocyclic groups and the 5 to 10-membered heteroaryl groups are optionally substituted by 1 to 3 independently selected halogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy and -NR Qa R Qb The substituents are substituted, and the two C 1-6 The alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbon ring; and R Qa and R Qb are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and (C 1- 6-alkyl)carbonyl;

[0147] R1, R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected halogen atoms, C 1-6 Substitution of alkoxy and hydroxy groups;

[0148] R4, R5 and R6 are each independently selected from hydrogen, halogen and C 1-6 alkyl;

[0149] R7 and R8 are independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 3-15 The substituent of the cycloalkyl group is substituted, or R7 and R8 together with the carbon atom to which they are attached form a C 3-15 Carbocyclic ring; wherein R7 and R8 together form a C 3-15 The carbocyclic ring is optionally substituted by one to three C 1-6 Alkyl substituted, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR 7a R 7b , C 1-6 substituted with an alkoxy group and a 3- to 12-membered heterocyclic group, and R 7a and R 7b are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0150] n1 is 0, 1, 2, or 3;

[0151] n2 is 0, 1, 2, 3, 4, or 5;

[0152] R9 is selected from the following groups:

[0153] -CO2R 9f and -C(=O)-NR 9g R 9h ; and R 9a , R 9b , R 9c , R 9d and R 9g are each independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 1-6 Alkoxy substituents substituted; R 9e is hydrogen or C optionally substituted by one or more halogen atoms 1-6 Alkyl; R 9f is hydrogen or C 1-6 Alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 alkyl)carbonyl, cyano or -S(=O) n3 -R 9i ; n3 is 0, 1 or 2; R 9i It is C 1-6 alkyl;

[0154] Z1 is selected from the following groups:

[0155] where R za Selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, R zb and R zc Independent hydrogen or C 1-6 alkyl;

[0156] n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10;

[0157] Z2 is selected from C 1-6 Alkyl, C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10Aryl and 5- to 10-membered heteroaryl are independently optionally substituted with one to five Gs; G is selected from the following groups:

[0158] a. Oxo;

[0159] b. Halogen;

[0160] c. cyano;

[0161] d.-NR zd R ze , where R zd and R ze are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0162] e.-C(=O)-NR zf R zg , where R zf and R zg are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted by one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups;

[0163] f.-S(=O) n7 -R zh , where n7 is 0, 1 or 2; R zh is hydrogen or C 1-6 alkyl;

[0164] C 1-6 Alkyl, where C 1-6 Alkyl is optionally substituted by one or more independently selected from halogen, hydroxy, -NR zi R zj 、C 1-6 substituted with an alkoxy group and a 3 to 12-membered heterocyclic group; wherein R zi and R zj Each independently selected from hydrogen or C 1-6 alkyl, and the 3 to 12 membered heterocyclic group is optionally substituted by one or more cyano groups, C 1-6 Alkyl and 3- to 12-membered heterocyclic substituents;

[0165] hC 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl groups, halogen groups and C 1-6 Substitution of alkoxy groups;

[0166] i. 3 to 12 membered heterocyclic group, wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 alkyl)carbonyl substituted with a substituent;

[0167] JC 6-10 Aryl, where C 6-10 Aryl is optionally substituted by one or more (C 1-6 alkyl)carbonyl substituted, and

[0168] k. 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted by one or more independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl and substituted with a 3- to 12-membered heterocyclic group; wherein R zk and R zl are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, and wherein the 3 to 12 membered heterocyclic group is optionally replaced by one or more independently selected C 1-6 Alkyl and (C 1-6 The substituent of the (alkyl)carbonyl group is substituted.

[0169] l.-P(O)R g1 R g2 , where R g1 or R g2 Independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl.

[0170] In some embodiments, the compound of formula (I) further has the structure of formula (III),

[0171] In some embodiments, the compound of formula (III) also has a structure of formula (V),

[0172] Where Rm is C 1-6 alkyl.

[0173] In some embodiments, the compound of formula (II) also has the structure of formula (IV),

[0174] In some embodiments, the compound of formula (IV) also has the structure of formula (VI),

[0175] In some embodiments, the compound of formula (II) is selected from any one of the following compounds,

[0176] or a stereoisomer thereof, a pharmaceutically acceptable salt or a deuterated compound and at least one pharmaceutically acceptable carrier; preferably, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, calcium salt and magnesium salt.

[0177] In some embodiments, the active compound is Compound 1,

[0178] or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier.

[0179] Preferably, the pharmaceutically acceptable salt is selected from:

[0180] (1) A sodium salt comprising compound 2:

[0181] Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3;

[0182] (2) a potassium salt comprising compound 3,

[0183] Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3;

[0184] (3) a calcium salt comprising compound 4,

[0185] Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3;

[0186] (4) a magnesium salt comprising compound 5,

[0187] Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3.

[0188] Another aspect of the present invention provides a long-acting injection preparation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound 6 or its stereoisomer, pharmaceutically acceptable salt or deuterated compound and at least one pharmaceutically acceptable carrier:

[0189] Preferably, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, calcium salt and magnesium salt.

[0190] In some embodiments, according to the long-acting injection preparation provided herein, the active compound is dissolved in a lipophilic carrier to form an oil solution, and the lipophilic carrier includes an oily solvent and an organic solvent;

[0191] Preferably, the active compound is selected from Compound 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, and most preferably Compound 1-5;

[0192] Preferably, the oily solvent is selected from castor oil, sesame oil, fatty acid glyceride, benzyl benzoate or any mixture thereof; more preferably, the oily solvent is medium-chain fatty acid glyceride;

[0193] Preferably, the organic solvent is benzyl alcohol or ethanol; more preferably, the organic solvent is benzyl alcohol.

[0194] In some embodiments, according to the oil solution provided herein, the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL;

[0195] The weight ratio of the oily solvent to the organic solvent is in the range of 6:4 to 9:1;

[0196] Preferably, the weight ratio of the oily solvent to the organic solvent is in the range of 7:3 to 9:1;

[0197] More preferably, the weight ratio of the oily solvent to the organic solvent is in the range of 8:2.

[0198] In some embodiments, according to the long-acting injection preparation provided herein, the active compound is dissolved in a hydrophilic solvent to form a hydrophilic solution;

[0199] Preferably, the active compound is selected from Compound 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, and most preferably Compound 1-5;

[0200] Preferably, the hydrophilic solvent comprises one of polyethylene glycol, an organic solvent and water or any mixture thereof;

[0201] Preferably, the polyethylene glycol is selected from polyethylene glycol 300 and polyethylene glycol 400; more preferably, the polyethylene glycol is polyethylene glycol 300;

[0202] Preferably, the organic solvent is selected from one of benzyl alcohol, ethanol and N-methylpyrrolidone (NMP); more preferably, the organic solvent is selected from one of benzyl alcohol and ethanol.

[0203] In some embodiments, according to the hydrophilic solution provided herein, the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL;

[0204] In some embodiments, according to the hydrophilic solution provided herein, the weight ratio of polyethylene glycol to organic solvent is in the range of 6:4 to 10:0;

[0205] More preferably, the weight ratio of polyethylene glycol to organic solvent is in the range of 7:3 to 10:0; more preferably, the weight ratio of polyethylene glycol to organic solvent is in the range of 9:1 to 10:0;

[0206] Preferably, the weight ratio of polyethylene glycol 300: organic solvent is in the range of 6:4 to 10:0; more preferably, the weight ratio of polyethylene glycol 300: organic solvent is in the range of 7:3 to 10:0; more preferably, the weight ratio of polyethylene glycol 300: organic solvent is in the range of 9:1 to 10:0.

[0207] Preferably, the weight ratio of polyethylene glycol 400: organic solvent is in the range of 6:4 to 10:0; more preferably, the weight ratio of polyethylene glycol 400: organic solvent is in the range of 7:3 to 10:0; more preferably, the weight ratio of polyethylene glycol 400: organic solvent is in the range of 9:1 to 10:0.

[0208] In some embodiments, the hydrophilic solution provided herein further comprises a pH adjuster, wherein the pH adjuster is selected from one of sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, phosphoric acid, sodium hydrogen phosphate, or any mixture thereof. Preferably, the pH range of the preparation is 4-10.

[0209] In some embodiments, the hydrophilic solution provided herein further comprises a release retardant, wherein the release retardant is selected from poly(lactic-co-glycolic acid) (PLGA) or polylactic acid (PLA), and its weight ratio in the hydrophilic solvent is 1% to 10%.

[0210] In some embodiments, according to the long-acting injection preparation provided herein, the active compound is dispersed in a stabilizer solution to form a drug-loaded microparticle or nanoparticle suspension;

[0211] Preferably, the active compound is selected from Compound 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, and most preferably Compound 1-5;

[0212] Wherein, the stabilizer solution is selected from polyethylene glycol, poloxamer, Tween, vitamin E polyethylene glycol succinate (TPGS), distearoyl phosphatidylethanolamine (DSPE)-polyethylene glycol (PEG), polyvinyl pyrrolidone, mannitol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose or any combination thereof; preferably, the stabilizer is poloxamer and polyethylene glycol, the polyethylene glycol is polyethylene glycol 400 to 6000, more preferably polyethylene glycol 1000 to 4000, most preferably polyethylene glycol 3350, and the poloxamer is poloxamer 407, poloxamer 338, or poloxamer 188;

[0213] In some embodiments, according to the drug-loaded microparticle or nanoparticle suspension provided herein, the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL;

[0214] The weight ratio of poloxamer in the drug-loaded microparticle or nanoparticle suspension is 1% to 10%.

[0215] Wherein, the weight ratio of polyethylene glycol in the drug-loaded microparticle or nanoparticle suspension is 0.5% to 5%;

[0216] Preferably, the active ingredient in the microparticle or nanoparticle suspension is in the form of particles with a median particle size of about 0.1 to 10 μm; more preferably, the median particle size of the drug-loaded microparticle suspension is in the range of 1 to 10 microns; more preferably, the median particle size of the drug-loaded nanosuspension is in the range of 100 to 1000 nanometers.

[0217] In some embodiments, according to the long-acting injection preparation provided herein, the active compound is dispersed in a biodegradable polymer solution to prepare a polymer gel solution preparation, wherein the polymer gel solution comprises a polymer gel material and an organic solvent;

[0218] Preferably, the active compound is selected from Compound 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, and most preferably Compound 1-5;

[0219] Wherein, preferably, the polymer gel material is selected from poly (lactic-co-glycolic acid) copolymer (PLGA), polylactic acid (PLA), polyoxyethylene-polycaprolactone block copolymer, polyoxyethylene-polyoxypropylene block copolymer;

[0220] Preferably, the polymer gel material is poly(lactic-co-glycolic acid) (PLGA);

[0221] Preferably, the ratio of lactic acid to glycolic acid in the lactic acid-glycolic acid copolymer molecule is 75:25 or 50:50;

[0222] Preferably, the intrinsic viscosity of the lactic acid-glycolic acid copolymer is in the range of 0.1 to 0.3 dL / g;

[0223] Preferably, the organic solvent is selected from one of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol, benzyl benzoate or any combination thereof;

[0224] Preferably, the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL;

[0225] Preferably, the weight ratio of the lactic acid-glycolic acid copolymer in the polymer gel solution is 10% to 80%;

[0226] Preferably, the organic solvent is selected so that its weight ratio in the polymer gel solution is 20% to 90%.

[0227] The long-acting injection preparation provided by the present application is suitable for intramuscular administration or subcutaneous administration.

[0228] IV. Treatment Methods

[0229] According to another aspect of the present invention, the present disclosure relates to a pharmaceutical composition of a compound of formula (I) for treating GLP-1-mediated diseases or symptoms, including: T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain caused by the use of other drugs, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, lung Arterial hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperlipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and substance addiction.

[0230] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or conditions recommended by the manufacturer.

[0231] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0232] The above-mentioned features of the present invention or the features described in the embodiments may be combined in any combination. All features disclosed in this patent specification may be used in any combination, and each feature disclosed in the specification may be replaced by any alternative feature that can provide the same, equal, or similar purpose. Therefore, unless otherwise specified, the features disclosed are only general examples of equal or similar features.

[0233] Figures in the specification

[0234] Figure 1 PK curves of compound 1 in formulations 4, 8, and 12 after subcutaneous injection into SD rats

[0235] Figure 2 PK curves of compound 1 in formulations 2-1, 5-2, and 11-1 after subcutaneous injection into SD rats

[0236] Figure 3 PK curves of compound 1 in formulations 2-2, 6-1, and 11-2 after subcutaneous injection into SD rats

[0237] Figure 4: PK curve of the comparative compound PF-06882961 in the formulation of formula 4 after subcutaneous injection into SD rats Specific embodiments

[0238] Preparation process of compounds and salts

[0239] Compound 1 was prepared according to the method disclosed in CN109790161A. Compound II was prepared according to the method disclosed in CN115698003A, and compound 6 was prepared according to the method disclosed in CN116390926A.

[0240] Preparation of the sodium salt: Dissolve 1.0 g of the compound in THF (10 ml), add sodium hydroxide ethanol solution (46.2 mg, 1 ml) dropwise, and stir at room temperature for 1 hour. Concentrate to dryness and crystallize from 10 ml of tertiary methyl ether to obtain the title compound as a white powder (930 mg).

[0241] Preparation of the calcium salt: Add 1.0 g of the compound to 10 ml of ethanol and dropwise add calcium hydroxide solution (66 mg, 0.5 ml). Stir at room temperature until dissolved. After approximately one day, a solid precipitates and is filtered to obtain the desired calcium salt.

[0242] Other salts can be prepared by referring to the above steps to obtain the target product.

[0243] Example 1: Preparation of oil solution

[0244] The active compounds (i.e., API) of the present application were dissolved in lipophilic carrier solutions, which contained castor oil, medium-chain fatty acid glycerides (MCT), benzyl benzoate, benzyl alcohol, and ethanol, and prepared into oil solution preparations by ultrasonic dissolution, as shown in Table 1.

[0245] Table 1

[0246] Example 2: Preparation of hydrophilic solution

[0247] The active compounds (i.e., API) of the present application were dissolved in hydrophilic solvents, including PEG300, PEG400, ethanol, water, and benzyl alcohol, and prepared into hydrophilic solution preparations by ultrasonic dissolution, as shown in Table 2.

[0248] Table 2

[0249] Example 3: Preparation of micron or nanoscale suspensions

[0250] The active compound of the present application (i.e., API) was dispersed in an aqueous solution containing a stabilizer and prepared into a micron or nanometer suspension injection via a media milling process, wherein the stabilizer was selected from polyethylene glycol 3350, poloxamer 188, poloxamer 338, and poloxamer 407. The following suspensions were prepared according to the formulation in the table below, controlling the media milling speed and time, as shown in Table 3.

[0251] Table 3

[0252] Example 4: Preparation of polymer gel solution

[0253] The active compound of the present application (i.e., AP1) was dispersed in a biodegradable polymer solution and prepared into a polymer gel solution preparation by ultrasonic dissolution method, wherein the polymer gel solution excipients were selected from PLGA, PLA, and NMP, as shown in Table 4.

[0254] Table 4

[0255] The preparations covered in this application are long-acting injectables (LAIs), which are injections that deliver sustained-release, long-lasting effects. Compared to oral preparations, long-acting injections offer stable blood concentrations, a duration of effective action lasting weeks or even months, and reduced dosing frequency. The targeted development of these preparations will not only facilitate patient treatment but also have significant social benefits.

[0256] Example 5: Subcutaneous administration of different injections in SD rats

[0257] Preparation samples containing Compound 1 of the present application prepared according to Prescription 4 of Example 1, Prescription 8 of Example 2, and Prescription 12 of Example 3 were selected and administered subcutaneously (SC) to SD rats, as shown in Table 5 below.

[0258] Table 5

[0259] Experimental results: As shown in Table 6 and Figure 1:

[0260] Table 6

[0261] Prescriptions 4, 8, and 12 all have significant beneficial effects such as better therapeutic effective blood drug concentrations, relatively small fluctuations in blood drug concentrations, relatively stable blood drug concentrations, and longer maintenance times, and can meet the requirements for long-term drug delivery effects.

[0262] Example 6: Subcutaneous administration of different injections to SD rats

[0263] Select compound 1 (i.e., API) to prepare preparation samples according to Prescription 2-1 of Example 1, Prescription 5-2 of Example 2, and Prescription 11-1 of Example 3, and perform subcutaneous injection (SC) administration to SD rats as shown in Table 7 below.

[0264] Table 7

[0265] Experimental results: As shown in Table 8 and Figure 2:

[0266] Table 8

[0267] Prescriptions 2-1, 5-2, and 11-1 all have significant beneficial effects such as better therapeutic effective blood drug concentrations, relatively small fluctuations in blood drug concentrations, relatively stable blood drug concentrations, and longer maintenance times, and can meet the requirements for long-term drug delivery effects.

[0268] Example 7: Subcutaneous administration of different injections to SD rats

[0269] Select preparation samples containing compound 1 of the present application prepared according to Prescription 2-2 of Example 1, Prescription 6-1 of Example 2, and Prescription 11-2 of Example 3, and perform subcutaneous injection (SC) administration to SD rats as shown in Table 9 below.

[0270] Table 9

[0271] Experimental results: As shown in Table 10 and Figure 3:

[0272] Table 10

[0273] For Prescriptions 2-2, 6-1, and 11-2, after 96 hours of administration, no blood drug concentration could be detected in the SD rats (<LLOQ, LLOQ = 1 ng / ml), and the long-term drug delivery effect could not be achieved. At the same time, AUC 0-696h significantly decreased and was inferior to the in-vivo results of the corresponding preparations in Example 5 and Example 6.

[0274] Comparative Example 1: Preparation of the oil solution of the comparative compound PF-06882961

[0275] The comparative compound PF-06882961 (prepared according to the method disclosed in CN110325530B) was dissolved in a lipophilic carrier solution, which included castor oil, medium-chain fatty acid glycerides (MCT), benzyl benzoate, benzyl alcohol, medium-chain fatty acid glycerides (MCT) in ethanol, and benzyl alcohol, and prepared into an oil solution preparation by ultrasonic dissolution (see Prescription 4).

[0276] Table 11

[0277] Comparative Example 2: Subcutaneous administration of the injection of the comparative compound PF-06882961 Prescription 4 to SD rats

[0278] The injection sample of PF-06882961 prescription 4 prepared in Comparative Example 1 was administered to SD rats by subcutaneous injection (SC), as shown in Table 12 below.

[0279] Table 12

[0280] Experimental results: As shown in Table 13 and Figure 4:

[0281] Table 13

[0282] After 24 hours of administration, the blood drug concentration in SD rats could not be detected (

Claims

1. A long-acting injection preparation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof: in X is selected from -N= or -CR a ; R a Selected from hydrogen atoms, halogen or C 1-6 alkyl; Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 , Z 11 , Z 12 , Z 13 Selected from -N= or -C=; Q1 is selected from C 6-10 Aryl or 5- to 10-membered heteroaryl, wherein C 6-10 Aryl or 5 to 10 membered heteroaryl is optionally substituted by one to five independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Substitution of alkoxy groups; Q2 is selected from 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the 3 to 12 membered heterocyclyl and the 5 to 10 membered heteroaryl are optionally substituted by 1 to 3 independently selected halogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6 Alkoxy and -NR Qa R Qb Substituents are substituted, and the two C 1-6 The alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbon ring; and R Qa and R Qb are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and (C 1- 6-alkyl)carbonyl; R1, R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen atoms, C 1-6 Substitution of alkoxy and hydroxy groups; R4, R5 and R6 are each independently selected from hydrogen, halogen and C 1-6 alkyl; R7 and R8 are independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 3-15 or R7 and R8 together with the carbon atom to which they are attached form ChengC 3-15 Carbocyclic ring; wherein R7 and R8 together form a C 3-15 The carbocyclic ring is optionally substituted with one to three C 1-6 Alkyl substituted, where C 1-6 The alkyl group is optionally substituted with one or more independently selected from halogen, hydroxy, -NR 7a R 7b , C 1-6 substituted with an alkoxy group and a 3- to 12-membered heterocyclic group, and R 7a and R 7b are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; n1 is 0, 1, 2, or 3; n2 is 0, 1, 2, 3, 4 or 5; R9 is selected from the following groups: -CO2R 9f and -C(=O)-NR 9g R 9h ; and R 9a , R 9b , R 9c , R 9d and R 9g are each independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 1-6 Substituents of the alkoxy group; R 9e is hydrogen or C optionally substituted by one or more halogen atoms 1-6 Alkyl; R 9f is hydrogen or C 1-6 Alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 alkyl)carbonyl, cyano or -S(=O) n3 -R 9i ; n3 is 0, 1 or 2; R 9i It is C 1-6 alkyl; Z1 is selected from the following groups: Where R za Selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, R zb and R zc Independent hydrogen or C 1-6 alkyl; n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10; Z2 is selected from C 1-6 Alkyl, C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently optionally substituted with one to five G; G is selected from the following groups: a. Oxygen; b. Halogen; c. cyano; d.-NR zd R ze , where R zd and R ze are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted with one or more independently selected from hydroxy, halogen and C 1-6 The substituents of the alkoxy group are generation; e.-C(=O)-NR zf R zg , where R zf and R zg are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted with one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups; f.-S(=O) n7 -R zh , where n7 is 0, 1 or 2; R zh is hydrogen or C 1-6 alkyl; C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more independently selected from halogen, hydroxy, -NR zi R zj , C 1-6 substituted with alkoxy and 3 to 12 membered heterocyclic groups; wherein R zi and R zj are each independently selected from hydrogen or C 1-6 alkyl, and the 3 to 12 membered heterocyclic group is optionally substituted by one or more cyano groups, C 1-6 Alkyl and 3 to 12-membered heterocyclic group are substituted; HkDJ 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl groups, halogen groups and C 1-6 Substitution of alkoxy groups; i. 3 to 12 membered heterocyclic group, wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 alkyl)carbonyl is substituted with a substituent; JC 6-10 Aryl, where C 6-10 The aryl group is optionally substituted with one or more (C 1-6 alkyl)carbonyl substituted, and k. 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted by one or more independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl and a 3- to 12-membered heterocyclic group; wherein R zk and R zl are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, and wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 The substituent of the carbonyl group is substituted with an alkyl) group.

2. A long-acting injection preparation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (II) and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds and at least one pharmaceutically acceptable carrier: in X is selected from -N= or -CR a ; R a Selected from hydrogen atoms, halogen or C 1-6 alkyl; Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z 10 , Z 11 , Z 12 , Z 13 Selected from -N= or -C=; Z 14 Select from N or C Q1 is selected from C 6-10 Aryl or 5- to 10-membered heteroaryl, wherein C 6-10 Aryl or 5 to 10 membered heteroaryl is optionally substituted by one to five independently selected from halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Substitution of alkoxy groups; Q2 is selected from 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the 3 to 12 membered heterocyclyl and the 5 to 10 membered heteroaryl are optionally substituted by 1 to 3 independently selected halogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6 Alkoxy and -NR Qa R Qb Substituents are substituted, and the two C 1-6 The alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbon ring; and R Qa and R Qb are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and (C 1- 6-alkyl)carbonyl; R1, R2 and R3 are each independently selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen atoms, C 1-6 Substitution of alkoxy and hydroxy groups; R4, R5 and R6 are each independently selected from hydrogen, halogen and C 1-6 alkyl; R7 and R8 are independently selected from hydrogen or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 3-15 The cycloalkyl group is substituted by a substituent, or R7 and R8 together with the carbon atom to which they are attached form a C 3-15 Carbocyclic ring; wherein R7 and R8 together form a C 3-15 The carbocyclic ring is optionally substituted with one to three C 1-6 Alkyl substituted, where C 1-6 The alkyl group is optionally substituted with one or more independently selected from halogen, hydroxy, -NR 7a R 7b , C 1-6 substituted with an alkoxy group and a 3- to 12-membered heterocyclic group, and R 7a and R 7b are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; n1 is 0, 1, 2, or 3; n2 is 0, 1, 2, 3, 4 or 5; R9 is selected from the following groups: -CO2R 9f and -C(=O)-NR 9g R 9h ; and R 9a , R 9b , R 9c , R 9d and R 9g are each independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halogen and C 1-6 Substituents of the alkoxy group; R 9e is hydrogen or C optionally substituted by one or more halogen atoms 1-6 Alkyl; R 9f is hydrogen or C 1-6 alkyl; R 9h It is hydrogen, C 1-6 Alkyl, (C 1-6 alkyl)carbonyl, cyano or -S(=O) n3 -R 9i ; n3 is 0, 1 or 2; R 9i It is C 1-6 alkyl; Z1 is selected from the following groups: Where R za Selected from hydrogen, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl, R zb and R zc Independent hydrogen or C 1-6 alkyl; n4 is 1, 2 or 3; n5 and n6 are independently integers from 0 to 10; Z2 is selected from C 1-6 Alkyl, C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein C 3-15 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently optionally substituted with one to five G; G is selected from the following groups: a. Oxygen; b. Halogen; c. cyano; d.-NR zd R ze , where R zd and R ze are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted with one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups; e.-C(=O)-NR zf R zg , where R zf and R zg are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; wherein C 1-6 The alkyl group is optionally substituted with one or more independently selected from hydroxy, halogen and C 1-6 Substitution of alkoxy groups; f.-S(=O) n7 -R zh , where n7 is 0, 1 or 2; R zh is hydrogen or C 1-6 alkyl; C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more independently selected from halogen, hydroxy, -NR zi R zj , C 1-6 substituted with alkoxy and 3 to 12 membered heterocyclic groups; wherein R zi and R zj are each independently selected from hydrogen or C 1-6 alkyl, and the 3 to 12 membered heterocyclic group is optionally substituted by one or more cyano groups, C 1-6 Alkyl and 3 to 12-membered heterocyclic group are substituted; HkDJ 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl groups, halogen groups and C 1-6 Substitution of alkoxy groups; i. 3 to 12 membered heterocyclic group, wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 alkyl)carbonyl is substituted with a substituent; JC 6-10 Aryl, where C 6-10 The aryl group is optionally substituted with one or more (C 1-6 alkyl)carbonyl substituted, and k. 5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted by one or more independently selected from C1-6 alkyl, C1-6 alkoxy, -NR zk R zl and a 3- to 12-membered heterocyclic group; wherein R zk and R zl are independently selected from hydrogen, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, and wherein the 3 to 12 membered heterocyclic group is optionally substituted by one or more independently selected from C 1-6 Alkyl and (C 1-6 alkyl)carbonyl is substituted with a substituent; l.-P(O)R g1 R g2 , where R g1 or R g2 Independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl.

3. The preparation as claimed in claim 1, wherein the compound of formula (I) also has the structure of formula (III), 4. The preparation as claimed in claim 3, wherein the compound of formula (III) also has the structure of formula (V), in, Rm is C 1-6 alkyl.

5. The preparation as claimed in claim 2, wherein the compound of formula (II) also has the structure of formula (IV), 6. The formulation of claim 5, wherein the compound of formula (IV) also has the structure of formula (VI), 7. The preparation according to claim 2, wherein the compound of formula (II) is selected from any one of the following compounds. Or a stereoisomer thereof, a pharmaceutically acceptable salt or a deuterated compound and at least one pharmaceutically acceptable carrier; preferably, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, calcium salt and magnesium salt.

8. The preparation of claim 1, wherein the active compound is compound 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable salt is selected from: (1) A sodium salt comprising compound 2: Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3; (2) a potassium salt comprising compound 3, Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3; (3) a calcium salt comprising compound 4, Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3; (4) a magnesium salt comprising compound 5, Wherein X is the number of crystal waters, selected from 0, 0.5, 1, 2 or 3.

9. A long-acting injection preparation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound 6 or its stereoisomer, pharmaceutically acceptable salt or deuterated compound and at least one pharmaceutically acceptable carrier: Preferably, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, calcium salt and magnesium salt.

10. The preparation according to any one of claims 1 to 9, wherein the active compound is dissolved in a lipophilic carrier to form an oil solution, and the lipophilic carrier comprises an oily solvent and an organic solvent; Preferably, the active compound is selected from Compound 1, 6, 7-15 or a stereoisomer thereof, a pharmaceutically acceptable salt or a deuterated compound, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, most preferably Compound 1-5； Preferably, the oily solvent is selected from castor oil, sesame oil, fatty acid glyceride, benzyl benzoate or any mixture thereof; more preferably, the oily solvent is medium-chain fatty acid glyceride; Preferably, the organic solvent is benzyl alcohol or ethanol; more preferably, the organic solvent is benzyl alcohol.

11. The formulation of claim 10, wherein the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL; The weight ratio of the oily solvent to the organic solvent is in the range of 6:4 to 9:1; Preferably, the weight ratio of the oily solvent to the organic solvent is in the range of 7:3 to 9:1; More preferably, the weight ratio of the oily solvent to the organic solvent is in the range of 8:

2.

12. The formulation of any one of claims 1 to 9, wherein the active compound is dissolved in a hydrophilic solvent to form a hydrophilic solution; Preferably, the active compound is selected from Compound 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, most preferably Compound 1-5; Preferably, the hydrophilic solvent comprises one of polyethylene glycol, an organic solvent and water or any mixture thereof; Preferably, the polyethylene glycol is selected from polyethylene glycol 300 and polyethylene glycol 400; more preferably, the polyethylene glycol is polyethylene glycol 300; Preferably, the organic solvent is selected from benzyl alcohol, ethanol and N-methylpyrrolidone (NMP); more preferably, the organic solvent is selected from benzyl alcohol and ethanol.

13. The formulation of claim 12, wherein the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL; in, The weight ratio of polyethylene glycol to organic solvent is in the range of 6:4 to 10:0; More preferably, the weight ratio of polyethylene glycol: organic solvent is in the range of 7:3 to 10:0; more preferably, the weight ratio of polyethylene glycol: organic solvent is in the range of 9:1 to 10:0; Preferably, the weight ratio of polyethylene glycol 300 to organic solvent is in the range of 6:4 to 10:0; more preferably Preferably, the weight ratio of polyethylene glycol 300: organic solvent is in the range of 7:3 to 10:0; more preferably, the weight ratio of polyethylene glycol 300: organic solvent is in the range of 9:1 to 10:

0. Preferably, the weight ratio of polyethylene glycol 400: organic solvent is in the range of 6:4 to 10:0; more preferably, the weight ratio of polyethylene glycol 400: organic solvent is in the range of 7:3 to 10:0; more preferably, the weight ratio of polyethylene glycol 400: organic solvent is in the range of 9:1 to 10:

0.

14. The preparation as claimed in claim 12, further comprising a pH adjuster, wherein the pH adjuster is selected from one of sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, phosphoric acid, sodium hydrogen phosphate, or any mixture thereof, and preferably, the pH range of the preparation is 4-10.

15. The preparation as claimed in claim 12, further comprising a release retardant, wherein the release retardant is selected from poly(lactic-co-glycolic acid) (PLGA) or polylactic acid (PLA), and the weight ratio of the release retardant in the hydrophilic solvent is 1% to 10%.

16. The formulation of claims 1-9, wherein the active compound is dispersed in a stabilizer solution to form a drug-loaded microparticle or nanoparticle suspension; Preferably, the active compound is selected from Compound 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, most preferably Compound 1-5; in, The stabilizer solution is selected from polyethylene glycol, poloxamer, Tween, vitamin E polyethylene glycol succinate (TPGS), distearoyl phosphatidylethanolamine (DSPE)-polyethylene glycol (PEG), polyvinyl pyrrolidone, mannitol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose or any combination thereof; preferably, the stabilizer is poloxamer and polyethylene glycol, the polyethylene glycol is polyethylene glycol 400 to 6000, more preferably polyethylene glycol 1000 to 4000, most preferably polyethylene glycol 3350, and the poloxamer is poloxamer 407, poloxamer 338, or poloxamer 188; 17. The formulation of claim 16, wherein the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL; in, The weight ratio of poloxamer in the drug-loaded microparticle or nanoparticle suspension is 1% to 10%. Wherein, the weight ratio of polyethylene glycol in the drug-loaded microparticle or nanoparticle suspension is 0.5% to 5%; Preferably, the active ingredient in the microparticle or nanoparticle suspension is in the form of particles with a median particle size of about 0.1 to 10 μm; more preferably, the median particle size of the drug-loaded microparticle suspension is in the range of 1 to 10 microns; more preferably, the median particle size of the drug-loaded nanosuspension is in the range of 100 to 1000 nanometers.

18. The preparation according to any one of claims 1 to 9, wherein the active compound is dispersed in a biodegradable polymer solution to prepare a polymer gel solution preparation, wherein the polymer gel solution comprises a polymer gel material and an organic solvent; Preferably, the active compound is selected from Compound 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably Compound 1 or a pharmaceutically acceptable salt thereof, most preferably Compound 1-5; in, Preferably, the polymer gel material is selected from poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyoxyethylene-polycaprolactone block copolymer, polyoxyethylene-polyoxypropylene block copolymer; Preferably, the polymer gel material is poly(lactic-co-glycolic acid) (PLGA); Preferably, the ratio of lactic acid to glycolic acid in the lactic acid-glycolic acid copolymer molecule is 75:25 or 50:50; Preferably, the intrinsic viscosity of the lactic acid-glycolic acid copolymer is in the range of 0.1 to 0.3 dL / g; Preferably, the organic solvent is selected from one of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol, benzyl benzoate or any combination thereof; Preferably, the concentration of the active compound or its pharmaceutically acceptable salt in the formulation is 0.1 to 400 mg / mL, preferably 1 to 200 mg / mL; Preferably, the weight ratio of the lactic acid-glycolic acid copolymer in the polymer gel solution is 10% to 80%; Preferably, the organic solvent is selected so that its weight ratio in the polymer gel solution is 20% to 90%.

19. The formulation of any one of claims 1 to 18, wherein the formulation is suitable for intramuscular or subcutaneous administration.

20. A method of treating a GLP-1 mediated disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a formulation according to any one of claims 1 to 18.

21. The formulation of claim 20, wherein the GLP-1 mediated disease or condition comprises: T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain due to use of other medications, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, lung Arterial hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperlipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and substance addiction.