Biaryl compound and application thereof

Abstract

The invention provides a biaryl compound with a structure as shown in formula I, a pharmaceutical composition of the biaryl compound and application of the biaryl compound in medicine, and # imgabs0 #

Description

Technical Field

[0001] This application relates to the field of biomedical technologies, and specifically relates to a biaryl compound and the use of such compounds for the treatment and / or prevention of GIPR / GLP1R / GCGR-mediated diseases and symptoms. Background Art

[0002] Glucose-dependent insulinotropic polypeptide (GIP) is a polypeptide hormone secreted by the intestine, which can promote insulin secretion by pancreatic islet β cells, and at the same time inhibit the secretion of glucose-elevating hormone (glucagon) by pancreatic islet α cells, thereby helping to regulate blood glucose levels after meals. GIP is the first incretin discovered, and the currently known incretins are GIP and GLP-1. In normal humans, the insulin secretion stimulated by the incretin effect (after meals) accounts for about 70% of the total insulin secretion, and GIP accounts for 2 / 3 of the entire incretin effect, with a much higher proportion than GLP-1.

[0003] The mechanism of action of GIPR agonists is to bind to and activate the GIP receptor, mimic the stimulatory effect of GIP on pancreatic islet β cells, promote the release of more insulin by pancreatic islet β cells, thereby increasing the physiological effect of insulin and reducing blood glucose levels. Since GIPR agonists can increase insulin release and action, they are widely used in the treatment of type 2 diabetes. Such drugs can improve blood glucose control, reduce insulin requirements, and help control postprandial hyperglycemia, and may also have a certain impact on pancreatic islet β cell function and body weight. Summary of the Invention

[0004] Overview

[0005] An object of the present invention is to provide compounds, methods, compositions, and manufacturing methods of novel GIPR / GLP1R / GCGR-mediated agonists or modulators.

[0006] On the one hand, this application includes a compound of formula I and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds:

[0007]

[0008] A, B, and C are each independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , -(CO)Raa 、 -O-(CO)R aa , wherein C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted by substituents selected from -OH, -NH2, halogen, pseudohalogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group; wherein R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0009] X, Y, and Z are each independently selected from N or CR b ; wherein R b is selected from a hydrogen atom, -OH, -NH2, halogen, pseudohalogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , -(CO)R bb , -O-(CO)R bb , wherein C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted by substituents selected from -OH, -NH2, halogen, pseudohalogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group; wherein R bb is selected from H, halogen, pseudohalogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0010] D is selected from a C 1-6 cycloalkyl optionally substituted by -OH, NH2, halogen, pseudohalogen, oxo, -CN, -OC 3-6 alkyl, -OC 1-6 alkyl or C 3-6 cycloalkyl-substituted C 3-10 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group or bridged ring;

[0011] R 1 is selected from C1-6 alkyl, C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -S(O)2C 1-6 alkyl, -S(O)2C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group may be optionally substituted with -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group;

[0012] R 2 selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OR 2a , R 2a selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl group, 6- to 0-membered aryl group or 5- to 0-membered heteroaryl group, wherein C 1-6 alkyl or C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group may be optionally substituted with -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group;

[0013] R 3 and R 3’ each independently selected from a hydrogen atom, -OH, -NH2, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group may be optionally substituted with -OH, -NH2, halogen, oxo or C 1-6 alkyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C═O, C═S, C 3-6Cycloalkyl, 4-6 membered heterocyclic group, wherein said C 3-6 The cycloalkyl, 4-6 membered heterocyclic group may optionally be substituted by -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl;

[0014] R 4 and R 4’ are each independently selected from a hydrogen atom, C 1-6 alkyl or halogen;

[0015] And the compound of formula 1 does not include the following compounds:

[0016]

[0017] On the other hand, the present application relates to a composition comprising a compound of formula I, or its stereoisomers, pharmaceutically acceptable salts or deuterated compounds, and a pharmaceutically acceptable excipient.

[0018] On the other hand, the present application relates to a method for treating a disease or symptom mediated by GIPR / GLP1R / GCGR; comprising the step of administering to a subject an effective amount of a compound of formula I, its stereoisomers, pharmaceutically acceptable salts or deuterated compounds or an effective amount of a composition comprising a compound of formula I.

[0019] On the other hand, the present application relates to the use of a compound of formula I, its stereoisomers, pharmaceutically acceptable salts or deuterated compounds or an effective amount of a composition comprising a compound of formula I in the manufacture of a medicament for treating a disease or symptom mediated by GIPR / GLP1R / GCGR.

[0020] The diseases or symptoms mediated by GIPR / GLP1R / GCGR include: T1DM, 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, long-term weight management, obesity, eating disorders, weight gain caused by other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular diseases, 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, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, 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, hyperapolipoprotein B lipoproteinemia, 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.

[0021] I. DETAILED DESCRIPTION

[0022] In the following description, certain specific details are included to provide a thorough understanding of the various disclosed embodiments. However, those 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.

[0023] Unless otherwise required in this disclosure, throughout the specification and the claims that follow, the words "comprising" and "including" shall be construed in an open, inclusive sense, i.e., "including but not limited to".

[0024] As used in this disclosure and the appended claims, unless the context clearly dictates otherwise, singular reference without an indication of quantity includes plural references.

[0025] As used throughout this specification, the phrases "an embodiment", "embodiment", "in another embodiment", or "in certain embodiments" mean that a particular referenced element, structure, or characteristic associated with that embodiment is included in at least one embodiment. Thus, the phrases "in an embodiment", "in embodiments", "in another embodiment", or "in certain embodiments" that appear in various places throughout the specification do not necessarily all refer to the same embodiment. Additionally, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0026] It should be understood that the singular forms of the articles "a", "an", and "the" (corresponding to the English "a", "an", and "the") used in the specification and appended claims of the present disclosure include plural referents unless the context clearly dictates otherwise. Thus, for example, a sustained-release tablet that includes a "pharmaceutically acceptable excipient" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0027] II. Definitions

[0028] 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. The dashes at the front or end of a chemical group are for convenience in indicating the point of attachment to the parent; a chemical group may be described with or without one or more dashes without losing its ordinary meaning. Prefixes such as "C u-v " or "C u -C v " denote 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 has 1 to 6 carbon atoms.

[0029] "Alkyl" is a monovalent or divalent linear or branched saturated hydrocarbon group. For example, an alkyl may have 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4alkyl). Examples of alkyl include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-Propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (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, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH2CH3), 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 (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 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), and the alkyl may be unsubstituted or substituted.

[0030] The "C 1-6 alkyl optionally substituted" described in this application not only includes the separately pointed out C 1-6 alkyl, but also includes the C 1-6 alkyl in the substituents combined with other groups. For example, it includes the C 1-6 alkyl in "-OC 1-6 alkyl". The alkyl can be optionally substituted, and other groups such as C 3-6 cycloalkyl also have a similar meaning.

[0031] "Alkoxy" means the group -O-alkyl, where alkyl is defined as above. For example, C 1-4An alkoxy group refers to an -O-alkyl group having 1 to 4 carbon atoms. The alkoxy group can be unsubstituted or substituted.

[0032] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, such that the alkyl group is divalent. For example, C 2-6 Alkoxyalkyl includes -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. Alkoxyalkyl can be unsubstituted or substituted.

[0033] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0034] "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 can be the same or different, such that the alkyl group is divalent. The alkyl group and the halogen can be any of those described above. In some embodiments, the haloalkyl defines the number of carbon atoms in the alkyl moiety. For example, C 1-4 Haloalkyl includes CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH3, and C(CH3)2(CF2H). Haloalkyl can be unsubstituted or substituted.

[0035] "Haloalkoxy" is an alkoxy group as defined herein, wherein one or more hydrogen atoms in the alkoxy group are independently replaced by a halogen, which can be the same or different, such that the alkyl group is divalent. The alkoxy group and the halogen can be any of those described above. In some embodiments, the haloalkoxy defines the number of carbon atoms in the alkyl moiety. For example, C1-4 haloalkoxy includes OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH3, and OC(CH3)2(CF2H). Haloalkoxy can be unsubstituted or substituted.

[0036] "Cycloalkyl" is a monovalent or divalent single fully carbon ring or multiple fused fully 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. Cycloalkyl also includes multiple fused ring systems having about 7 to 12 carbon atoms (e.g., a ring system including 2 rings). Where valence requirements permit, the rings of the multiple fused ring systems can be connected to each other by fusion bonds, spiro bonds, or bridging bonds. Exemplary polycyclic cycloalkyls include octahydropentalene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2-ene, and spiro[2.5]octane. The cycloalkyl group can be unsubstituted or substituted.

[0037] "Alkylcycloalkyl" refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently substituted by a cycloalkyl, which can be the same or different. The alkyl and cycloalkyl can be any of those described above. In some embodiments, the number of carbon atoms in the alkyl and cycloalkyl moieties can be specified separately, e.g., C1-6 alkyl-C3-12 cycloalkyl. The alkylcycloalkyl group can be unsubstituted or substituted.

[0038] "Aryl" as used herein refers to a monovalent or divalent single fully carbon aromatic ring or multiple fused fully carbon ring systems, wherein the ring is aromatic. For example, in some embodiments, an aryl 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. Aryl also includes multiple fused ring systems having about 9 to 20 carbon atoms (e.g., a ring system composed of 2, 3, or 4 rings), wherein the multiple rings are aromatic. Where valence requirements permit, the rings of the multiple fused ring systems can be connected to each other by fusion bonds. It is also understood that when referring to a member of an aryl having a certain atomic range (such as an aryl having 6 - 10 members), the atomic range refers to the total ring atoms of the aryl. For example, a 6-membered aryl includes a phenyl, and a 10-membered aryl includes a naphthyl. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, etc. Aryl can be unsubstituted or substituted.

[0039] "Alkylaryl" means an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by an aryl group, which may be the same or different. The alkyl and aryl groups can be any of those described above, and such an alkyl is divalent. In some embodiments, an alkylaryl has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. The alkylaryl defined by the number of carbon atoms refers to the total number of carbon atoms present in the alkyl and aryl groups. For example, a C7 alkylaryl refers to benzyl, and a C 11 Alkylaryls include 1-methylnaphthalene and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl moieties can be specified separately, e.g., C 1-6 alkyl-C 6-10 aryl. Non-limiting examples of alkylaryls include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, and the like. Alkylaryls can be unsubstituted or substituted.

[0040] As used herein, "heterocycle" or "heterocyclic" or "heterocyclic group" means a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system that contains at least one heteroatom (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, heterocyclic groups have 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 having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms (e.g., 3-, 4-, 5-, 6-, or 7-membered rings), where the heteroatoms in these rings are selected from the group consisting of oxygen, nitrogen, and sulfur. Where valence requirements permit, the rings of multiple fused ring (e.g., bicyclic heterocyclic) systems can be connected to each other by fused bonds, spiro bonds, and bridging bonds. Heterocycles include, but are not limited to, azetidine, azabenzene, imidazolidine, morpholine, ethylene oxide, oxacycle, thiacycle, piperazine, piperidine, pyrazolidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, and the like. Heterocyclic groups can be unsubstituted or substituted.

[0041] "Pseudohalogen" refers to molecules formed by certain atomic groups, which have properties similar to those of halogen elemental molecules, and their anions also have properties similar to those of halogen anions, so they are often called pseudohalogens; important pseudohalogens include cyano (CN), thiocyano (SCN), selenocyano (SeCN), and oxycyano (OCN).

[0042] "Alkylene", by itself or as part of another substituent, refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Generally, the alkyl (or alkylene) group has 1 to 10 carbon atoms, and in the present disclosure, groups having 6 or fewer carbon atoms are more preferred.

[0043] "Alkenylene", by itself or as part of another substituent, refers to a divalent group derived from an alkene.

[0044] "Alkynylene", by itself or as part of another substituent, refers to a divalent group derived from an alkyne.

[0045] "Cycloalkylene" and "heterocycloalkylene", by itself or as part of another substituent, refer to divalent groups derived from cycloalkyl and heterocycloalkyl groups, respectively.

[0046] "Arylene" and "heteroarylene", by itself or as part of another substituent, refer to divalent groups derived from aryl and heteroaryl groups, respectively.

[0047] "Alkylheterocyclic group" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a heterocyclic group, which may be the same or different. The alkyl and heterocyclic groups can be any of the above, and such an alkyl group is divalent. In some embodiments, the number of atoms in the alkyl and heterocyclic moieties can be specified separately. For example, C 1-6 alkyl-3- to 12-membered heterocyclic group having 1 to 3 heteroatoms, each heteroatom independently being N, O, or S. The alkylheterocyclic group can be unsubstituted or substituted.

[0048] "5-10 membered heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "5-10 membered heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, which multiple fused ring systems will be further described below. Thus, "5-10 membered heteroaryl" includes a monocyclic aromatic ring having about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms can also be in an oxidized form, provided that the ring is aromatic. Exemplary 5-10 membered heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "5-10 membered heteroaryl" also includes multiple fused ring systems (e.g., ring systems composed of 2, 3, or 4 rings), wherein a 5-10 membered heteroaryl as defined above is fused with one or more rings selected from 5-10 membered heteroaryl (forming, for example, 1,8-naphthyridinyl) and aryl (forming, for example, benzimidazolyl or indazolyl) to form multiple fused ring systems. Thus, 5-10 membered heteroaryl (a single aromatic ring or multiple fused ring systems) can have about 1-20 carbon atoms and about 1-6 heteroatoms within the 5-10 membered heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring. Where valence requirements permit, the rings of multiple fused ring systems can be interconnected by fused bonds. It should be understood that the individual rings of multiple fused ring systems can be interconnected in any order. It should be understood that the point of attachment of a 5-10 membered heteroaryl or a 5-10 membered heteroaryl multiple fused ring system can be any suitable atom of the 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a member heteroaryl of a certain atomic range (e.g., 5 to 10 membered heteroaryl), the atomic range is for the total ring atoms of the heteroaryl, including carbon atoms and heteroatoms. It should also be understood that the rings of multiple fused ring systems can include an aryl ring fused to a heterocyclic ring (e.g., 3, 4, 5, 6, or 7 membered ring) having saturated or partially unsaturated bonds, the ring having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. For example, 5-10 membered heteroaryl includes thiazolyl, and 5-10 membered heteroaryl includes quinolinyl. Exemplary 5-10 membered heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolyl, benzofuryl, benzimidazolyl, thiophenyl, pyrrolo[2,3-b]pyridyl, quinazolin-4(3H)-one, triazolyl, and tetrazolyl. 5-10 membered heteroaryl can be unsubstituted or substituted.

[0049] "Alkyl - heteroaryl" means an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a heteroaryl, which heteroaryl can be the same or different, such that the alkyl is divalent. The alkyl and heteroaryl can be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl moieties are specified separately, e.g., C 1-6 alkyl - heteroaryl having 5 to 10 members and having 1 to 4 heteroatoms, each heteroatom independently being N, O, or S. The alkyl heteroaryl can be unsubstituted or substituted.

[0050] "Oxo" as used herein means ═O.

[0051] "Substituted" as used herein means that one or more hydrogen atoms of the group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4 or more), as indicated.

[0052] "Compounds of the present disclosure" include the compounds disclosed herein. For example, the 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.

[0053] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, lubricant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0054] "Therapeutically effective amount" or "effective amount" as used herein means an amount that is effective in eliciting the 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 factors such as the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. The effective amount can include a range of amounts. As understood in the art, the effective amount can be one or more doses, i.e., it may be necessary to administer one dose or multiple doses to achieve the desired therapeutic endpoint. The effective amount can be considered in the context of administering one or more therapeutic agents, and if a single agent, when used in combination with one or more other agents, may or has achieved a desirable or beneficial result, then the single agent is considered to have been administered in an effective amount. Due to the combined action of the compounds (e.g., additive or synergistic), the appropriate dose of any co - administered compound can be selectively reduced.

[0055] 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 the 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 the compound of the present disclosure is administered first, and then a unit dose of one or more additional therapeutic agents is administered within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of the compound of the present disclosure is administered within seconds or minutes. In some embodiments, a unit dose of the compound of the present disclosure is administered first, and then, several hours later (e.g., 1 - 12 hours), a unit dose of one or more additional therapeutic agents is administered. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then, several hours later (e.g., 1 - 12 hours), a unit dose of the compound of the present disclosure is administered. Co - administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering the compound disclosed herein and one or more additional therapeutic agents either simultaneously or sequentially such that a therapeutically effective amount of each agent is present in the body of the subject.

[0056] Also provided are pharmaceutically acceptable salts, hydrates, solvates, isomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0057] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0058] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as the free base. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound, which have the required pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, bisulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, caprates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methanesulfonates, propanesulfonates, benzenesulfonates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-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 & Wilkins, Philadelphia, PA, 2006.

[0059] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1-C4 alkyl) 4+ . Also included are base addition salts, such as sodium or potassium salts.

[0060] Also provided are the compounds or pharmaceutically acceptable salts, isomers, or mixtures thereof described herein, wherein 1 to n hydrogen atoms attached to a carbon atom can be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are a non-radioactive isotope of hydrogen atoms. Such compounds can increase resistance to metabolism and can therefore be used to increase the half-life of the compounds or pharmaceutically acceptable salts, isomers, or mixtures thereof described herein when administered to a mammal. See "Foster, "Deuterium Isotope Effects in Drug Metabolism Studies" Trends Pharmacol. Sci. 5(12):524-527 (1984)". Such compounds are synthesized by methods well known in the art, such as using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0061] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2H, 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 for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the following examples, using appropriate isotope-labeled reagents in place of the previously used unlabeled reagents.

[0062] Compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus may exist in enantiomeric, diastereomeric, and other stereoisomeric forms, which can be defined as (R)- or (S)- in terms of absolute stereochemistry, or, for amino acids, as (D)- or (L)-. This statement is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L)-isomers can be prepared using chiral syntheses or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, these compounds are intended to include E and Z geometric isomers unless otherwise specified. Similarly, all tautomeric forms are also included. When a compound is represented in its chiral form, it is understood that the embodiment includes, but is not limited to, specific diastereomeric or enantiomerically enriched forms. If chirality is present but not specified, it is understood that the embodiment is directed to a specific diastereomeric or enantiomerically enriched form; or a racemic or scalar mixture of such compounds. As used herein, "scalar mixture" refers to a mixture of stereoisomers in a non-1:1 ratio.

[0063] As used herein, "stereoisomers" refer to compounds having the same atomic connectivity but different three-dimensional structures that 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.

[0064] As used herein, "tautomers" refer to the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, the present disclosure includes tautomers of the compounds.

[0065] As used herein, "solvates" refer to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0066] As used herein, "hydrates" refer to the compounds of the present invention that are chemically bound to one or more water molecules.

[0067] "Prevent" or "prevent from" refers to any treatment of a disease or disorder that causes the clinical symptoms of the disease or disorder not to develop. In some embodiments, the compounds may be administered to a subject (including a human) having a risk or family history of a disease or disorder.

[0068] As used herein, "prodrugs" refer to derivatives of a drug that are converted to the parent drug upon administration to a human body according to a certain chemical or enzymatic pathway. In some embodiments, the prodrug is a bioactive derivative of the drug that is converted to the bioactive parent drug upon administration to a human body according to some chemical or enzymatic pathway.

[0069] As used herein, "treatment" or "treating" or "treat" refers to a method of obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and / or reducing the severity of the disease or disorder); b) slowing or arresting the development of one or more symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, delaying the worsening or progression of the disease or disorder); and c) alleviating the disease or disorder, e.g., causing the clinical symptoms to subside, improving the disease state, delaying the progression of the disease, improving the quality of life, and / or extending the survival period. As used herein, "at-risk individual" refers to an individual at risk of developing a disease that requires treatment. An individual "at risk" may or may not have a detectable disease or disorder 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 associated with the development of a disease or condition and are known in the art to confer a higher probability of developing a disease or disorder compared to an individual without such risk factors.

[0070] III. Compounds

[0071] One aspect of the present application relates to biaryl compounds of the structure shown in Formula I, and their stereoisomers, pharmaceutically acceptable salts or deuterated compounds:

[0072]

[0073] A, B, and C are each independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , -(CO)R aa , -O-(CO)R aa , wherein C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with a group selected from -OH, -NH2, a halogen, a pseudohalogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6Substituted by a substituent of a cycloalkyl group, a 4- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group; wherein R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0074] X, Y, and Z are each independently selected from N or CR b ; wherein R b is selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , -(CO)R bb , -O-(CO)R bb , wherein C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted by a substituent selected from -OH, -NH2, a halogen, a pseudohalogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, a 4- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group; wherein R bb is selected from H, a halogen, a pseudohalogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0075] D is selected from a cycloalkyl group, a 4- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a bridged ring, which is optionally substituted by -OH, NH2, a halogen, a pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, or C 3-6 cycloalkyl; 3-10 is selected from C

[0076] R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -S(O)2C 1-6 alkyl, -S(O)2C 3-6Cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 Cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group;

[0077] R 2 selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OR 2a , R 2a selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group, wherein C 1-6 alkyl or C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group;

[0078] R 3 and R 3’ each independently selected from a hydrogen atom, -OH, -NH2, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, oxo or C 1-6 alkyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C=S, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may be optionally substituted by -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C1-6 Alkyl substitution;

[0079] R 4 and R 4’ are each independently selected from a hydrogen atom, C 1-6 alkyl, or a halogen;

[0080] and the compound of Formula 1 does not include the following compounds:

[0081]

[0082] In some embodiments, A, B, and C are each independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with a substituent selected from OH, -NH2, a halogen, a 6-membered aryl, a 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0083] In some embodiments, X, Y, and Z are each independently selected from N and CR b ; wherein R b is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl.

[0084] In some embodiments, R aSelected from a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -OCH3, -OCH2CH3, F, Cl.

[0085] In some embodiments, R b Selected from a hydrogen atom, F, Cl, a cyano group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -(SO2)F, -O-(SO2)F.

[0086] In some embodiments, wherein D is selected from an optionally -OH, -NH2, halogen, pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 a cycloalkyl-substituted 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring.

[0087] In some embodiments, wherein D is selected from or bridged ring, wherein R c Selected from a hydrogen atom, -OH, -NH2, halogen, pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl.

[0088] In some embodiments, wherein R c Selected from a hydrogen atom, -OH, -NH2, halogen, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group.

[0089] In some embodiments, wherein D is preferably selected from

[0090]

[0091] In some embodiments, wherein R 1 Selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC1-6 haloalkyl, -OC 3-6 substituted by halo cycloalkyl.

[0092] In some embodiments, wherein R 1 is selected from C 1-6 alkyl optionally substituted by halogen.

[0093] In some embodiments, R 1 is selected from

[0094]

[0095] In some embodiments, R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted by -OH, -NH2, halogen.

[0096] In some embodiments, R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by F.

[0097] In some embodiments, wherein R 2 is selected from methyl, -OCH3 or -OCF3.

[0098] In some embodiments, R 3 , R 3’ are each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4-6 membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group may optionally be substituted by -OH, -NH2, halogen, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4-6 membered heterocyclic group may optionally be substituted by -OH, -NH2, halogen or C 1-6 alkyl.

[0099] In some embodiments, R 3 and R 3’Each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or R 3 and R 3’ Optionally together with the carbon atom to which they are attached form C═O, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0100] In some embodiments, R 3 is H; R 3’ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl.

[0101] In some embodiments, R 4 and R 4’ are independently selected from a hydrogen atom or a halogen.

[0102] In some embodiments, the compound of formula I of the present application has the structure shown in formula II:

[0103]

[0104] Wherein, R a1 is selected from a hydrogen atom, -OH, -NH2, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with substituents selected from OH, NH2, halogen, 6-membered aryl, 5- to 6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0105] R b1 is selected from a hydrogen atom, -OH, -NH2, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with substituents selected from -OH, -NH2, halogen; R bb is selected from H, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl;

[0106] B and C are each independently selected from N and CR a ; where R a is selected from a hydrogen atom, -OH, -NH2, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , where C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with substituents selected from OH, -NH2, halogen, 6-membered aryl, 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0107] Y and Z are each independently selected from N and CR b ; where R b is selected from a hydrogen atom, -OH, -NH2, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , where C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with substituents selected from -OH, -NH2, halogen; R bb is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0108] D is selected from a 6-10 membered aryl ring or 5-10 membered heteroaryl ring optionally substituted with -OH, -NH2, halogen, pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl;

[0109] R 1 is selected from C 1-6 alkyl, -C(O)C1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group may optionally be substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl substituted;

[0110] R 2 selected from cyano, C 1-6 alkyl, -OR 2a , R 2a selected from C 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted by -OH, -NH2, halogen;

[0111] R 3 、R 3’ each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4-6 membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group may optionally be substituted by -OH, -NH2, halogen, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4-6 membered heterocyclic group may optionally be substituted by -OH, -NH2, halogen or C 1-6 alkyl substituted;

[0112] R 4 and R 4’ independently selected from a hydrogen atom or a halogen;

[0113] and the compound of formula II does not include the following compounds:

[0114]

[0115] In some embodiments, wherein R a1Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl; R b1 Selected from a hydrogen atom, a halogen, a cyano group, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -O-(SO2)F.

[0116] In some embodiments, wherein B and C are each independently selected from N and CR a ; wherein R a Selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl;

[0117] Y and Z are each independently selected from N and CR b ; wherein R b Selected from a hydrogen atom, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -O-(SO2)F.

[0118] In some embodiments, wherein D is selected from or a bridged ring, wherein R c Selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl.

[0119] In some embodiments, wherein R c Selected from a hydrogen atom, -OH, -NH2, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl.

[0120] In some embodiments, wherein D is selected from

[0121]

[0122] In some embodiments, wherein R 1 Selected from optionally halogen-substituted C 1-6 alkyl;

[0123] In some embodiments, wherein R 1 Selected from

[0124]

[0125] In some embodiments, wherein R 2 Selected from cyano, C 1-6 alkyl, -OR 2a wherein R 2a Selected from C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with F.

[0126] In some embodiments, where R 2 is selected from methyl, -OCH3 or -OCF3.

[0127] In some embodiments, where R 3 and R 3’ are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C═O, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0128] In some embodiments, where R 3 is H; R 3’ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl.

[0129] In some embodiments, the compound of formula I of the present application has the structure shown in formula III:

[0130]

[0131] wherein, R a1 is selected from H, halogen, -NH2, C 1-6 alkyl, -OC 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted by halogen, 6-membered aryl or 5- to 6-membered heteroaryl;

[0132] R b1 is selected from a hydrogen atom, halogen, C 1-6 alkyl, -(SO2)R bb , -O(SO2)R bb , wherein C 1-6 alkyl may optionally be substituted by halogen; R bb is selected from H, halogen, C 1-6 alkyl;

[0133] B, C, Y, Z are each independently selected from N or CH;

[0134] R c is selected from a hydrogen atom, -OH, -NH2, halogen, pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl;

[0135] R1 Selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group may optionally be substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl substituted;

[0136] R 2 Selected from cyano, C 1-6 alkyl, -OR 2a , R 2a Selected from C 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted by -OH, -NH2, -halogen;

[0137] R 3 、R 3’ Each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may optionally be substituted by OH, NH2, halogen, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may optionally be substituted by OH, NH2, halogen or C 1-6 alkyl substituted;

[0138] And the compound of formula III does not include the following compounds:

[0139]

[0140] In some embodiments, wherein R a1Selected from a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -OCH3, -OCH2CH3, F, Cl;; R b1 Selected from a hydrogen atom, a halogen, a cyano group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -(SO2)F, -O-(SO2)F.

[0141] In some embodiments, wherein R c Selected from a hydrogen atom, -OH, -NH2, a halogen, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group.

[0142] In some embodiments, wherein R 1 Selected from C 1-6 alkyl optionally substituted with a halogen;

[0143] In some embodiments, wherein R 1 Selected from

[0144]

[0145] In some embodiments, wherein R 2 Selected from a cyano group, C 1-6 alkyl, -OR 2a , R 2a Selected from C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with F.

[0146] In some embodiments, wherein R 2 Selected from methyl, -OCH3 or -OCF3.

[0147] In some embodiments, wherein R 3 and R 3’ are each independently selected from H, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, a 4-6 membered heterocyclic group.

[0148] In some embodiments, wherein R 3 is H, R 3’ Selected from H, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group.

[0149] In some embodiments, the compound of formula I of the present application has the structure shown in formula IV:

[0150]

[0151] wherein R a1 is selected from H, F, Cl, -NH2, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3;

[0152] R b1 is selected from H, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -(SO2)F;

[0153] R 1 is selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl;

[0154] R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein the C 1-6 alkyl may be optionally substituted by -OH, -NH2, halogen;

[0155] R 3 , R 3’ are each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may be optionally substituted by OH, NH2, halogen, or R 3 and R 3’ may optionally form, together with the carbon atom to which they are attached, C=O, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may be optionally substituted by OH, NH2, halogen or C1-6 Alkyl substitution;

[0156] and the compound of formula IV does not include the following compounds:

[0157]

[0158] In some embodiments, R a1 is selected from -OCH3, R b1 is selected from F.

[0159] In some embodiments, R 1 is selected from

[0160]

[0161] In some embodiments, R 2 is selected from methyl, -OCH3 or -OCF3.

[0162] In some embodiments, R 3 is H, R 3’ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4-6 membered heterocyclic group.

[0163] In some embodiments, the compound of formula I of the present application has the structure shown in formula V:

[0164]

[0165] wherein, R a1 is selected from a hydrogen atom, -OH, -NH2, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa 、-O-(SO2)-R aa ,wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted by substituents selected from OH, NH2, halogen, 6-membered aryl, 5-6 membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0166] R b1Selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, and a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0167] B and C are each independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, a halogen, a 6-membered aryl, and a 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0168] Y and Z are each independently selected from N and CR b ; wherein selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, and a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6Naphthenyl;

[0169] D is selected from optionally -OH, -NH2, halogen, pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 naphthenyl, C 1-6 alkyl, C 3-6 a 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring substituted with naphthenyl;

[0170] R 1 is selected from being C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 naphthenyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 naphthenyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group may optionally be substituted with -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 naphthenyl, -OC 1-6 alkyl, -OC 3-6 naphthenyl, C 1-6 haloalkyl, C 3-6 halonaphthenyl, -OC 1-6 haloalkyl, -OC 3-6 halonaphthenyl substituted;

[0171] R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted with -OH, -NH2, halogen;

[0172] R 4 and R 4’ are independently selected from a hydrogen atom or a halogen.

[0173] In some embodiments, wherein R a1 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl; R b1 is selected from a hydrogen atom, a halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -O-(SO2)F.

[0174] In some embodiments, wherein B, C are each independently selected from N and CR a ; wherein R aSelected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl;

[0175] In some embodiments, Y and Z are each independently selected from N and CR b ; where R b is selected from a hydrogen atom, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,, -(SO2)F, -O(SO2)F;

[0176] In some embodiments, wherein D is selected from or bridged ring, where R c is selected from a hydrogen atom, -OH, -NH2, a halogen, pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl;

[0177] In some embodiments, wherein R c is selected from a hydrogen atom, -OH, -NH2, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl.

[0178] In some embodiments, wherein D is selected from

[0179]

[0180] In some embodiments, wherein R1 is selected from C 1-6 alkyl optionally substituted with a halogen.

[0181] In some embodiments, wherein R 1 is selected from

[0182]

[0183] In some embodiments, wherein R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with F.

[0184] In some embodiments, wherein R 2 is selected from methyl, -OCH3 or -OCF3.

[0185] In some embodiments, the compound of formula I of the present application has the structure shown in formula VI:

[0186]

[0187] wherein, R a1 is selected from H, halogen, -NH2, C 1-6 alkyl, -OC 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted by halogen, 6-membered aryl or 5-6-membered heteroaryl;

[0188] R b1 is selected from a hydrogen atom, halogen, C 1-6 alkyl, -(SO2)R bb , -O(SO2)R bb , wherein C 1-6 alkyl may optionally be substituted by halogen; R bb is selected from H, halogen, C 1-6 alkyl;

[0189] B, C, Y, Z are each independently selected from N or CH;

[0190] R c is selected from a hydrogen atom, -OH, -NH2, halogen, pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl;

[0191] R 1 is selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4-10-membered heterocyclic group, 6-10-membered aryl, 5-10-membered heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10-membered heterocyclic group, 6-10-membered aryl, 5-10-membered heteroaryl may optionally be substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl;

[0192] R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein C1-6 The alkyl group may optionally be substituted with -OH, -NH2, or a halogen.

[0193] In some embodiments, where R a1 is selected from a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -OCH3, -OCH2CH3, F, Cl;

[0194] In some embodiments, R b1 is selected from a hydrogen atom, a halogen, a cyano group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -(SO2)F, -O-(SO2)F.

[0195] In some embodiments, where R c is selected from a hydrogen atom, -OH, -NH2, a halogen, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group.

[0196] In some embodiments, where R 1 is selected from a C1-6 alkyl group optionally substituted with a halogen.

[0197] In some embodiments, where R 1 is selected from

[0198]

[0199] In some embodiments, where R 2 is selected from a cyano group, a C 1-6 alkyl group, -OR 2a , R 2a is selected from a C 1-6 alkyl group, where the C 1-6 alkyl group is optionally substituted with F.

[0200] In some embodiments, where R 2 is selected from a methyl group, -OCH3, or -OCF3.

[0201] In some embodiments, the compound of formula I is selected from:

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209] and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds.

[0210] On the other hand, the present application relates to a composition comprising the compound described in any one of the above, and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds, and a pharmaceutically acceptable excipient.

[0211] On the other hand, the present application relates to a method for treating a disease or symptom mediated by GIPR / GLP1R / GCGR, comprising the steps of: administering to a subject an effective amount of the compound described in any one of the above, and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds, or an effective amount of the above composition.

[0212] On the other hand, the present application relates to the use of the compound described in any one of the above in the preparation of a medicament for treating a disease or symptom mediated by GIPR / GLP1R / GCGR, comprising the steps of: administering to a subject an effective amount of the above compound, and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds, or an effective amount of the above composition.

[0213] The diseases or symptoms mediated by GIPR / GLP1R / GCGR include: T1DM, 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, long-term weight management, obesity, eating disorders, weight gain caused by other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular diseases, atherosclerosis, coronary artery disease, peripheral vascular diseases, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial diseases, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, 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, hyperapolipoprotein B lipoproteinemia, 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.

[0214] Route of administration

[0215] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural), etc. It is understood that the preferred route may vary depending on, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0216] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one embodiment, the compound is administered daily or intermittently for the duration of the individual's life.

[0217] The dosage or frequency of administration of the compounds of the present disclosure can be adjusted during the course of treatment based on the judgment of the administering physician.

[0218] The compound can be administered to an individual (such as a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0219] The compound can be administered by any useful route and means, such as orally or parenterally (e.g., intravenously). The therapeutically effective amount of the compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

[0220] The compounds of the present disclosure can be combined with one or more additional therapeutic agents in any dosage amount of the compounds of the present disclosure (e.g., from 1 mg to 1000 mg of the compound). The therapeutically effective amount can include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450 or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16, or 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or 7 days. A single dose can also be administered once every 1 week, 2, 3, or 4 weeks. In some embodiments, a single dose can be administered once a week. A single dose can also be administered once a month.

[0221] Kits containing a compound of the present disclosure, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing are also included in the present disclosure. In one embodiment, a kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, isomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, and a label and / or instructions for using the compound in the treatment of an indication described herein, such as a disease or disorder. In one embodiment, a kit is provided that comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

[0222] Articles of manufacture are also provided herein that comprise a compound of the present disclosure or a pharmaceutically acceptable salt, isomer, mixture of stereoisomers, prodrug or deuterated analogue thereof in a suitable container. The container can be a vial, jar, ampule, prefilled syringe and intravenous bag. Example 1:

[0223] Synthesis

[0224] The compounds of the present invention can be prepared by the methods disclosed herein and their conventional modifications, which are obvious in view of the methods disclosed herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used.

[0225] The synthesis of a representative compound of formula I or a pharmaceutically acceptable salt thereof, e.g., a compound having one or more of the structures described in formula I, or other formulas or compounds disclosed herein, can be accomplished as described in the following examples.

[0226] General synthetic method

[0227] Exemplary embodiments of the compounds according to the present disclosure can be synthesized using the general reaction schemes and / or examples described below. In view of the description herein, it is obvious that the general scheme can be varied by substituting other materials having similar structures for the starting materials, thereby producing correspondingly different products. The following synthesis descriptions provide many examples of how the starting materials are varied to provide the corresponding products. The starting materials are generally obtained from commercial sources or synthesized using published methods for synthesizing compounds that are embodiments of the present disclosure. Examining the structure of the compound to be synthesized will provide the identity of each substituent, and in view of the examples herein, the identity of the necessary starting materials will usually become obvious through a simple examination process for the identity of the final product. The group labels (such as R1, R2) used in the reaction schemes herein are for illustrative purposes only and are not necessarily consistent in name or function with the labels used elsewhere to describe the compounds of formula I or aspects or fragments thereof, unless otherwise stated.

[0228] Synthesis reaction parameters

[0229] The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It is understood that typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given; other process conditions can also be used unless otherwise specified. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0230] In addition, for those skilled in the art, traditional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Protecting groups for various functional groups and the appropriate conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in T.W. Greene and G.M. Wuts (1999) Protective Groups in Organic Synthesis, Third Edition, Wiley, New York, and the references cited therein.

[0231] In addition, the compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as a stereoisomer-enriched mixture. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are included within the scope of this claim. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Additionally, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0232] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by the procedures described in standard references or obvious modifications thereof, such as Fieser's Reagents for Organic Synthesis: Volumes 1 - 15 (John Wiley, and Sons, 1991); Rodd's Chemistry of Carbon Compounds: Volumes 1 - 5, and Supplemental Editions (Elsevier Science Publishers, 1989); Organic Reactions Volumes 1 - 40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5 thEdition, 2001), and Larock's "Comprehensive Organic Transformations" (VCH Publishers, 1989).

[0233] The terms "solvent", "inert organic solvent" or "inert solvent" refer to an inert solvent under the reaction conditions associated therewith (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, dichloromethane (or methylene chloride), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvent used in the reactions of the present disclosure is an inert organic solvent, and the reactions are carried out under an inert gas, preferably nitrogen.

[0234] The term "q.s." means adding an amount sufficient to achieve the stated function, e.g., to bring the solution to the desired volume (i.e., 100%).

[0235] The compounds provided herein can be synthesized according to the general scheme provided below. In the schemes below, it should be understood that each of the compounds shown therein can be present with protecting groups as required at any step. Standard protecting groups are within the purview of those skilled in the art.

[0236] Synthesis experiments

[0237] Route 1: Synthesis of Intermediate A1:

[0238]

[0239] Step 1: Synthesis of Compound A1-2:

[0240] At 0 °C, TEA (20.08 g, 198.41 mmol) was added to a solution of 2-(3-methoxyphenyl)ethan-1-amine (20 g, 132.27 mmol) in DCM (180 mL), then acetyl chloride (11.42 g, 145.50 mmol) was added and the mixture was stirred at RT for 2 h. The mixture was quenched with H2O and the aqueous phase was extracted with DCM (100 mL) * 2. The combined organic layers were washed with aqueous HCl solution (0.5 N) and brine (80 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure to give N-(2-(3-methoxyphenyl)ethyl)acetamide A1-2 as an orange oil (26.1 g, yield 102.12%, crude).

[0241] Step 2: Synthesis of Compound A1-3:

[0242] To a solution of A1-2 (26 g, 134.55 mmol) in acetonitrile (250 mL) was added phosphorus trichloride (24.76 g, 161.46 mmol), and the mixture was stirred at 75 °C for 3 h. The mixture was poured into an aqueous solution of K3PO4, and the aqueous phase was extracted with EA (150 mL) * 2. The combined organic layers were washed with brine (200 mL) and dried over Na2SO4, concentrated to dryness under reduced pressure to give 6-methoxy-1-methyl-3,4-dihydroisoquinoline A1-3 as an orange solid (16 g, yield 67.86%).

[0243] Step 3: Synthesis of compound A1-4:

[0244] To a solution of A1-3 (9 g, 51.36 mmol) in acetonitrile (80 mL) were added N,N-diethylethylamine, formic acid (33.32 g, 77.04 mmol), (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethane diamine (p-cumene) ruthenium(II) chloride (326.76 mg, 0.51 mmol), and the mixture was stirred overnight at room temperature under N2. Then it was diluted with EA and washed twice with aqueous K2CO3 (3 M) and brine. Concentrated to dryness under reduced pressure to give a residue that was dissolved in water, and tert-butoxycarbonic anhydride (11.21 g, 51.36 mmol) was added. The mixture was stirred with water at room temperature for 2 h. NaHCO3 was added and the mixture was extracted with DCM (150 mL) * 2. The combined organic layers were washed with brine (300 mL) and dried over Na2SO4, concentrated to dryness under reduced pressure to give tert-butyl 6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate, namely A1-4 (15 g, yield 63.18%)

[0245] Step 4: Synthesis of compound A1-5:

[0246] To a solution of A1-4 (15 g, 32.45 mmol) in acetic acid (70 mL) was added sodium acetate trihydrate (6.62 g, 48.68 mmol), and the mixture was stirred at room temperature for 0.5 h. Then N-bromosuccinimide (6.35 g, 35.70 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was quenched with NaHCO3 (aqueous solution), and the aqueous phase was extracted with EA (100 mL) * 2. The combined organic layers were washed with brine (150 mL) and dried over Na2SO4, concentrated to dryness under reduced pressure to give a residue, which was purified by silica gel chromatography, eluted with PE∶EA = 10∶1 to give a crude product, and the crude product was purified by preparative HPLC to give A1-5 as a yellow solid (1.7 g, yield 14.71%).

[0247] Step 5: Synthesis of compound A1-6:

[0248] Hydrogen chloride (4 M in dioxane, 8 mL, 32 mmol) was added to a solution of A1-5 (1.7 g, 4.77 mmol) in 1,4-dioxane (15 mL), and the mixture was stirred at RT for 3 hours. The mixture was concentrated to dryness under reduced pressure to give A1-6 as a white solid (1.1 g, yield 81.00%).

[0249] Step 6: Synthesis of compound A1:

[0250] 4-Isopropylacetophenone (126.54 mg, 0.78 mmol) and titanium tetraethoxide (2176.03 mg, 9.54 mmol) were added to a solution of A1-6 (200 mg, 0.78 mmol) in THF (3 mL), and the mixture was stirred at 75 °C overnight. Then sodium borohydride (59.01 mg, 1.56 mmol) was added, and the mixture was stirred at RT for 2 hours. The mixture was purified by preparative HPLC to give A1 as a white solid (37 mg, yield 12.20%).

[0251] Synthesis of compounds A2, A3, A4 and A5: Refer to the synthesis method of A1

[0252]

[0253] Route 2: Synthesis of intermediates A6, A7 and A8:

[0254]

[0255] Synthesis of compound A6-1:

[0256] 1,4-Diacetylbenzene (1265 mg, 7.8 mmol) and titanium tetraethoxide (21 g, 95.4 mmol) were added to a solution of A1-6 (2000 mg, 7.8 mmol) in THF (3 mL), and the mixture was stirred at 75 °C overnight. Then sodium borohydride (600.01 mg, 16 mmol) was added, and the mixture was stirred at RT for 2 hours. The mixture was purified by preparative HPLC to give A6-1 as a solid (380 mg, yield 12.20%).

[0257] Synthesis of compound A6:

[0258] MeLi (0.55 mL, 0.55 mmol) was added to a solution of A6-1 (200 mg, 0.515 mmol) in THF (3 mL) at -75 °C for 15 minutes and stirred for 2 hours. The mixture was purified by preparative HPLC to give A6 as a solid (201 mg, yield 95%).

[0259] Synthesis of compound A7:

[0260]

[0261] To a solution of A6 (100 mg, 0.25 mmol) in DCM (3 mL) at 0 °C was added DAST (88 mg, 0.55 mmol) over 15 minutes and stirred for 2 hours. The mixture was purified by preparative HPLC to give solid A7 (101 mg, 95% yield).

[0262] Synthesis of compound A8:

[0263]

[0264] Synthesis of compound A8-1:

[0265] To a solution of A6-1 (403 mg, 1.0 mmol) in THF (3 mL) at room temperature was added NH3·MeOH (0.5 mL, 3.5 mmol) over 15 minutes and stirred for 2 hours. The above mixture was concentrated under reduced pressure. A8-1 was obtained and used directly without further purification.

[0266] Synthesis of compound A8:

[0267] To a solution of A8-1 in THF (3 mL) at -75 °C was added MeLi (0.55 mL, 0.55 mmol) over 15 minutes and stirred for 2 hours. The mixture was purified by preparative HPLC to give solid A8 (201 mg, 95% yield).

[0268] Route 3: Synthesis of compound A9:

[0269]

[0270] Synthesis of compound A9-2:

[0271] To a solution of A9-1 (20 g, 100 mmol) in THF (100 mL) at 0 °C was added iPrMgBr (100 mL, 100 mmol) over 15 minutes and stirred for 2 hours. Cyclopropanone was added via syringe. The above mixture was quenched with saturated NH4Cl and extracted with EA. The organic phase was concentrated under reduced pressure. A9-2 was obtained and used directly without further purification.

[0272] Synthesis of compound A9-3:

[0273] To a solution of A9-2 (25 g, 97 mmol) and pyridine (15 mL) in DCM (100 mL) at -50 °C was added Ms2O (20.88 g, 150 mmol) over 30 min, and the mixture was stirred at 0 °C for 2 h. The above mixture was quenched by adding PE and recrystallized, and washed with cold PE. A9-3 was obtained and used directly without further purification.

[0274] Synthesis of compound A9:

[0275] To a solution of A1-6 (255 mg, 1.0 mmol) and K2CO3 (414 mg, 3.0 mmol) in THF (10 mL) at room temperature was added A9-3 (256 mg, 1.0 mol), and the mixture was stirred at 55 °C for 2 h. The mixture was purified by preparative HPLC to give solid A9 (400 mg, yield 96%).

[0276] Synthesis of compounds A10 and A11: Refer to the synthesis method of A2

[0277]

[0278] Route 3: Synthesis of compound A12:

[0279]

[0280] Synthesis of compound A12-2:

[0281] To a solution of A12-1 (19 g, 90 mmol) in THF (100 mL) at room temperature was added SeO2 (33.3 g, 300 mmol), and the mixture was stirred at 60 °C for 2 h. The above mixture was filtered and concentrated under reduced pressure to obtain A12-2, which was used directly without further purification.

[0282] Synthesis of compound A12-3:

[0283] To a solution of A12-2 (20 g, 100 mmol) in THF (100 mL) at room temperature was added NH3·MeOH (30 mL, 210 mmol) and stirred for 2 h. Then NaBH4 (7.2 g, 200 mmol) was added portionwise, and the mixture was stirred at room temperature for 2 h. The above mixture was quenched with saturated NH4Cl and extracted with EA. The organic phase was concentrated under reduced pressure and then subjected to chiral resolution to obtain A12-3.

[0284] Synthesis of compound A12-4:

[0285] To a solution of A12-3 (8.6 g, 40 mmol) and TEA (4 mL) in THF (40 mL) at -50 °C was added methyl oxalyl chloride (5 g, 41 mmol), and the mixture was stirred at 0 °C for 2 h. Then 100 mL of aqueous NaOH solution was added, and the mixture was stirred at RT for 5 h. The above mixture was acidified with aqueous HCl solution (6 N), recrystallized with brine and washed. A12-4 was obtained and used directly without further purification.

[0286] Synthesis of compound A12-6:

[0287] According to the literature-reported method, compound A12-4 was subjected to Friedel-Crafts acylation catalyzed by ACl3 to produce A12-5, and A12-5 was deoxygenated and hydrogenated with LiAlH4 to give compound A12-6 in good to moderate yield.

[0288] Synthesis of compound A12: Refer to the synthesis method of A2

[0289] Route 4: Synthesis of compound A13:

[0290]

[0291] Synthesis of compound A13-1:

[0292] A13-0 was synthesized by referring to the synthesis method of A12-5. To a THF solution (40 mL) of A13-0 (5.5 g, 20 mmol) and 1,2-ethanedithiol (4 mL) was added titanium tetraethoxide (2176.03 mg, 9.54 mmol), and the mixture was stirred at 75 °C overnight. The above mixture was purified by silica gel column to obtain solid A13-1 (4.3 g, yield 60.20%).

[0293] Synthesis of compound A13-2:

[0294] To a DCM solution (3 mL) of A13-1 (3.61 g, 10 mmol) at 0 °C was added DAST (4.18 g, 25 mmol) for 15 min and stirred for 2 h. The mixture was purified by preparative HPLC to obtain solid A13-2 (1.67 g, yield 55%).

[0295] Synthesis of compound A13-3:

[0296] According to the literature-reported procedure, A12-5 was deoxygenated and hydrogenated with LiAlH4 to give compound A13-3 in good to moderate yield.

[0297] Synthesis of compound A13: Refer to the synthesis method of A2

[0298] Route 5: Synthesis of Compound A14

[0299]

[0300] Step 1: Synthesis of Compound A14-2

[0301] At 0 °C, TEA (20.08 g, 198.41 mmol) was added to a DCM solution (180 mL) of 14-1 (20 g, 141 mmol), then acetyl chloride (11.42 g, 145.50 mmol) was added and the mixture was stirred at RT for 2 h. The mixture was quenched with H2O and the aqueous phase was extracted with DCM (100 mL) * 2. The combined organic layers were washed with aqueous HCl solution (0.5 N) and brine (80 mL), dried over Na2SO4, and concentrated to dryness under reduced pressure to obtain A14-2 as an orange oil (25.1 g, yield 102.12%, crude).

[0302] Step 2: Synthesis of Compound A14-3

[0303] Phosphorus trichloride (24.76 g, 161.46 mmol) was added to an acetonitrile solution (250 mL) of A14-2 (25 g, 140 mmol), and the mixture was stirred at 75 °C for 3 h. The mixture was poured into an aqueous solution of K3PO4 and the aqueous phase was extracted with EA (150 mL) * 2. The combined organic layers were washed with brine (200 mL) and dried over Na2SO4, and concentrated to dryness under reduced pressure to obtain solid A14-3 (16 g, yield 67.86%).

[0304] Step 3: Synthesis of Compound A14-4

[0305] At 0 °C, NaBH4 (3.7 g, 100 mmol) was added to a MeOH solution (80 mL) of A14-3 (9 g, 51.36 mmol) and stirred for 3 h. The above mixture was quenched with saturated NH4Cl and extracted with EA. The organic phase was concentrated under reduced pressure to obtain a racemic mixture of A14-4. Optically pure A14-4 was obtained by chiral resolution.

[0306] Step 4: Synthesis of Compound A14-5

[0307] At room temperature, NH3·MeOH (0.5 mL, 3.5 mmol) was added to a 1,4-dioxane solution (70 mL) of A1-4 (15 g, 32.45 mmol), and the mixture was stirred at 85 °C for 5 h. The above mixture was concentrated under reduced pressure. A14-5 was obtained and used directly without further purification.

[0308] Step 5: Synthesis of Compound A14-6

[0309] To a solution of A14-5 (15 g, 32.45 mmol) in acetic acid (70 mL) was added sodium acetate trihydrate (6.62 g, 48.68 mmol), and the mixture was stirred at room temperature for 0.5 h. Then N-bromosuccinimide (6.35 g, 35.70 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was quenched with NaHCO3 (aqueous solution), and the aqueous phase was extracted with EA (100 mL) * 2. The combined organic layers were washed with brine (150 mL) and dried over Na2SO4, concentrated to dryness under reduced pressure to obtain a residue, which was purified by silica gel chromatography, eluted with PE∶EA = 10∶1, to obtain a crude product, which was purified by preparative HPLC to obtain solid A14-6 (1.7 g, yield 14.71%).

[0310] Step 6: Synthesis of compound A14: Refer to the synthesis method of A2

[0311] Route 6: Synthesis of intermediate B1:

[0312]

[0313] Step 1: Synthesis of compound B1-2:

[0314] To a THF solution (1 mL) of 2-amino-4-bromo-6-fluorophenol (200 mg, 0.97 mmol) was added trimethylacetaldehyde (83.55 mg, 0.97% mmol), then acetic acid (419.97 mg, 6.99% mmol) and methanol (3 mL) were added at 0 °C, and the mixture was stirred for 2 min. Borane-2-methylpyridine complex (155.63 mg, 1.46 mmol%) was added and the mixture was stirred at 60 °C overnight. The mixture was concentrated to dryness under reduced pressure to obtain a residue, which was purified by silica gel chromatography eluted with PE∶EA = 9∶1 to obtain B1-2 as a brown oil (120 mg, yield 44.76%).

[0315] Step 2: Synthesis of compound B1:

[0316] To a 1,4-dioxane solution (5 mL) of 4-bromo-2-[(2,2-dimethylpropyl)amino]-6-fluorophenol (120 mg, 0.43 mmol) was added [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (31.46 mg, 0.043 mmol). Water was added and the aqueous phase was extracted with EA (10 mL) * 2. The combined organic layers were washed with brine (15 mL) and dried over Na2SO4, concentrated to dryness under reduced pressure to obtain B1 as a brown oil (220 mg, yield 125.31%, crude product).

[0317] Synthesis of Compounds B2, B3, and B4: Refer to the synthesis method of B1

[0318]

[0319] Route 7: Synthesis of Compounds cpd 1 - cpd 17:

[0320]

[0321] Synthesis of Compound cpd 2:

[0322] To a solution of B1 (20.95 mg, 0.060 mmol) in 1,4 - dioxane (1.5 mL) and water (0.5 mL) was added A1 (23.30 mg, 0.060 mmol), tripotassium phosphate (31.84 mg, 0.15 mmol), and XPhos G3 (5.08 mg, 0.0060 mmol). The mixture was stirred at 90 °C under N2 for 3 hours. The mixture was concentrated to dryness under reduced pressure to give a residue, which was purified by preparative - scale HPLC to give cpd 2 (6 mg, yield 18.85%) as a solid.

[0323] Synthesis of Compounds cpd 1 - cpd 17: Refer to the synthesis method of cpd 2

[0324]

[0325]

[0326]

[0327] According to the preparation methods described herein, using appropriate starting materials and intermediates, and, when necessary, appropriate protecting - group chemistry, the following compounds were prepared. Their structures were confirmed by MS and 1 1H - NMR.

[0328]

[0329]

[0330]

[0331]

[0332]

[0333] Synthesis of Intermediates A1a and A1b

[0334]

[0335] To a reaction flask containing 1-(1-chloroethyl)-4-isopropylbenzene (1.85 g, 10.15 mmol), N,N-diisopropylethylamine (2.02 g, 15.62 mmol) and potassium iodide (1.43 g, 8.56 mmol), N,N-dimethylacetamide (10 mL) was added. The mixture was stirred at room temperature for 10 min, and then (R)-5-bromo-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline A1-6 (2 g, 7.81 mmol) was added. The reaction was carried out at 70 °C for 3 h. After the reaction was completed, ethyl acetate (50 mL) and water (50 mL) were added for extraction. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was carefully separated and purified by column chromatography to obtain a pair of enantiomers A1a (790 mg) and A1b (558 mg). MS (ESI + ) m / z: 402.24 (M+H + ).

[0336] A1a: 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.68 (q, J = 6.5 Hz, 1H), 3.11–2.87 (m, 3H), 2.83–2.58 (m, 2H), 1.42 (d, J = 6.5 Hz, 3H), 1.33 (d, J = 6.7 Hz, 3H), 1.30 (d, J = 6.9 Hz, 6H).

[0337] A1b: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 9.5 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.09–3.98 (m, 1H), 3.91 (s, 3H), 3.76 (q, J = 6.4 Hz, 1H), 3.11–2.76 (m, 4H), 2.72–2.63 (m, 1H), 1.41 (d, J = 5.2 Hz, 3H), 1.36–1.32 (m, 3H), 1.29 (d, J = 6.9 Hz, 6H).

[0338] Synthesis of intermediates A15a and A15b

[0339]

[0340] Step 1: To a solution of (1R)-5-bromo-2-(1-(4-isopropylphenyl)ethyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline A1a (120 mg, 0.30 mmol) in DCM (4 mL) at 0 °C was added boron tribromide (2.99 g, 11.94 mmol). The solution was stirred at 20 °C for 2 h under a nitrogen atmosphere to obtain a red solution. LCMS showed that the reaction was complete. The mixture was quenched with methanol (5 mL) at 0 °C, and the solvent was removed by concentration under reduced pressure. It was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution (20 mL). Washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A1a-1 (116 mg, yield: 100%). MS m / z (ESI): 388.2 [m+1].

[0341] Step 2: To a solution of compound A1a-1 (39 mg, 0.1 mmol) and potassium carbonate (55 mg, 0.4 mmol) in acetonitrile (2 mL) was added (2-bromoethyl)benzene (29 mg, 0.16 mmol). The reactant was stirred at 88 °C for 2 h to obtain a yellow solution. LCMS showed that the reaction was complete. Filtered and the solvent was removed by concentration under reduced pressure, and purified by silica gel column chromatography to obtain compound A15a (30 mg, yield: 59%). MS m / z (ESI): 492.31 [m+1].

[0342] Referring to the synthetic route of reference compound A15a, A1a was replaced with A1b, and compound A15b was synthesized and prepared.

[0343] Synthesis of intermediates A16a and A16b

[0344]

[0345] Referring to the synthetic route of reference compound A15a, (2-bromoethyl)benzene was replaced with (3-bromopropyl)benzene, and compound A16a was synthesized and prepared. MS m / z (ESI): 506.38 [m+1].

[0346] Referring to the synthetic route of reference compound A15a, (2-bromoethyl)benzene was replaced with (3-bromopropyl)benzene, and A1a was replaced with A1b, and compound A16b was synthesized and prepared.

[0347] Intermediate A17

[0348]

[0349] To a reaction flask containing 1-(bromomethyl)-4-isopropylbenzene (756 mg, 2.73 mmol), N,N-diisopropylethylamine (706 mg, 5.46 mmol) and potassium iodide (499 mg, 3.00 mmol), N,N-dimethylacetamide (10 mL) was added. The mixture was stirred at room temperature for 10 min, then (R)-5-bromo-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline A1-6 (700 mg, 2.73 mmol) was added, and the reaction was carried out at 70 °C for 3 h. After the reaction was completed, ethyl acetate (50 mL) and water (50 mL) were added for extraction. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE / EA) to obtain compound A17 (623 mg). MS (ESI + ) m / z: 388.24 (M+H + ). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 3.96–3.88 (m, 4H), 3.79 - 3.69 (m, 2H), 3.16–3.07 (m, 1H), 3.02–2.90 (m, 1H), 2.90–2.69 (m, 3H), 1.40 (d, J = 6.7 Hz, 3H), 1.31 (d, J = 6.9 Hz, 6H).

[0350] Intermediate A18

[0351]

[0352] To a solution of (R)-5-bromo-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline A1-6 (46 mg, 0.18 mmol), 4-isopropylbenzoic acid (44 mg, 0.27 mmol), ethyldiisopropylamine (28 mg, 0.22 mmol), 4-dimethylaminopyridine (66 mg, 0.54 mmol) in N,N-dimethylformamide (2 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 1 h to obtain a yellow solution. LCMS showed that the reaction was complete. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL × 2), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to obtain compound A18 (60 mg, yield: 83%). MS m / z (ESI): 402.3 [M+1].

[0353] Intermediate A19

[0354]

[0355] Referring to the synthesis of intermediate A18, 4-isopropylbenzoic acid was replaced with 4-tert-butylbenzoic acid, and compound A19 was synthesized and prepared. MS m / z (ESI): 831.42 [2m + 1]

[0356] Intermediate A20

[0357]

[0358] Referring to the synthesis of intermediate A18, 4-isopropylbenzoic acid was replaced with 3-fluoro-4-methylbenzoic acid, and compound A20 was synthesized and prepared. MS m / z (ESI): 392.15 [m + 1]

[0359] Intermediate A21

[0360]

[0361] Referring to the synthesis of intermediate A18, 4-isopropylbenzoic acid was replaced with 4-butylbenzoic acid, and compound A21 was synthesized and prepared. MS m / z (ESI): 831.42 [2m + 1]

[0362] Intermediate A22

[0363]

[0364] Referring to the synthesis of intermediate A18, 4-isopropylbenzoic acid was replaced with 2-fluoro-4-trifluoromethylbenzoic acid, and compound A22 was synthesized and prepared. MS m / z (ESI): 446.14 [m + 1]

[0365] Intermediate A23

[0366]

[0367] Referring to the synthesis of intermediate A18, 4-isopropylbenzoic acid was replaced with 4-trifluoromethylbenzoic acid, and compound A23 was synthesized and prepared. MS m / z (ESI): 428.17 [m + 1].

[0368] Intermediate A24

[0369]

[0370] Referring to the synthesis of intermediate A18, 4-cyanobenzoic acid was replaced with 4-trifluoromethylbenzoic acid, and compound A24 was synthesized and prepared. MS m / z (ESI): 385.2 [m + 1].

[0371] Synthesis of Intermediate A25 and A26:

[0372]

[0373] Step 1: Synthesis of Compound A25-2:

[0374] To a mixture of A25-1 (250 mg, 1.66 mmol) and potassium carbonate (504.74 mg, 3.65 mmol) in acetonitrile (4 mL) was added 1-iodo-2-methylpropane (458.21 mg, 2.49 mmol). The solution was stirred at 75 °C for 1.5 h under a N2 atmosphere. Then it was stirred at 88 °C for 1.5 h, followed by filtration and concentration under reduced pressure to remove the solvent. It was purified by silica gel column chromatography to obtain the title compound A25-2 (150 mg, yield 43.68%).

[0375] MS m / z (ESI): 207.15 [M+1] + .

[0376] Step 2: Synthesis of Compounds A25 and A26:

[0377] Referring to the synthesis of Intermediate A1, replacing A1-6 with A25-2, the diastereomers of Compounds A25 and A26 were synthesized and prepared. MS m / z (ESI): 446.25 [M+1] + .

[0378] Synthesis of Intermediate A27:

[0379]

[0380] Step 1: Synthesis of Compound A27-2:

[0381] To a reaction flask containing A27-1 (racemate, 10 g, 48.25 mmol) and triethylamine (14.65 g, 144.75 mmol) was added dichloromethane (100 mL), and then trifluoroacetic anhydride (15.2 g, 72.38 mmol) was added under an ice bath. The reaction was carried out at 25 °C for 2 h. It was quenched with 1 M hydrochloric acid solution, and then extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (PE / EA) to obtain the target product A27-2 (13.68 g). MS (ESI + ) m / z: 304.10 (M+H + ).

[0382] Step 1: Synthesis of Compound A27-3:

[0383] To a reaction flask containing A27-2 (13.63 g, 44.94 mmol), dichloromethane (100 mL) was added, and then bromine (7.9 g, 49.43 mmol) was added under an ice bath. The reaction was carried out at 25 °C for 12 h. The reaction was quenched by adding water, and then extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (PE / EA) to obtain the target product A27-3

[0384] (9.65 g). MS (ESI + ) m / z: 382.10 (M + H + ).

[0385] Step 1: Synthesis of compound A27-4:

[0386] To a reaction flask containing A27-3 (300 mg, 0.78 mmol) and potassium carbonate (216 mg, 1.56 mmol), methanol (10 mL) was added, and the mixture was stirred at 50 °C for 2 h. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH) to obtain the target product A27-4 (216 mg). MS (ESI + ) m / z: 286.07 (M + H + ). 1 1H NMR (400 MHz, CDCl3) δ 6.69 (s, 1H), 4.10 (q, J = 6.6 Hz, 1H), 3.88 (d, J = 7.5 Hz, 6H), 3.35–3.29 (m, 1H), 3.08–3.01 (m, 1H), 2.77–2.72 (m, 2H), 1.50 (d, J = 6.7 Hz, 3H).

[0387] Step 2: Synthesis of compound A27:

[0388] To a reaction flask containing 1-(1-chloroethyl)-4-isopropylbenzene (151 mg, 0.83 mmol), N,N-diisopropylethylamine (194 mg, 1.5 mmol) and potassium iodide (137 mg, 0.83 mmol), add N,N-dimethylformamide (10 mL), stir at room temperature for 10 min, then add A27-4 (216 mg, 0.75 mmol), and stir at 70 °C for 3 h. After the reaction is completed, add water (30 mL) and ethyl acetate (300 mL) for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (PE / EA) to obtain two pairs of enantiomers of the target product, diastereomers A27-P1 (a mixture of R / R and S / S chiralities, 73 mg) and A27-P2 (a mixture of R / S and S / R chiralities, 37 mg), where P1 and P2 each contain a pair of corresponding isomers. MS (ESI + ) m / z: 432.25 (M+H + ).

[0389] Synthesis of Intermediate A28:

[0390]

[0391] Step 1: Synthesis of Compound A28-2:

[0392] To a solution of A28-1 (500 mg, 3.20 mmol) in methanol (4 mL) at 0 °C, add sodium borohydride (0.12 g, 3.2 mmol). Stir the mixture at 25 °C for 2 h. TLC shows the reaction is complete. Dilute the reactants with water (50 mL) and ethyl acetate (50 mL). Wash the organic phase with brine (50 mL), dry over sodium sulfate, filter and evaporate in vacuo to obtain A28-2 (441.1 mg).

[0393] Step 2: Synthesis of Compound A28-3:

[0394] To a solution of A28-2 (440 mg, 2.78 mmol) in dichloromethane (3 mL) at 0 °C, add thionyl chloride (0.50 g, 4.17 mmol). Stir the solution at 25 °C for 2 h. Then quench the reaction with an aqueous solution of NaHCO3 (50 mL) and extract with EA (50 mL). Wash the organic phase with brine (50 mL), dry over sodium sulfate, filter and evaporate in vacuo to obtain A28-3 (122.2 mg), a yellow oily liquid.

[0395] Step 3: Synthesis of Compound A28:

[0396] To a solution of A28-3 (0.059 g, 0.34 mmol) and potassium iodide (0.040 g, 0.24 mmol) in N,N-dimethylacetamide (0.5 mL) was added ethyldiisopropylamine (0.093 g, 0.72 mmol). The mixture was stirred at 25 °C for 10 minutes. Then (1R)-5-bromo-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-bromide (80 mg, 0.24 mmol) was added to the mixture, and the reaction was carried out at 60 °C for 16 h. Purification by flash column chromatography on silica gel (EA / PE = 10%) gave A28 (71.2 mg, yield 75.70%), a yellow oily liquid. MS (ESI + ) m / z: 396 (M+H) + .

[0397] Synthesis of intermediates A29 and A30:

[0398]

[0399] Referring to the synthesis of intermediate A28, A28-1 was replaced with 1-(3-(trifluoromethyl)phenyl)ethyl-1-one, and the diastereoisomers A29 and A30 were synthesized and prepared. MS (ESI + ) m / z: 428.2 (M+H) + .

[0400] Synthesis of intermediate A31:

[0401]

[0402] Referring to the synthesis of intermediate A28, A28-1 was replaced with 1-(2,4,5-trifluorophenyl)ethyl-1-one, and the diastereoisomer A31 was synthesized and prepared. MS (ESI + ) m / z: 414.13 (M+H) + .

[0403] Synthesis of intermediate A32:

[0404]

[0405] Referring to the synthesis of intermediate A28, A28-1 was replaced with 1-(4-(trifluoromethyl)phenyl)propan-1-one, and the diastereoisomer A32 was synthesized and prepared. MS (ESI + ) m / z: 414.11 (M+H) + .

[0406] Synthesis of intermediates A33 and A34:

[0407]

[0408] Referring to the synthesis of intermediate A28, replace A28-3 with 1-(1-chloroethyl)-4-fluorobenzene, and synthesize and prepare the compound diastereomers A33 and A34. MS(ESI + )m / z: 378.14(M+H) + .

[0409] Synthesis of intermediate A35:

[0410]

[0411] Referring to the synthesis of intermediate A28, replace A28-3 with 1-(chloromethyl)-2,4,5-trifluorobenzene, and synthesize and prepare the compound A35. MS(ESI + )m / z: 400.12(M+H) + .

[0412] Synthesis of intermediate A36:

[0413]

[0414] Referring to the synthesis of intermediate A28, replace A28-3 with 1-(1-chloroethyl)-2-trifluoromethylbenzene, and synthesize and prepare the compound diastereomers A36. MS(ESI + )m / z: 428.17(M+H) + .

[0415] Synthesis of intermediate A37:

[0416]

[0417] Referring to the synthesis of intermediate A28, replace A28-3 with 1-chloromethyl-2,4-difluorobenzene, and synthesize and prepare the compound A37. MS(ESI + )m / z: 382.13(M+H) + .

[0418] Synthesis of intermediate A38:

[0419]

[0420] Referring to the synthesis of intermediate A28, replace A28-3 with 1-(2-chloroethyl)-4-methoxyphenyl, and synthesize and prepare the compound A38. MS(ESI + )m / z: 390.18(M+H) + .

[0421] Synthesis of intermediates A39 and A40:

[0422]

[0423] Referring to the synthesis of Intermediate A28, replace A28-2 with 3-(1-hydroxyethyl)benzonitrile, and synthesize and prepare a mixture of compound diastereoisomers A39 and A40. MS(ESI + ) m / z: 385.14 (M+H) + .

[0424] Synthesis of Intermediate A41:

[0425]

[0426] Step 1: Synthesis of Compound A41-1

[0427] Add N,N-dimethylacetamide (20 mL) to a reaction flask containing 1-(bromomethyl)-4-isopropylbenzene (5.58 g, 26.2 mmol), N,N-diisopropylethylamine (4.52 g, 34.94 mmol) and potassium iodide (3.19 g, 19.22 mmol). After stirring at 25 °C for 10 min, add A27-4 (5 g, 17.47 mmol), and react at 70 °C for 3 h. After cooling to room temperature, add water (50 mL) and ethyl acetate (50 mL) to the reaction solution for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is purified by column chromatography (PE / EA) to obtain the target product A41-1 (5.18 g). MS(ESI+) m / z: 418.11 (M+H + ).

[0428] Step 2: Synthesis of Compound A41-2

[0429] Add dichloromethane (20 mL) to a reaction flask containing A41-1 (2 g, 4.78 mmol), and then add a dichloromethane solution of boron tribromide (14.34 mL, 14.34 mmol, 1 M dichloromethane solution of boron tribromide) under an ice bath. React at 25 °C for 2 h. Quench the reaction with methanol and then concentrate to obtain a crude product. Dissolve the crude product in water, adjust the pH to 6 with saturated sodium bicarbonate solution, and the product precipitates. Filter, wash the filter cake with water, then dissolve the filter cake in dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate to obtain product A41-2

[0430] (1.41 g). MS(ESI + ) m / z: 390.07 (M+H + ). 1 H NMR(400 MHz, DMSO) δ 7.60–

[0431] 7.50 (m, 2H), 7.38–7.34 (m, 2H), 6.68 (s, 1H), 4.54–4.17 (m, 3H), 3.68–3.41 (m, 1H), 3.36–3.28 (m, 1H), 3.03–2.79 (m, 3H), 1.61–1.55 (m, 3H), 1.23 (d, J=6.9 Hz, 6H).

[0432] Step 3: Synthesis of Compound A41

[0433] To a reaction flask containing A41-2 (50 mg, 0.13 mmol), diiodomethane (104 mg, 0.39 mmol) and cesium carbonate (127 mg, 0.39 mmol), add N,N-dimethylformamide (5 mL), and react at 110 °C for 4 h. After cooling to room temperature, add water (15 mL) and ethyl acetate (15 mL) to the reaction solution for extraction. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (PE / EA) to obtain the target product A41 (11 mg). MS(ESI+) m / z: 402.19 (M + H + ).

[0434] Synthesis of Intermediate A42:

[0435]

[0436] Referring to the synthesis of Intermediate A28, replace A28-1 with cyclopropyl(4-methoxyphenyl)methanone, and synthesize to obtain the diastereoisomer A42. MS(ESI + ) m / z: 416.18 (M + H) + .

[0437] Synthesis of Intermediate A43:

[0438]

[0439] Referring to the synthesis of Intermediate A28, replace A28-1 with 1-(4-isobutoxyphenyl)pentan-1-one, and synthesize to obtain the diastereoisomer A43. MS(ESI + ) m / z: 474.3 (M + H) + .

[0440] Synthesis of Intermediate A44:

[0441]

[0442] A mixture of 5-bromo-1-methyl-2-[(4-(propan-2-yl)phenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol (20 mg, 0.051 mmol), 4-ethynylbenzonitrile (6.48 mg, 0.051 mmol), and dodecacarbonyltriruthenium (0.65 mg, 0.0010 mmol) in toluene (0.5 mL) was stirred at 100 °C for 16 h. Then, the mixture was filtered and concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain the title compound A44 (6 mg). MS m / z (ESI): 517.32 [M+1] + .

[0443] Synthesis of intermediates A45 and A46:

[0444]

[0445] Referring to the synthesis of intermediate A28, A28-1 was replaced with 1-(1-methyl-1H-indazol-6-yl)ethan-1-one, and the diastereoisomers A45 and A46 were synthesized and prepared. MS (ESI + ) m / z: 414.16 (M+H) + .

[0446] Synthesis of intermediate A47:

[0447]

[0448] Referring to the synthesis of intermediate A44, 4-ethynylbenzonitrile was replaced with 4-chloro-1-ethynyl-2-fluorophenethan-1-one, and the racemate A47 was synthesized and prepared. MS (ESI + ) m / z: 544.28 (M+H) + .

[0449] Synthesis of intermediate A48:

[0450]

[0451] A mixture of A41-2 (20 mg, 0.051 mmol), 1,2-dibromoethane (9.58 mg, 0.051 mol), and potassium carbonate (14.10 mg, 0.10 mmol) in DMF (0.5 mL) was stirred at room temperature overnight. Then the mixture was concentrated in vacuo. The residue was purified by SGC to obtain A48 (13 mg, yield 60.93%). (ESI + ) m / z: 415.11 (M+H + ).

[0452] Synthesis of intermediate A49:

[0453]

[0454] Referring to the synthesis of intermediate A41-1, replace A27-4 with (1R)-5-bromo-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-bromide, and compound A49 was synthesized and prepared. MS (ESI + ) m / z: 387.4 (M+H) + .

[0455] Intermediate B6

[0456]

[0457] Step 1: Add tetrahydrofuran (10 mL) and methanol (40 mL) to a reaction flask containing 2-amino-4-bromo-6-fluorophenol (2.1 g, 10 mmol), isobutyraldehyde (0.72 g, 10 mmol), and acetic acid (1.2 g, 20 mmol). Stir for 10 min in an ice bath, then add 2-methylpyridine borane (2.14 g, 20 mmol), and stir at 60 °C for 16 h. After the reaction is complete, concentrate, add ethyl acetate and saturated sodium bicarbonate solution for extraction, wash the organic phase with saturated brine, separate by filtration, dry and concentrate to obtain the crude product, which is purified by silica gel column chromatography to obtain compound B6-1 (1.7 g, yield 65%).

[0458] Step 2: Add potassium carbonate (1.03 g, 7.5 mmol) to a reaction flask containing 4-bromo-2-fluoro-6-(isobutylamino)phenol B6-1 (1.31 g, 5 mmol), bromomethyl methyl ether (0.75 g, 6 mmol), and acetonitrile (20 mL). Heat and stir at 60 °C for 3 hours. After the reaction is complete, add ethyl acetate and saturated sodium bicarbonate solution for extraction, wash the organic phase with saturated brine, concentrate, and the crude product is purified by column chromatography to obtain compound B6-2 (1.11 g, yield 73%).

[0459] Step 3: Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.22 g, 0.3 mmol) to a solution of 5-bromo-3-fluoro-N-isobutyl-2-(methoxymethoxy)aniline (0.92 g, 3 mmol), bis(pinacolato)diboron (1.52 g, 6 mmol), and potassium acetate (1.2 g, 12 mmol) in 1,4-dioxane (30 mL). Protect the reactants with nitrogen and stir at 110 °C for 2 h to detect the completion of the reaction. Add ethyl acetate and saturated sodium bicarbonate solution for extraction, wash the organic phase with saturated brine, concentrate, and the crude product is purified by column chromatography to obtain compound B6 (0.8 g, yield 75%), MS (ESI+) m / z: 354.2 (M+H)+.

[0460] Intermediate B7

[0461]

[0462] Step 1: Synthesis of Compound B7-2:

[0463] Add dichloromethane (10 mL) to a reaction flask containing 2-amino-4-bromo-6-fluorophenol (500 mg, 2.43 mmol) and N,N-diisopropylethylamine (628 mg, 4.86 mmol). Add chloromethyl methyl ether (196 mg, 2.43 mmol) under an ice bath and stir at 25 °C for 1 h. After the reaction is complete, quench with water, then extract with saturated sodium bicarbonate solution (10 mL) and dichloromethane (10 mL). Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify the crude product by column chromatography (PE / EA) to obtain the target product B7-2 (330 mg). MS (ESI + ) m / z: 249.95 (M+H + ). 1 1H NMR (400 MHz, CDCl3) δ 6.72–6.65 (m, 2H), 5.12 (s, 2H), 4.09 (s, 2H), 3.61 (s, 3H).

[0464] Step 2: Synthesis of Compound B7:

[0465] Add 1,4-dioxane (5 mL) to a reaction flask containing B7-2 (330 mg, 1.32 mmol), bis(pinacolato)diboron (402 mg, 1.58 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (108 mg, 0.13 mmol), and potassium acetate (389 mg, 3.96 mmol). Replace the air with nitrogen and react at 110 °C for 4 h. After the reaction is complete, concentrate to obtain the crude product. Purify the crude product by column chromatography (PE / EA) to obtain the target product (318 mg). MS (ESI + ) m / z: 298.14 (M+H + ).

[0466] Intermediate B8

[0467]

[0468] Refer to the synthesis of Intermediate B6, replace isobutyraldehyde with isovaleraldehyde to obtain Compound B8. MS (ESI + ) m / z: 368.4 (M+H + ).

[0469] Synthesis of Intermediate C1:

[0470]

[0471] To a reaction flask containing (R)-5-bromo-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (300 mg, 0.89 mmol), 3-fluoro-2-(methoxymethoxy)-N-neopentyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (360 mg, 0.98 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (75 mg, 0.089 mmol) and potassium phosphate (756 mg, 3.56 mmol), add 1,4-dioxane (10 mL) and water (2 mL). Protect with nitrogen and heat and stir at 100 °C for 3 h. After the reaction is completed, concentrate, and purify the crude product by column chromatography (PE / EA) to obtain the target product (184 mg). MS (ESI + ) m / z: 417.33 (M+H + ).

[0472] Synthesis of Intermediate D1:

[0473]

[0474] Referring to the synthetic route of Reference Compound 28-3, replace A28-1 with 1-(2,6-dichloro-3-fluorophenyl)ethyl-1-one to synthesize and prepare the racemic compound D1.

[0475] Examples Compounds 18 and 19:

[0476]

[0477] Step 1: To a reaction flask containing (1R)-5-bromo-2-(1-(4-isopropylphenyl)ethyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline A1a (300 mg, 0.75 mmol), 2-amino-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (285 mg, 1.13 mmol), and 1,1-bis(diphenylphosphino)ferrocene dichloride palladium (61 mg, 0.075 mmol) and sodium carbonate (238 mg, 2.25 mmol), add 1,4-dioxane (10 mL) and water (0.5 mL). Protect with N2 and heat and stir at 90 °C overnight. After the reaction is completed, concentrate, and purify the crude product by column chromatography (PE / EA) to obtain Compound Cpd 18-1 (71 mg).

[0478] Step 2: Add tetrahydrofuran (2 mL) and methanol (8 mL) to a reaction flask containing 2-amino-6-fluoro-4-((1R)-2-(1-(4-isopropylphenyl)ethyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)phenol 18-1 (50 mg, 0.11 mmol), isovaleraldehyde (9 mg, 0.1 mmol), and acetic acid (119 mg, 1.98 mmol). Stir for 10 min in an ice bath, then add 2-methylpyridine borane (21 mg, 0.2 mmol) and stir at 60 °C for 16 h. After completion of the reaction, concentrate, add ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL) for extraction, wash the organic phase with saturated brine, separate by filtration, dry and concentrate to obtain the crude product, which is purified by preparative liquid chromatography to obtain compound 18 (18.1 mg). MS (ESI + ) m / z: 519.56 (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 7.37–7.35 (m, 2H), 7.34–7.32 (m, 2H), 6.95–6.85 (m, 2H), 6.78–6.58 (m, 1H), 6.53–6.38 (m, 1H), 4.25–4.22 (m, 1H), 4.10–4.06 (m, 1H), 4.82–4.76 (m, 5H), 3.35–3.20 (m, 3H), 2.08–2.02 (m, 1H), 1.65–1.60 (m, 5H), 1.31 (d, J = 6.7 Hz, 12H), 0.97 (d, J = 6.1 Hz, 6H).

[0479] Referring to the synthetic route of compound 18, replace A1a with intermediate A1b to synthesize and prepare compound 19. MS (ESI + ) m / z: 519.58 (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 7.39–7.37 (m, 3H), 7.28–7.23 (m, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 6.58–6.48 (m, 2H), 4.88–4.68 (m, 1H), 4.36–4.28 (m, 1H), 3.78 (s, 3H), 3.73–3.71 (m, 1H), 3.66–3.58 (m, 1H), 3.27–3.21 (m, 3H), 2.08–2.02 (m, 1H), 1.77–1.55 (m, 4H), 1.33–1.25 (m, 6H), 1.26 (d, J = 6.9 Hz, 6H), 0.98–0.92 (m, 6H).

[0480] Examples Compounds 20 and 21

[0481]

[0482] Referring to the synthetic route of Reference Compound 18, replacing isovaleraldehyde with 3,3-dimethylbutyraldehyde, Compound 20 was synthesized and prepared. MS (ESI + ) m / z: 533.53 (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 7.39–7.33 (m, 2H), 7.32–7.30 (m, 2H), 6.94–6.86 (m, 2H), 6.72–6.68 (m, 1H), 6.51–6.38 (m, 1H), 4.27–4.21 (m, 1H), 4.12–4.04 (m, 1H), 3.83–3.72 (m, 5H), 3.38–3.12 (m, 3H), 3.05–2.87 (m, 3H), 1.75–1.51 (m, 5H), 1.31 (d, J = 6.8 Hz, 9H), 0.98 (s, 9H).

[0483] Referring to the synthetic route of Reference Compound 18, replacing A1a with Intermediate A1b and isovaleraldehyde with 3,3-dimethylbutyraldehyde, Compound 21 was synthesized and prepared. MS (ESI + ) m / z: 533.57 (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 7.39–7.37 (m, 3H), 7.28–7.23 (m, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 6.50–6.36 (m, 2H), 4.88–4.72 (m, 1H), 4.35–4.19 (m, 1H), 3.79 (s, 3H), 3.74–3.72 (m, 1H), 3.66–3.56 (m, 1H), 3.28–3.19 (m, 3H), 3.00–2.88 (m, 3H), 2.09–1.99 (m, 1H), 1.33–1.28 (m, 6H), 1.26 (d, J = 6.9 Hz, 6H), 1.01–0.94 (m, 9H).

[0484] Examples Compounds 2a and 2b:

[0485]

[0486] Referring to the synthetic route of Reference Compound 18, replacing isovaleraldehyde with pivalaldehyde, Compound 2a was synthesized and prepared. MS (ESI+ ) m / z: 519.62 (M+H + ).

[0487] Referring to the synthetic route of Compound 18, replacing A1a with intermediate A1b and pivalaldehyde with isovaleraldehyde, Compound 2b was synthesized and prepared, MS (ESI + ) m / z: 519.63 (M+H + ).

[0488] Example Compound 22

[0489]

[0490] Referring to the synthetic route of Compound 19, replacing isovaleraldehyde with trifluoroacetaldehyde, Compound 22 was synthesized and prepared, MS (ESI + ) m / z: 531.5 (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 7.38–7.30 (m, 2H), 7.24–7.18 (m, 2H), 7.11–7.02 (m, 1H), 6.94–6.83 (m, 1H), 6.39–6.32 (m, 1H), 6.31–6.25 (m, 1H), 4.09–3.95 (m, 1H), 3.84–3.69 (m, 6H), 3.40–3.24 (m, 1H), 2.91–2.83 (m, 2H), 2.62–2.33 (m, 2H), 1.25–1.21 (m, 12H).

[0491] Example Compound 23

[0492]

[0493] Referring to the synthetic route of Compound 19, replacing isovaleraldehyde with 3,3,3-trifluoropropionaldehyde, Compound 23 was synthesized and prepared, MS (ESI + ) m / z: 545.5 (M+H + ). 11H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.2 Hz, 2H), 7.18–7.13 (m, 2H), 7.00 (d, J = 8.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.38–6.34 (m, 1H), 6.22 (s, 1H), 4.20–4.05 (m, 1H), 3.94–3.84 (m, 1H), 3.70 (s, 3H), 3.49–3.39 (m, 2H), 3.10–2.96 (m, 1H), 2.94–2.84 (m, 1H), 2.76–2.66 (m, 1H), 2.65–2.49 (m, 1H), 2.48–2.31 (m, 3H), 1.48–1.40 (m, 6H), 1.22 (d, J = 6.9 Hz, 6H).

[0494] Examples Compounds 24 and 25

[0495]

[0496] (R)-5-Bromo-2-((R)-1-(4-isopropylphenyl)ethyl)-1-methyl-6-phenethoxy-1,2,3,4-tetrahydroisoquinoline A15a (29 mg, 0.059 mmol), 2-fluoro-6-(isobutylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol B2 (37 mg, 0.12 mmol), tripotassium phosphate (31 mg, 0.15 mmol), and XPhos G3 (10 mg, 0.012 mmol) were dissolved in dioxane (1 mL) and water (0.3 mL). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. LCMS showed that the reaction was complete. The solvent was removed by filtration and concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give Compound 24 (17 mg, 50% yield). MS m / z (ESI): 595.6 [m+1]. 1 1H NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 7.60–6.72 (m, 11H), 6.14 (m, 2H), 5.14–4.77 (m, 1H), 4.61–3.87 (m, 3H), 3.62 (m, 1H), 3.28–2.56 (m, 9H), 1.90 (m, 1H), 1.65–1.13 (m, 12H), 0.89 (m, 6H).

[0497] Referring to the synthesis of 24, Intermediate A15b was used instead of A15a to synthesize and prepare Compound 25. MS m / z (ESI): 595.5 [m+1]. 11H NMR (400 MHz, CDCl3) δ 7.36 (m, 1H), 7.23–7.07 (m, 6H), 7.04–6.76 (m, 4H), 6.21 (m, 2H), 4.41–3.70 (m, 4H), 3.01–2.48 (m, 9H), 1.97 (m, 1H), 1.62–1.27 (m, 6H), 1.23 (d, J = 6.9 Hz, 6H), 1.11–0.88 (m, 6H).

[0498] Examples Compounds 26 and 27

[0499]

[0500] (R)-5-Bromo-2-((R)-1-(4-isopropylphenyl)ethyl)-1-methyl-6-(3-phenylpropoxy)-1,2,3,4-tetrahydroisoquinoline A16a (30 mg, 0.059 mmol), 2-fluoro-6-(isobutylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol B2 (37 mg, 0.12 mmol), tripotassium phosphate (31 mg, 0.15 mmol), and XPhos G3 (10 mg, 0.012 mmol) were dissolved in dioxane (1 mL) and water (0.3 mL). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The solvent was removed by filtration and concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give Compound 26 (13 mg, 35% yield), MS m / z (ESI): 609.6 [m + 1]. 1 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 1H), 7.24–7.03 (m, 8H), 6.85 (m, 2H), 6.32 (m, 2H), 4.16 (s, 1H), 3.81 (m, 3H), 3.01–2.78 (m, 6H), 2.57 (t, J = 7.5 Hz, 3H), 1.91 (t, J = 7.5 Hz, 3H), 1.41 (d, J = 21.6 Hz, 6H), 1.25 (d, J = 6.9 Hz, 6H), 0.94 (m, 6H).

[0501] Referring to the synthesis of Compound 26, using Intermediate A16b in place of A16a, Compound 27 was synthesized and prepared, MS m / z (ESI): 609.6 [m + 1]. 11H NMR (400 MHz, CDCl3) δ 7.34 (m, 1H), 7.23–6.89 (m, 9H), 6.75 (m, 1H), 6.42–6.11 (m, 2H), 4.16 (m, 1H), 3.86 (m, 3H), 3.22–2.71 (m, 6H), 2.57 (t, J = 7.6 Hz, 3H), 1.90 (t, J = 7.6 Hz, 3H), 1.52 (m, 6H), 1.24 (d, J = 6.9 Hz, 6H), 0.97 (m, 6H).

[0502] Example Compound 28

[0503]

[0504] (R)-5-Bromo-2-(4-isopropylbenzyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline A17 (23 mg, 0.059 mmol), 2-fluoro-6-(neopentylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol B1 (39 mg, 0.12 mmol), tripotassium phosphate (31 mg, 0.15 mmol), and XPhos G3 (10 mg, 0.012 mmol) were dissolved in dioxane (1 mL) and water (0.3 mL). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. LCMS showed that the reaction was complete. The solvent was removed by filtration and concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give Compound 28 (12 mg, yield 39%), MS m / z (ESI): 505.5 [m + 1]. 1 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.39–6.25 (m, 2H), 4.14–4.02 (m, 1H), 3.93–3.89 (m, 1H), 3.83–3.76 (m, 1H), 3.75 (s, 3H), 3.10–3.01 (m, 1H), 2.96–2.89 (m, 3H), 2.79–2.71 (m, 1H), 2.65–2.55 (m, 1H), 2.53–2.44 (m, 1H), 1.30–1.27 (m, 9H), 1.03 (s, 9H).

[0505] Example Compound 29

[0506]

[0507] Step 1. Intermediate A19 (60 mg, 0.14 mmol), 3-fluoro-2-(methoxymethoxy)-N-(2-methylpropyl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline B6 (49.45 mg, 0.14 mmol), tripotassium phosphate (74.29 mg, 0.35 mmol), and XPhos G3 (23.70 mg, 0.028 mmol) were dissolved in dioxane (3 mL) and water (0.6 mL). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The mixture was diluted with ethyl acetate (30 mL), washed with water (5 mL × 2), saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to give compound 29-1 (80 mg, yield: 98.65%). MS m / z (ESI): 584.78 [m+1].

[0508] Step 2. Hydrochloric acid solution (0.60 mL, 19.75 mmol) was added to a solution of 29-1 (80 mg, 0.14 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 0.5 h. LCMS indicated that the reaction was complete. The solvent was removed by concentration under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O) to give compound 29 (26.35 mg, yield: 35.73%). MS m / z (ESI): 519.5 [m+1]. 1 H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 28.1, 7.4 Hz, 4H), 7.19 (m, 1H), 6.82 (m, 1H), 6.59–6.18 (m, 2H), 5.87–5.61 (m, 1H), 4.94 (s, 1H), 3.76 (m, 4H), 3.40–2.22 (m, 4H), 1.94 (m, 3H), 1.47 (m, 2H), 1.31 (s, 10H), 0.99 (d, J = 12.0 Hz, 6H).

[0509] Example Compound 30

[0510]

[0511] Referring to the synthetic route of reference compound 29, replacing intermediate A19 with intermediate A18, compound 30 can be synthesized and prepared. MS m / z (ESI): 505.5 [m+1]. 1H NMR (400 MHz, CDCl3) δ 7.43–7.26 (m, 4H), 7.23–7.14 (m, 1H), 6.86 (m, 1H), 6.50–6.17 (m, 2H), 5.75 (s, 1H), 4.78 (m, 1H), 3.76 (m, 4H), 3.42–2.27 (m, 6H), 1.94 (m, 1H), 1.53 (m, 3H), 1.25-1.23 (m, 7H), 1.08–0.95 (m, 6H).

[0512] Example compound 31

[0513]

[0514] Referring to the synthetic route of reference compound 29, replacing intermediate A19 with intermediate A20, compound 31 can be synthesized and prepared. MS m / z (ESI): 495.5 [m+1]. 1 1H NMR (400 MHz, CDCl3) δ 7.23–6.69 (m, 5H), 6.40–6.13 (m, 2H), 5.71 (s, 1H), 4.73 (d, J=119.0 Hz, 1H), 3.69 (m, 4H), 3.40–2.18 (m, 9H), 1.93 (s, 1H), 1.53 (s, 3H), 0.99 (m, 6H).

[0515] Example compound 32

[0516]

[0517] Referring to the synthetic route of reference compound 29, replacing intermediate A19 with intermediate A21, compound 32 can be synthesized and prepared. MS m / z (ESI): 519.5 [m+1]. 1 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=7.7 Hz, 2H), 7.19 (m 3H), 6.86 (m, 1H), 6.47–6.16 (m, 2H), 5.74 (m, 1H), 4.76 (d, J=119.7 Hz, 1H), 3.73 (s, 4H), 3.37–2.33 (m, 8H), 1.92 (s, 1H), 1.58–1.45 (m, 4H), 1.43–1.22 (m, 3H), 1.05–0.92 (m, 9H).

[0518] Example compound 33

[0519]

[0520] Referring to the synthetic route of Reference Compound 29, replacing Intermediate A19 with Intermediate A22, Compound 33 can be synthesized and prepared. MS m / z (ESI): 549.4 [m+1]. 1 H NMR (400 MHz, CDCl3) δ 7.57–7.36 (m, 3H), 7.19 (d, J = 8.5 Hz, 1H), 6.99–6.77 (m, 1H), 6.40–6.13 (m, 2H), 5.79 (m, 1H), 4.66 (m, 1H), 3.73 (m, 4H), 3.48–2.35 (m, 6H), 1.92 (m, 1H), 1.61 (d, J = 6.6 Hz, 3H), 1.02–0.95 (m, 6H).

[0521] Example Compound 34

[0522]

[0523] Referring to the synthetic route of Reference Compound 29, replacing Intermediate A19 with Intermediate A23, Compound 34 can be synthesized and prepared. MS m / z (ESI): 531.4 [m+1]. 1 H NMR (400 MHz, CDCl3) δ 7.67 (m, 2H), 7.58–7.45 (m, 2H), 7.22–7.13 (m, 1H), 6.85 (m, 1H), 6.34 (m, 2H), 5.75 (m, 1H), 4.73 (m, 1H), 3.71 (m, 4H), 3.63–2.25 (m, 6H), 1.97 (s, 1H), 1.60 (d, J = 6.5 Hz, 3H), 1.00 (m, 6H).

[0524] Example Compound 35

[0525]

[0526] Referring to the synthetic route of Reference Compound 29, replacing Intermediate A19 with Intermediate A24, Compound 35 can be synthesized and prepared. MS m / z (ESI): 488.5 [m+1]. 11H NMR (400 MHz, CDCl3) δ 7.72 (m, 2H), 7.59–7.44 (m, 2H), 7.19 (m, 1H), 6.97–6.75 (m, 1H), 6.34 (m, 2H), 5.79–5.67 (m, 1H), 4.66 (m, 1H), 3.72 (m, 4H), 3.61–2.10 (m, 6H), 1.95 (m, 1H), 1.60 (d, J = 6.5 Hz, 3H), 1.05–0.96 (m, 6H).

[0527] Example Compound 36

[0528]

[0529] Referring to the synthetic route of Reference Compound 29, replacing Intermediate A19 with Intermediate A27-P1, Compound 36 can be synthesized and prepared. It is a mixture of enantiomers with chiral centers of R / R and S / S. MS (ESI + )

[0530] m / z: 535.5 (M+H + ).

[0531] Example Compound 37

[0532]

[0533] Referring to the synthetic route of Reference Compound 29, replacing Intermediate A19 with Intermediate A27-P2, Compound 37 can be synthesized and prepared. It is a mixture of enantiomers with chiral centers of R / S and S / R.

[0534] MS (ESI + ) m / z: 535.5 (M+H + ).

[0535] Example Compound 38

[0536]

[0537] Step 1: Synthesis of Compound 38-1:

[0538] To a reaction flask containing (R)-5-bromo-2-((S)-1-(4-isopropylphenyl)ethyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline A1b (90 mg, 0.22 mmol), B7 (72 mg, 0.24 mmol), XPhos Pd G3 (19 mg, 0.022 mmol) and potassium phosphate (140 mg, 0.66 mmol) were added 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen protection, the mixture was heated and stirred at 100 °C for 3 h. After completion of the reaction, it was concentrated, and the crude product was purified by column chromatography (PE / EA) to obtain the target product (95 mg). MS (ESI + ) m / z: 493.36 (M+H + ).

[0539] Step 2: Synthesis of Compound 38-2:

[0540] To a reaction flask containing 38-1 (25 mg, 0.051 mmol) and triethylamine (10 mg, 0.1 mmol) was added dichloromethane (2 mL), and then pivaloyl chloride (6.8 mg, 0.056 mmol) was added under ice bath. The reaction was carried out at 25 °C for 1 h. After completion of the reaction, it was quenched with water, then saturated sodium bicarbonate solution and dichloromethane were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (PE / EA) to obtain the target product (19 mg). MS (ESI + ) m / z: 577.53 (M+H + ).

[0541] Step 3: Synthesis of Compound 38:

[0542] To a reaction flask containing 38-2 (19 mg, 0.033 mmol) was added dichloromethane (2 mL), and then a 1,4-dioxane solution of hydrogen chloride (0.5 mL, 4 mol / L) was added. The mixture was stirred at 25 °C for 1 h. After completion of the reaction, it was concentrated, then saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL) were added for extraction. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by preparative liquid chromatography to obtain the target product (8.08 mg). MS (ESI + ) m / z: 533.4 (M+H + ). 1HNMR(400MHz,CDCl3)δ7.41–7.39(m,1H),7.31–7.29(m,1H),7.21–7.15(m,2H),7.01–6.94(m,2H),6.83–6.67(m,2H),4.25–4.21(m,1H),4.05–3.65(m,1H),3.66–3.65(m,3H),3.26–3.03(m,1H),2.93–2.86(m,1H),2.74–2.69(m,1H),2.24–2.18(m,1H),2.02–1.98(m,1H),1.59(d,J=6.5Hz,3H),1.34–1.32(m,9H),1.24(s,9H).

[0543] Example Compound 39

[0544]

[0545] Referring to the synthetic route of Reference Compound 38, replacing intermediate pivaloyl chloride with intermediate propylsulfonyl chloride, Compound 39 can be synthesized and prepared. MS(ESI + )m / z:555.4(M+H + ). 1 H NMR(400MHz,CDCl3)δ7.35–7.26(m,2H),7.19–7.16(m,2H),7.08–7.06(m,1H),7.02–6.96(m,1H),6.81–6.72(m,2H),4.20–4.03(m,1H),3.95–3.85(m,1H),3.67(s,3H),3.08–3.04(m,2H),2.91–2.82(m,1H),2.64–2.55(m,1H),2.40–2.25(m,1H),2.24–2.17(m,1H),1.46–1.40(m,6H),1.24–1.22(m,9H),0.99(t,J=7.4Hz,3H).

[0546] Example Compound 40

[0547]

[0548] Referring to the synthetic route of Reference Compound 29, replacing intermediate A19 with intermediate A25, Compound 40 can be synthesized and prepared. MS m / z(ESI):549.5[m+1]. 11H NMR (400 MHz, CDCl3) δ 7.39 (m, 2H), 6.95 (m, 4H), 6.41–6.06 (m, 2H), 4.32 (m, 1H), 3.71 (m, 6H), 3.24 (m, 1H), 3.02–2.89 (m, 2H), 2.61–1.87 (m, 8H), 1.52 (s, 3H), 1.08–0.94 (m, 12H), 0.67 (m, 3H).

[0549] Example compound 41

[0550]

[0551] Referring to the synthetic route of reference compound 29, replacing intermediate A19 with intermediate A26, compound 41 can be synthesized and prepared. MS m / z (ESI): 549.5 [M+1]. 1 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 2H), 6.93 (m, 4H), 6.27 (m, 2H), 4.18 (s, 1H), 3.72 (m, 6H), 3.54 (m, 1H), 2.94 (m, 2H), 2.58–1.90 (m, 8H), 1.48 (s, 3H), 1.01 (m, 12H), 0.63 (d, J = 6.9 Hz, 3H).

[0552] Example compounds 42 and 43

[0553]

[0554] Step 1: Synthesis of compounds 42-1 and 43-1:

[0555] To a reaction flask containing D1 (25 mg, 0.11 mmol), N,N-diisopropylethylamine (19 mg, 0.14 mmol) and potassium iodide (13 mg, 0.079 mmol), add N,N-dimethylacetamide (5 mL), stir at room temperature for 10 min, then add C1 (30 mg, 0.072 mmol), and react at 70 °C for 16 h. After the reaction is completed, add ethyl acetate (20 mL) and water (20 mL) for extraction, wash the organic phase with saturated brine, separate the organic phase, dry it with anhydrous sodium sulfate, filter and concentrate. The crude product is purified by column chromatography (PE / EA) to obtain the target products 42-1 and 43-1 (7 mg). MS (ESI + ) m / z: 607.40 (M+H + ).

[0556] Step 2: Synthesis of compounds 42 and 43:

[0557] To the reaction flask containing the product of Step 1 (7 mg, 0.012 mmol), add dichloromethane (2 mL), and then add a 1,4-dioxane solution of hydrogen chloride (0.5 mL, 4 mol / L), and stir at 25 °C for 1 h. After the reaction is completed, concentrate, then add saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL) for extraction, wash the organic phase with saturated brine, separate, dry over anhydrous sodium sulfate, filter, concentrate to obtain the crude product, and purify by preparative liquid chromatography to obtain the target products 42 (0.52 mg) and 43 (0.90 mg). MS (ESI + ) m / z: 563.3 (M + H + ).

[0558] Example Compound 44

[0559]

[0560] Referring to the synthetic route of Compound 42, using intermediate 1-chloromethyl-3,5-bis(trifluoromethyl)benzene to replace intermediate D1, Compound 44 can be synthesized and prepared. MS (ESI + ) m / z: 599.4 (M + H + ). 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 2H), 7.75 (s, 1H), 7.09–7.01 (m, 1H), 6.89–6.79 (m, 1H), 6.35–6.20 (m, 2H), 3.92–3.86 (m, 2H), 3.80–3.77 (m, 1H), 3.71 (s, 3H), 2.98–2.77 (m, 3H), 2.61–2.49 (m, 2H), 2.45–2.29 (m, 1H), 1.43–1.39 (m, 3H), 0.98 (s, 9H).

[0561] Example Compound 45

[0562]

[0563] Referring to the synthetic route of Compound 29, starting from intermediate A28 and intermediate B8, Compound 45 can be synthesized and prepared. MS (ESI + ) m / z: 518 (M + H) + . 11H NMR (400 MHz, CDCl3) δ 7.68–7.09 (m, 2H), 7.13–6.74 (m, 3H), 6.37–6.06 (m, 2H), 4.30–3.90 (m, 2H), 3.78 (s, 3H), 3.58–3.36 (m, 1H), 2.98–2.82 (m, 3H), 2.12–1.72 (m, 5H), 1.28 (s, 3H), 1.09–0.95 (m, 9H).

[0564] Example Compound 46

[0565]

[0566] Referring to the synthetic route of Reference Compound 29, replacing Intermediate A19 with Intermediate A29, Compound 46 can be synthesized and prepared. MS (ESI + ) m / z: 545.4 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ 8.72–7.37 (m, 4H), 6.87 (s, 2H), 6.43–6.08 (m, 2H), 4.27–3.85 (m, 3H), 3.78–3.70 (m, 3H), 3.60–3.18 (m, 1H), 3.02–2.39 (m, 4H), 1.99–1.41 (m, 6H), 1.00 (s, 9H).

[0567] Example Compound 47

[0568]

[0569] Referring to the synthetic route of Reference Compound 29, replacing Intermediate A19 with Intermediate A30, Compound 47 can be synthesized and prepared. MS (ESI + ) m / z: 545.4 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ 8.43–7.44 (m, 4H), 7.15–6.95 (m, 1H), 6.96–6.82 (m, 1H), 6.33–6.01 (m, 2H), 4.77–3.94 (m, 2H), 3.73 (s, 3H), 3.44–3.12 (m, 1H), 2.96–2.74 (m, 3H), 2.63–2.32 (m, 2H), 1.86–1.61 (m, 6H), 1.07–0.91 (m, 9H).

[0570] Example Compound 48

[0571]

[0572] Referring to the synthetic route of reference compound 42, replacing intermediate D1 with intermediate 1-(chloromethyl)-3-fluorobenzene, compound 48 can be synthesized and prepared. MS(ESI + )m / z: 481.4(M+H) + . 1 H NMR(400 MHz, CDCl3) δ 12.51(s, 1H), 7.73–7.54(m, 1H), 7.49–7.34(m, 2H), 7.20–6.91(m, 3H), 6.39–6.22(m, 2H), 4.48–4.03(m, 3H), 3.76(s, 3H), 3.71–3.59(m, 1H), 3.31–3.03(m, 1H), 2.98–2.69(m, 4H), 1.84(d, J = 4.6 Hz, 3H), 1.08–1.01(m, 9H).

[0573] Example compound 49

[0574]

[0575] Referring to the synthetic route of reference compound 29, starting from intermediate A31 and intermediate B8, compound 49 can be synthesized and prepared. MS(ESI + )m / z: 531.4(M+H) + .

[0576] Example compound 50

[0577]

[0578] Referring to the synthetic route of reference compound 29, starting from intermediate A32 and intermediate B8, compound 50 can be synthesized and prepared. MS(ESI + )m / z: 559.4(M+H) + .

[0579] Example compound 51

[0580]

[0581] Referring to the synthetic route of reference compound 29, starting from intermediate A33 and intermediate B8, compound 51 can be synthesized and prepared. MS(ESI + )m / z: 495.4(M+H) + .

[0582] Example compound 52

[0583]

[0584] Referring to the synthetic route of reference compound 29, starting from intermediate A34 and intermediate B8, compound 52 can be synthesized and prepared. MS (ESI + ) m / z: 495.4 (M+H) + .

[0585] Example compound 53

[0586]

[0587] Referring to the synthetic route of reference compound 29, starting from intermediate A35 and intermediate B8, compound 53 can be synthesized and prepared. MS m / z (ESI): 517.4 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.20–6.79 (m, 3H), 6.31 (m, 2H), 4.29 (m, 1H), 3.96–3.38 (m, 8H), 3.24–2.72 (m, 4H), 1.25 (s, 3H), 1.03 (m, 9H).

[0588] Example compound 54

[0589]

[0590] Referring to the synthetic route of reference compound 29, starting from intermediate A36 and intermediate B8, compound 54 can be synthesized and prepared. MS m / z (ESI): 545.4 [M+1] + .

[0591] Example compound 55

[0592]

[0593] Referring to the synthetic route of reference compound 42, by replacing intermediate D1 with intermediate 1-(2-chloroethyl)-4-fluorobenzene, compound 55 can be synthesized and prepared. 1 H NMR (400 MHz, CDCl3) δ 7.25–7.16 (m, 2H), 7.06–6.86 (m, 4H), 6.43–6.16 (m, 2H), 3.74 (s, 3H), 3.68–3.55 (m, 1H), 3.47–3.30 (m, 2H), 3.30–3.15 (m, 2H), 2.96–2.87 (m, 2H), 2.81–2.69 (m, 1H), 1.92–1.86 (m, 2H), 1.76–1.73 (m, 1H), 1.28–1.23 (m, 3H), 1.07–1.00 (m, 9H). MS (ESI +) m / z: 495.4 (M+H) + .

[0594] Example Compound 56

[0595]

[0596] Referring to the synthetic route of reference compound 42, by replacing intermediate D1 with intermediate 1-(chloromethyl)-2-(trifluoromethyl)benzene, compound 56 can be synthesized and prepared. 1 H NMR (400 MHz, CDCl3) δ 7.84–7.41 (m, 4H), 7.11–6.78 (m, 2H), 6.41–6.02 (m, 2H), 4.57–4.26 (m, 2H), 3.75 (s, 3H), 3.45–3.23 (m, 1H), 2.90–2.81 (m, 2H), 2.77–2.57 (m, 1H), 2.06–1.86 (m, 3H), 1.29–1.21 (m, 3H), 1.00 (s, 9H). MS (ESI + ) m / z: 531.4 (M+H) + .

[0597] Example Compound 57

[0598]

[0599] Referring to the synthetic route of reference compound 29, starting from intermediate A37 and intermediate B8, compound 57 can be synthesized and prepared. MS m / z (ESI): 499.4 [m+1].[[]]END]] 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.67 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.84 (m, 3H), 6.36–6.11 (m, 2H), 4.11 (s, 1H), 4.02–3.88 (m, 2H), 3.72 (s, 3H), 3.16–2.99 (m, 1H), 2.95–2.73 (m, 3H), 2.69–2.43 (m, 2H), 1.55 (d, J = 4.7 Hz, 3H), 0.99 (s, 9H).

[0600] Example Compound 58

[0601]

[0602] To a solution of N-(2,2-dimethylpropyl)-3-fluoro-5-[(1R)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-(methoxymethoxy)aniline (10 mg, 0.024 mmol) and 1-(3-(trifluoromethyl)phenyl)propan-2-one (9.70 mg, 0.048 mmol) in THF (0.5 mL) was added tetraethyl titanate (0.011 g, 0.048 mmol), and the mixture was stirred overnight at 75 °C. Then, sodium borohydride (0.0027 g, 0.072 mmol) was added at 25 °C and stirred for hours, and then 1 mL of HCl (4 M 1,4-dioxane solution) was added to the solution. The reaction was stirred at 25 °C for 1 h and purified by HPLC to give compound 58 (2.95 mg, yield 22.01%), a white solid. MS (ESI + ) m / z: 559.4 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 7.52–7.34 (m, 4H), 7.13–6.97 (m, 1H), 6.91–6.79 (m, 1H), 6.41–6.15 (m, 2H), 3.77–3.66 (m, 3H), 3.37–3.14 (m, 2H), 2.96–2.80 (m, 3H), 2.76–2.50 (m, 3H), 1.66–1.55 (m, 2H), 1.28–1.23 (m, 3H), 1.15–1.10 (m, 3H), 1.01 (s, 9H).

[0603] Example Compound 59

[0604]

[0605] Step 1: Synthesis of Compound 59-1:

[0606] Referring to the synthetic route of Compound 38-1, starting from Intermediate A49 and Intermediate B7, Compound 59-1 can be synthesized and prepared. MS m / z (ESI): 479.4 [M+1] + .

[0607] Steps 2 and 3: Synthesis of Compound 59:

[0608] To a 0.5 mL THF solution of 59-1 (11.49 mg, 0.024 mmol) and 3-phenylcyclobutan-1-one (0.0053 g, 0.036 mmol) was added titanium tetraethoxide (0.011 g, 0.048 mmol). The mixture was stirred overnight at 75 °C. Then sodium borohydride (0.0027 g, 0.072 mmol) was added at 25 °C and stirred. 1 mL of HCl (4 M 1,4-dioxane solution) was added to the solution. The reaction was stirred at 25 °C for 1 h and purified by HPLC to give compound 59 (cis / trans isomer mixture, 1 mg, yield 7.38%), a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.39–7.28 (m, 5H), 7.25–7.14 (m, 5H), 7.11–7.04 (m, 1H), 6.87–6.80 (m, 1H), 6.39–6.22 (m, 1H), 4.08–3.96 (m, 1H), 3.95–3.79 (m, 2H), 3.73 (s, 3H), 3.72–3.70 (m, 2H), 3.28–3.15 (m, 1H), 3.01–2.82 (m, 3H), 2.74–2.52 (m, 2H), 2.48–2.37 (m, 1H), 2.06–1.93 (m, 2H), 1.28–1.20 (m, 9H). MS(ESI + ) m / z: 565 (M + H) + .

[0609] Example Compound 60

[0610]

[0611] Step 1: Synthesis of Compound 60-1:

[0612] 59-1 (20 mg, 0.042 mmol) and 2-phenylacetaldehyde (20.19 mg, 0.17 mmol) were dissolved in 1,2-dichloroethane (1.5 mL), and acetic acid (12.61 mg, 0.21 mmol) was added. The mixture was stirred at 20 °C for 2 h to obtain a black mixture. The mixture was stirred at 20 °C for 16 h to obtain a black mixture. LCMS showed that the reaction was complete. The mixture was dispersed in EA (20 mL) and saturated NaHCO3 (10 mL). The organic matter was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (EA:PE = 0 to 10%) to give 60-1 (10 mg). MS m / z (ESI): 583.5 [m + 1]

[0613] Step 2: Synthesis of Compound 60

[0614] Hydrogen chloride (0.073 mL, 2.40 mmol) was added to a solution of 60-1 (10 mg, 0.017 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 °C for 0.5 h under a N2 atmosphere. Then the solution was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography (ACN / H2O) to give Compound 60 (1.65 mg). MS m / z (ESI): 539.4 [M+1] + . 1 1H NMR (400 MHz, CDCl3) δ 7.46–7.26 (m, 5H), 7.23–7.13 (m, 4H), 7.05 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.40–6.22 (m, 2H), 4.09 (s, 1H), 3.86 (m, 2H), 3.72 (s, 3H), 3.38 (t, J = 6.8 Hz, 2H), 3.11 (s, 1H), 2.87 (m, 4H), 2.58 (m, 2H), 1.53 (d, J = 5.7 Hz, 3H), 1.24 (d, J = 7.2 Hz, 6H).

[0615] Example Compound 61

[0616]

[0617] Referring to the synthetic route of Reference Compound 29, starting from Intermediate A38 and Intermediate B8, Compound 61 can be synthesized and prepared. MS m / z (ESI): 507.4 [M+1] + . 1 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.3 Hz, 2H), 6.33–6.10 (m, 2H), 4.30 (s, 1H), 3.77 (m, 4H), 3.72 (s, 3H), 3.30 (s, 1H), 3.19–2.96 (m, 5H), 2.88 (s, 2H), 2.63 (m, 2H), 1.66 (s, 3H), 0.99 (s, 9H).

[0618] Example Compound 62

[0619]

[0620] Referring to the synthetic route of reference compound 60, starting from intermediate 3-(4-chlorophenyl)cyclobutan-1-one instead of intermediate 2-phenylacetaldehyde, compound 62 (cis / trans isomer mixture) can be synthesized and prepared. 1 H NMR(400MHz,CDCl3)δ7.39–7.27(m,3H),7.25–7.09(m,5H),7.08–6.96(m,1H),6.89–6.75(m,1H),6.40–6.24(m,1H),6.24–6.02(m,1H),4.13–3.62(m,7H),3.13–2.78(m,4H),2.78–2.37(m,5H),2.04–1.84(m,1H),1.55–1.44(m,3H),1.34–1.15(m,6H).MS(ESI + )m / z:599.5(M+H) + .

[0621] Example compound 63

[0622]

[0623] Referring to the synthetic route of reference compound 60, starting from intermediate 3,3-dimethylcyclobutan-1-one instead of intermediate 2-phenylacetaldehyde, compound 63 can be synthesized and prepared. 1 H NMR(400MHz,CDCl3)δ7.59–7.30(m,3H),7.25–7.19(m,2H),7.06(s,1H),6.92(d,J=8.2Hz,1H),6.36–6.19(m,1H),6.07(d,J=9.0Hz,1H),4.44–4.36(m,1H),4.36–4.18(m,1H),4.15–3.92(m,2H),3.89–3.80(m,1H),3.75(s,3H),3.17–2.97(m,1H),2.96–2.85(m,1H),2.78–2.60(m,2H),2.33–2.16(m,2H),2.03–1.50(m,11H),1.24(d,J=7.0Hz,6H).MS(ESI + )m / z:517.5(M+H) + .

[0624] Example compound 64

[0625]

[0626] Referring to the synthetic route of reference compound 60, starting from intermediate 3,3-dimethylcyclobutan-1-one instead of intermediate 2-phenylacetaldehyde, compound 64 (cis / trans isomer mixture) can be synthesized and prepared. MS (ESI + ) m / z: 533.5 (M+H) + .

[0627] Example compound 65

[0628]

[0629] Step 1: Synthesis of compound 65-1:

[0630] Under a nitrogen atmosphere, a xylene solution (1 mL) of 59-1 (15 mg, 0.031 mmol), 4-bromo-1-methyl-1H-pyrazole (4.99 mg, 0.031 mmol), tris(dibenzylideneacetone) dipalladium(0) (2.84 mg, 0.0031 mmol), sodium tert-butoxide (5.96 mg, 0.062 mmol), and 2'-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (1.32 mg, 0.0031 mmol) was stirred at 95 °C for 3 hours. Then the mixture was purified by SGC (PE:EA = 10:0 - 1:9) to obtain 65-1 (13 mg, yield 74.24%). MS (ESI + ) m / z: 559.4 (M+H + ).

[0631] Step 2: Synthesis of compound 65:

[0632] A solution of 65-1 (13 mg, 0.023 mmol) in 1,4-dioxane (1 mL) (4M HCl in dioxane) was stirred at room temperature for 4 hours. Then the solution was purified by preparative HPLC to obtain the title product 65 as a white solid (2.1 mg, yield 17.54%). MS (ESI + ) m / z: 515.4 (M+H) + .

[0633] Example compounds 66 and 67

[0634]

[0635] Referring to the synthetic route of reference compound 29, starting from a mixture of intermediates A39 and A40 and intermediate B8, compounds 66 and 67 can be synthesized and prepared. MS (ESI + ) m / z: 502.39 (M+H + ).

[0636] Example compound 68

[0637]

[0638] Referring to the synthetic route of reference compound 29, starting from intermediate A41 and intermediate B8, compound 68 can be synthesized and prepared as a racemate. MS (ESI + ) m / z: 519.5 (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.57 (s, 1H), 6.46–6.33 (m, 2H), 5.93 (s, 2H), 4.06–3.80 (m, 3H), 3.16–3.05 (m, 1H), 2.95–2.90 (m, 3H), 2.83–2.77 (m, 1H), 2.72–2.65 (m, 1H), 2.57–2.51 (m, 1H), 1.52 (d, J = 6.6 Hz, 3H), 1.28 (d, J = 6.9 Hz, 6H), 1.04 (s, 9H).

[0639] Example compound 69

[0640]

[0641] Referring to the synthetic route of reference compound 60, using intermediate 3-(benzyloxy)cyclobutan-1-one instead of intermediate 2-phenylacetaldehyde, compound 69 (cis / trans isomer mixture) can be synthesized and prepared. 1 H NMR (400 MHz, CDCl3) δ 7.37–7.27 (m, 7H), 7.16 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.41–6.29 (m, 1H), 6.20–6.06 (m, 1H), 3.99–3.88 (m, 1H), 3.83–3.75 (m, 1H), 3.70 (s, 3H), 3.67–3.57 (m, 1H), 2.99–2.84 (m, 2H), 2.84–2.68 (m, 2H), 2.62–2.46 (m, 2H), 2.44–2.31 (m, 2H), 2.26–2.14 (m, 2H), 2.05–1.81 (m, 3H), 1.44–1.37 (m, 3H), 1.28–1.20 (m, 6H). MS (ESI + ) m / z: 595.5 (M+H) + .

[0642] Example compound 70

[0643]

[0644] A solution of C1 (20 mg, 0.048 mmol) and 1-(3,4-dimethoxyphenyl)propan-2-one (93.23 mg, 0.48 mmol) in tetraethyl orthotitanate (0.54 g, 2.38 mmol) was stirred overnight at 75 °C. Then sodium borohydride (0.022 g, 0.58 mmol) was added and the mixture was stirred at 25 °C for 4 h. Then 1 mL of HCl (1,4-dioxane solution of 4 M HCl) was added to the solution and the mixture was stirred at 25 °C for 1 h. Compound 70 (1.84 mg, yield 6.96%) was obtained by HPLC purification as a white solid. 1 HNMR(400MHz,CDCl3)δ7.13–7.03(m,1H),6.87–6.76(m,2H),6.74–6.66(m,2H),6.37–6.17(m,2H),4.27–4.08(m,1H),3.89–3.80(m,6H),3.76–3.67(m,3H),3.22–2.98(m,3H),2.94–2.85(m,2H),2.81–2.68(m,1H),2.63–2.49(m,2H),2.44–2.32(m,1H),1.53–1.37(m,3H),1.32–1.24(m,3H),1.00(s,9H).MS(ESI + )m / z:551.5(M+H) + .

[0645] Example Compound 71

[0646]

[0647] Referring to the synthetic route of Compound 70, starting from the intermediate 1-(3-fluorophenyl)ethan-1-one instead of the intermediate 1-(3,4-dimethoxyphenyl)propan-2-one, Compound 71 can be synthesized and prepared. 1 H NMR(400MHz,CDCl3)δ7.34–7.27(m,1H),7.24–7.11(m,2H),7.03–6.89(m,2H),6.87–6.77(m,1H),6.34–6.17(m,2H),4.29–4.04(m,1H),3.96–3.82(m,1H),3.72(s,3H),3.06–2.70(m,4H),2.64–2.46(m,1H),2.42–2.25(m,1H),1.51–1.36(m,6H),1.10–0.93(m,9H).MS(ESI +)m / z:495.4(M+H) + .

[0648] Example Compound 72

[0649]

[0650] Referring to the synthetic route of Reference Compound 70, starting from intermediate 4-(3-fluorophenyl)benzaldehyde instead of intermediate 1-(3,4-dimethoxyphenyl)propan-2-one, Compound 72 can be synthesized and prepared. 1 H NMR(400MHz,CDCl3)δ7.52(q,J=8.2Hz,4H),7.42–7.32(m,2H),7.31–7.26(m,1H),7.11–6.96(m,2H),6.92–6.79(m,1H),6.36–6.16(m,2H),4.15–3.99(m,1H),3.94(d,J=13.5Hz,1H),3.85(d,J=13.5Hz,1H),3.72(s,3H),3.14–3.01(m,1H),2.89(s,2H),2.77(d,J=12.8Hz,1H),2.68–2.55(m,1H),2.52–2.41(m,1H),1.51(t,J=5.8Hz,3H),1.00(s,9H).MS(ESI + )m / z:557.5(M+H) + .

[0651] Example Compound 73

[0652]

[0653] Referring to the synthetic route of Reference Compound 70, starting from intermediate 9H-fluoren-2-carbaldehyde instead of intermediate 1-(3,4-dimethoxyphenyl)propan-2-one, Compound 73 can be synthesized and prepared. 11H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.43–7.33 (m, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.37–6.12 (m, 2H), 4.18–4.05 (m, 1H), 4.01–3.87 (m, 4H), 3.72 (s, 3H), 3.16–3.08 (m, 1H), 2.93–2.79 (m, 3H), 2.68–2.58 (m, 1H), 2.55–2.44 (m, 1H), 1.53 (t, J = 6.4 Hz, 3H), 1.00 (s, 9H). MS (ESI + ) m / z: 551.4 (M + H) + .

[0654] Example Compound 74

[0655]

[0656] Step 1: Synthesis of Compound 74-1:

[0657] To a reaction flask containing 59-1 (100 mg, 0.21 mmol), add dichloromethane (2 mL), and then add a 1,4-dioxane solution of hydrogen chloride (0.5 mL, 4 mol / L). Stir at 25 °C for 1 h. Then, concentrate, add saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL) for extraction. Wash the organic phase with saturated brine, separate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (PE / EA) to obtain the target product 74-1 (68 mg). MS (ESI + ) m / z: 435.34 (M + H + ).

[0658] Step 2: Synthesis of Compound 74:

[0659] To a reaction flask containing 74-1 (10 mg, 0.023 mmol) and 2-isopropylthiazole-5-carbaldehyde (4.3 mg, 0.028 mmol), add methanol (1 mL) and acetic acid (6.9 mg, 0.11 mmol). After stirring at 25 °C for 1 h, add sodium cyanoborohydride (4.3 mg, 0.069 mmol) and continue stirring at 25 °C for 2 h. After the reaction is complete, concentrate, then add saturated sodium bicarbonate solution (2 mL) and ethyl acetate (2 mL) for extraction. Wash the organic phase with saturated brine, separate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (PE / EA) to obtain the target product (3.46 mg). MS (ESI + ) m / z: 574.5 (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 7.31–7.26 (m, 2H), 7.17–7.15 (m, 2H), 7.02 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.37–6.34 (m, 1H), 6.28–6.26 (m, 1H), 4.42 (s, 2H), 3.92–3.84 (m, 1H), 3.79–3.71 (m, 1H), 3.67 (s, 3H), 3.63–3.55 (m, 1H), 3.34–3.22 (m, 1H), 2.94–2.83 (m, 2H), 2.56–2.36 (m, 2H), 2.35–2.25 (m, 1H), 1.36 (d, J = 6.9 Hz, 6H), 1.24–1.23 (m, 9H).

[0660] Example Compound 75

[0661]

[0662] Referring to the synthetic route of Step 2 of Reference Compound 74, starting with the intermediate 2-phenylthiazole-5-carbaldehyde instead of the intermediate 2-isopropylthiazole-5-carbaldehyde, Compound 75 can be synthesized and prepared. MS (ESI + ) m / z: 608.5 (M+H +). 1H NMR (400 MHz, CDCl3) δ 8.16–8.09 (m, 4H), 7.40–7.35 (m, 2H), 7.33–7.31 (m, 2H), 7.23–7.20 (m, 2H), 7.07–7.04 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 10.3 Hz, 1H), 6.25 (d, J = 20.7 Hz, 1H), 4.45–4.36 (m, 4H), 3.95–3.87 (m, 1H), 3.70 (s, 3H), 3.66–3.60 (m, 1H), 3.00–2.82 (m, 2H), 2.60–2.44 (m, 2H), 1.30–1.27 (m, 9H).

[0663] Example Compound 76

[0664]

[0665] Referring to the synthetic route of Step 2 of Reference Compound 74, starting from intermediate benzaldehyde instead of intermediate 2-isopropylthiazole-5-carbaldehyde, Compound 76 can be synthesized and prepared. MS (ESI + ) m / z: 525.4 (M+H + ). 1H NMR (400 MHz, CDCl3) δ 8.17–8.06 (m, 5H), 7.47–7.44 (m, 2H), 7.21–7.17 (m, 2H), 7.06 (d, J = 8.9 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 10.8 Hz, 1H), 6.34 (d, J = 12.9 Hz, 1H), 4.58 (s, 2H), 4.43–4.40 (m, 2H), 3.71 (s, 3H), 3.01–2.85 (m, 2H), 2.63–2.51 (m, 2H), 2.42–2.38 (m, 2H), 1.30–1.28 (m, 9H).

[0666] Example Compound 77

[0667]

[0668] Referring to the synthetic route of Step 2 of Reference Compound 74, starting from intermediate 4-chlorobenzaldehyde instead of intermediate 2-isopropylthiazole-5-carbaldehyde, Compound 77 can be synthesized and prepared. MS (ESI + ) m / z: 559.4, 561.4 (M+H + ).

[0669] Example Compound 78

[0670]

[0671] Referring to the synthetic route of reference compound 60, starting from intermediate 1-benzylpiperidine-4-carbaldehyde instead of intermediate 2-phenylacetaldehyde, compound 78 can be synthesized and prepared. MS m / z (ESI): 311.8 [m / 2 + 1] 1 H NMR (400 MHz, CDCl3) δ 7.86–7.26 (m, 9H), 7.11–6.73 (m, 2H), 6.47–6.11 (m, 2H), 4.56–3.94 (m, 5H), 3.75–2.87 (m, 14H), 2.50 (m, 1H), 1.88 (m, 3H), 1.74 (m, 1H), 1.61 (m, 1H), 1.24 (t, J = 6.4 Hz, 9H).

[0672] Example compound 79

[0673]

[0674] Step 1: Synthesis of compound 79-1:

[0675] Dissolve B7 (50 mg, 0.17 mmol) and 2,2-diphenylacetaldehyde (80.07 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), add acetic acid (30.63 mg, 0.51 mmol), and stir the mixture at 20 °C for 2 h. Then add sodium cyanoborohydride (53.41 mg, 0.85 mmol), stir at 70 °C for 16 h, and disperse the mixture between EA (20 mL) and NaHCO3 (10 mL). Wash the organic matter with NaHCO3 (10 mL x 2) and brine (10 mL). Dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain a residue. Filter and concentrate under reduced pressure to obtain a residue. Purify by silica gel column chromatography to obtain the title compound 79-1 (20 mg). MS m / z (ESI): 478.27 [m + 1]

[0676] Step 2: Synthesis of compound 79-2:

[0677] Stir the mixture of A49 (25 mg, 0.064 mmol), 79-1 (39.72 mg, 0.083 mmol), tripotassium phosphate (33.96 mg, 0.16 mmol), and XPhos G3 (10.83 mg, 0.013 mmol) in 1,4-dioxane (1.5 mL) and water (0.4 mL) at 90 °C for 2 h under a N2 atmosphere, filter, and concentrate under reduced pressure to remove the solvent. Purify by silica gel column chromatography to obtain the title compound 79-2 (20 mg). MS m / z (ESI): 659.56 [m + 1]

[0678] Step 3: Synthesis of Compound 79:

[0679] Hydrogen chloride (0.13 mL, 4.23 mmol) was added to a solution of 79-2 (20 mg, 0.030 mmol) in dichloromethane (1 mL). The mixture was stirred under a nitrogen atmosphere at 25 °C for 0.5 h to obtain a yellow mixture. LCMS showed that the reaction was complete. The solvent was removed by concentration under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O) to obtain the title compound 79 (5.11 mg). MS m / z (ESI): 615.5 [M+1] + . 1 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 9H), 7.25–7.15 (m, 5H), 7.05 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.34 (m, 2H), 4.31 (t, J = 7.5 Hz, 1H), 4.02 (s, 1H), 3.85 (d, J = 9.4 Hz, 1H), 3.75 (m, 5H), 3.05 (s, 1H), 2.97–2.33 (m, 6H), 1.49 (s, 3H), 1.24 (d, J = 6.9 Hz, 6H).

[0680] Example Compound 80

[0681]

[0682] Step 1: Synthesis of Compound 80-1:

[0683] Triethylamine (9.71 mg, 0.096 mmol) was added to a solution of C1 (20 mg, 0.048 mmol) and 1H-indazole-6-carbaldehyde (11.22 mg, 0.077 mmol) in 1,2-dichloroethane (1 mL). After the mixture was stirred at 20 °C for 20 min, sodium triacetoxyborohydride (30.52 mg, 0.14 mmol) was added. After stirring at 20 °C for 16 h, the solution was partitioned between EA (30 mL) and sat NaHCO3 (20 mL). The organic layer was washed with NaHCO3 (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain the title compound 80-1 (12 mg). MS m / z (ESI): 547.45 [M+1] + .

[0684] Step 2: Synthesis of Compound 80:

[0685] To a solution of 1-2 (10 mg, 0.018 mmol) in dichloromethane (1 mL) was added hydrogen chloride (0.093 g, 2.54 mmol), and the mixture was stirred under a nitrogen atmosphere at 25 °C for 0.5 h to obtain a yellow mixture. The solvent was removed by concentration under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O) to give the title compound 80 (2.61 mg). MS m / z (ESI): 503.4 [M+1] + . 1H NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.18 (m, 2H), 4.11 (m, 3H), 3.71 (s, 3H), 3.22 (m, 1H), 2.91 (s, 3H), 2.78–2.49 (m, 2H), 1.54 (d, J = 5.2 Hz, 3H), 1.01 (s, 9H).

[0686] Example Compound 81

[0687]

[0688] Referring to the synthetic route of reference compound 80, starting from intermediate 4-(2-(trifluoromethyl)phenyl)benzaldehyde instead of intermediate 1H-indazole-6-carbaldehyde, compound 81 can be synthesized and prepared. MS m / z (ESI): 607.43 [M+1] + .

[0689] Example Compound 82

[0690]

[0691] Referring to the synthetic route of reference compound 80, starting from intermediate 4-(4-(fluorophenyl)benzaldehyde instead of intermediate 1H-indazole-6-carbaldehyde, compound 82 can be synthesized and prepared. MS m / z (ESI): 557.48 [M+1] + .

[0692] Example Compound 83

[0693]

[0694] Referring to the synthetic route of reference compound 60, starting from intermediate 3-[(benzyloxy)methyl]cyclobutan-1-one instead of intermediate 2-phenylacetaldehyde, compound 83 can be synthesized and prepared as a mixture of cis and trans isomers. MS m / z (ESI): 609.53 [M+1] + .

[0695] Example Compound 84

[0696]

[0697] Referring to the synthetic route of Reference Compound 29, starting from a mixture of Intermediate A42 and Intermediate B8, Compound 84 can be synthesized and prepared. MS m / z (ESI): 267.3 [m / 2 + 1] + . 1H NMR (400 MHz, MeOD) δ 7.26 (dd, J = 8.6, 1.5 Hz, 2H), 7.13 (dd, J = 8.7, 1.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.3 Hz, 2H), 6.14 (m, 2H), 4.65–4.57 (m, 1H), 4.21 (m, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.96–2.84 (m, 4H), 2.73–2.51 (m, 2H), 1.79 (m, 1H), 1.76–1.54 (m, 2H), 1.46 (m, 3H), 1.31 (m, 1H), 1.08–0.77 (m, 10H).

[0698] Example Compound 85

[0699]

[0700] Referring to the synthetic route of Reference Compound 29, starting from a mixture of Intermediate A43 and Intermediate B8, Compound 85 can be synthesized and prepared. MS m / z (ESI): 591.6 [M + 1] + . 1 1H NMR (400 MHz, MeOD) δ 7.27 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.03–6.73 (m, 4H), 6.20–6.03 (m, 2H), 4.36–3.90 (m, 1H), 3.70 (m, 7H), 3.10 (m, 1H), 2.97–1.94 (m, 6H), 1.84–1.56 (m, 1H), 1.43 (d, J = 5.9 Hz, 2H), 1.36 (m, 1H), 1.29 (m, 2H), 1.04 (d, J = 6.7 Hz, 9H), 0.98 (m, 9H), 0.82 (d, J = 7.2 Hz, 3H).

[0701] Example Compound 86

[0702]

[0703] Referring to the synthetic route of Compound 29, starting from the mixture of Intermediate A43 and Intermediate B8, Compound 86 can be synthesized and prepared. MS m / z (ESI): 634.5 [M+1] + . 1 H NMR (400 MHz, MeOD) δ 7.82–7.65 (m, 5H), 7.49–7.28 (m, 5H), 6.76 (s, 1H), 6.32 (m, 1H), 4.59 (m, 2H), 4.34 (m, 1H), 3.55 (s, 1H), 3.06–2.67 (m, 6H), 1.97 (m, 3H), 1.65 (m, 3H), 1.25 (m, 6H), 1.01 (s, 9H).

[0704] Example Compound 87

[0705]

[0706] Referring to the synthetic route of Compound 60, starting from 3,3-difluorocyclobutan-1-one instead of 2-phenylacetaldehyde as the intermediate, Compound 78 can be synthesized and prepared. 1 H NMR (400 MHz, CDCl3) δ 7.46–7.32 (m, 2H), 7.24–7.17 (m, 2H), 7.05 (dd, J = 8.5, 3.8 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.48–6.36 (m, 1H), 6.31 (t, J = 10.0 Hz, 1H), 4.21–4.08 (m, 1H), 4.04–3.80 (m, 2H), 3.72 (s, 3H), 3.65–3.50 (m, 4H), 3.27–3.14 (m, 2H), 2.95–2.84 (m, 1H), 1.65–1.58 (m, 2H), 1.55 (d, J = 6.2 Hz, 1H), 1.34–1.19 (m, 10H), 1.07–0.97 (m, 3H). MS (ESI + ) m / z: 555.4 (M+H) + .

[0707] Example Compound 88

[0708]

[0709] A solution of C1 (50 mg, 0.012 mmol) and adamantane-1-aminocarbaldehyde (39 mg, 0.024 mmol) in DCM (0.5 mL) was added with acetic acid (0.072 mg, 0.0012 mmol) and sodium triacetoxyborohydride (7.6 mg, 0.036 mmol). The mixture was stirred overnight at 25 °C. Then, the solution was quenched with H2O and extracted with EA. The organic layer was washed with brine and evaporated under vacuum. 1 mL of HCl (1,4-dioxane solution of 4 M) was added to the residue. The reaction was stirred at 25 °C for 1 h and purified by HPLC to obtain 88 (0.82 mg, yield 13.08%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.22–6.74 (m, 2H), 6.36–6.13 (m, 2H), 4.42–4.18 (m, 1H), 4.03–3.87 (m, 1H), 3.75 (s, 3H), 3.37–3.12 (m, 1H), 2.98–2.61 (m, 2H), 2.63–2.39 (m, 1H), 2.10–2.03 (m, 3H), 1.89–1.80 (m, 3H), 1.74–1.64 (m, 9H), 1.00 (s, 9H), 0.93–0.79 (m, 3H). MS (ESI + ) m / z: 521.5 (M + H) + .

[0710] Example Compound 89

[0711]

[0712] Referring to the synthetic route of reference compound 88, starting from intermediate 4-(2-phenylpropan-2-yl)benzaldehyde instead of intermediate adamantane-1-aminocarbaldehyde, compound 89 can be synthesized and prepared. 1 H NMR (400 MHz, CDCl3) δ 7.58–7.31 (m, 2H), 7.24–7.13 (m, 7H), 7.09–6.95 (m, 1H), 6.93–6.80 (m, 1H), 6.34–6.11 (m, 2H), 4.38–3.80 (m, 4H), 3.73 (s, 3H), 2.88 (s, 3H), 2.74–2.37 (m, 2H), 1.67 (s, 6H), 1.25 (s, 3H), 0.99 (s, 9H). MS (ESI + ) m / z: 581.5 (M + H) + .

[0713] Example Compound 90

[0714]

[0715] Referring to the synthetic route of reference compound 80, starting from intermediate 2'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde instead of intermediate 1H-indazole-6-carbaldehyde, compound 90 can be synthesized and prepared. MS (ESI + ) m / z: 607.5 (M+H + ).

[0716] Example compound 91

[0717]

[0718] Step 1: Synthesis of compound 91-1:

[0719] Add dichloromethane (2 mL) to a reaction flask containing 2-chloro-2-fluoroacetic acid (3.5 mg, 0.032 mmol). Add phosphorus oxychloride (4.2 mg, 0.027 mmol) at 0 °C and stir at 25 °C for 1 h. After the reaction is complete, add water to quench the reaction, then add saturated sodium bicarbonate solution (10 mL) and dichloromethane (10 mL) for extraction. Wash the organic phase with saturated brine, separate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (PE / EA) to obtain the target product (10 mg). MS (ESI + ) m / z: 573.37 (M+H + ).

[0720] Step 2: Synthesis of compound 91:

[0721] Add dichloromethane (2 mL) to a reaction flask containing 91-1 (10 mg, 0.017 mmol), then add a 1,4-dioxane solution of hydrogen chloride (0.5 mL, 4 mol / L) and stir at 25 °C for 1 h. After the reaction is complete, concentrate, then add saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL) for extraction. Wash the organic phase with saturated brine, separate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by preparative liquid chromatography to obtain the target product 91 (1.4 mg). MS (ESI + ) m / z: 529.4 (M+H + ). 11H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 7.3 Hz, 2H), 7.22 (d, J = 7.3 Hz, 2H), 7.05–7.00 (m, 1H), 6.89–6.83 (m, 1H), 6.75–6.65 (m, 1H), 6.50–6.31 (m, 1H), 4.37–4.26 (m, 1H), 4.18–4.00 (m, 2H), 3.69 (s, 3H), 3.40–3.30 (m, 1H), 3.28–3.17 (m, 1H), 3.16–3.05 (m, 2H), 2.95–2.84 (m, 1H), 1.23–1.22 (m, 9H).

[0722] Example Compound 92

[0723]

[0724] Referring to the synthetic route of Reference Compound 60, starting from the intermediate (3S)-tert-butyl 3-formylpyrrolidine-1-carboxylate instead of the intermediate 2-phenylacetaldehyde, Compound 92 can be synthesized and prepared. MS (ESI + ) m / z: 259.76 (1 / 2M + H + ).

[0725] Example Compound 93

[0726]

[0727] Referring to the synthetic route of Reference Compound 60, starting from the intermediate (3R)-tert-butyl 3-formylpyrrolidine-1-carboxylate instead of the intermediate 2-phenylacetaldehyde, Compound 93 can be synthesized and prepared. MS (ESI + ) m / z: 259.76 (1 / 2M + H + ).

[0728] Example Compound 94

[0729]

[0730] Referring to the synthetic route of Reference Compound 29, starting from the mixture of intermediate A45 and intermediate B8, Compound 94 can be synthesized and prepared. MS m / z (ESI): 531.5 [M + 1] + . 11H NMR (400 MHz, MeOD) δ 8.07 (m, 1H), 7.98–7.51 (m, 2H), 7.30 (m, 1H), 7.13–6.87 (m, 2H), 6.43–6.00 (m, 2H), 4.30 (s, 1H), 4.08 (m, 3H), 3.80 (m, 1H), 3.72 (s, 3H), 3.30–3.25 (m, 1H), 3.11–2.58 (m, 5H), 1.83 (m, 4H), 1.57 (d, J = 6.1 Hz, 2H), 1.02 (m, 9H).

[0731] Example Compound 95

[0732]

[0733] Referring to the synthetic route of Reference Compound 29, starting from a mixture of Intermediate A46 and Intermediate B8, Compound 95 can be synthesized and prepared. MS m / z (ESI): 531.5 [M+1] + . 1 1H NMR (400 MHz, MeOD) δ 7.83 (m, 3H), 7.43–7.18 (m, 2H), 7.15–6.83 (m, 1H), 6.40–6.00 (m, 2H), 4.10 (m, 3H), 3.70 (m, 5H), 3.30–3.24 (m, 1H), 3.16–2.50 (m, 5H), 1.86 (m, 5H), 1.55 (s, 1H), 1.01 (m, 9H).

[0734] Example Compound 96

[0735]

[0736] Referring to the synthetic route of Reference Compound 29, starting from a mixture of Intermediate A47 and Intermediate B8, Compound 96 can be synthesized and prepared. MS m / z (ESI): 331.5 [M / 2+1] + .

[0737] Example Compound 97

[0738]

[0739] Referring to the synthetic route of Reference Compound 80, using 4-bromo-2-(trifluoromethyl)benzaldehyde instead of 1H-indazole-6-carbaldehyde as the intermediate, Compound 97 can be synthesized and prepared. 11H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.98–7.71 (m, 2H), 7.12–6.83 (m, 2H), 6.59–6.19 (m, 2H), 4.63–4.07 (m, 3H), 3.86–3.55 (m, 4H), 3.46–3.22 (m, 1H), 3.05–2.76 (m, 3H), 2.72–2.53 (m, 1H), 1.95–1.78 (m, 3H), 1.13–0.97 (m, 9H). MS (ESI + ) m / z: 609.4 (M + H) + .

[0740] Example Compound 98

[0741]

[0742] Referring to the synthetic route of Reference Compound 80, starting from intermediate 4-bromo-2-fluorobenzaldehyde instead of intermediate 1H-indazole-6-carbaldehyde, Compound 98 can be synthesized and prepared. 1 1H NMR (400 MHz, CDCl3) δ 7.49–7.40 (m, 1H), 7.35–7.29 (m, 2H), 7.10–7.03 (m, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.37–6.14 (m, 2H), 4.51–4.12 (m, 2H), 3.75 (s, 3H), 3.67–3.51 (m, 1H), 3.19–3.03 (m, 1H), 2.98–2.87 (m, 2H), 2.84–2.66 (m, 2H), 2.06–1.98 (m, 1H), 1.96–1.85 (m, 3H), 1.05–1.00 (m, 9H). MS (ESI + ) m / z: 559.4 (M + H) + .

[0743] Example Compound 99

[0744]

[0745] Referring to the synthetic route of Reference Compound 29, starting from the mixture of intermediate A48 and intermediate B8, Compound 99 can be synthesized and prepared. MS (ESI + ) m / z: 533.47 (M + H) + .

[0746] Biological Experiments

[0747] GIP Receptor Synergist Assay

[0748] The functional activity of the GIP receptor (GIPR) was determined by cAMP formation in the HEK293 immortalized cell line expressing human GIPR. This assay measures compound-induced cAMP production in the presence of the GIPR agonist GIP(1-42) at the EC20 dose.

[0749] hGIPR-HEK293 immortalized cells were seeded in a 384-well plate with DMEM medium supplemented with GlutaMAXTM, 0.1% bovine casein, 250 μM 3-isobutyl-1-methylxanthine, and 20 mM HEPES and incubated overnight for attachment. 25 pM of GIP(1-42) and the indicated concentrations of the test compound were added and incubated at 37 °C for 30 min. The increase in intracellular cAMP was quantified using the CisBio cAMP Dynamic 2 HTRF assay kit. Briefly, the intracellular cAMP level was detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 μL), followed by the addition of the anti-cAMP-Eu 3+ -Cryptate antibody in cell lysis buffer (10 μL). The resulting competitive assay system was incubated at room temperature for at least 60 min and then detected using a microplate reader with an excitation wavelength of 320 nm and emission wavelengths of 665 nm and 620 nm. The peak area of the emitted light is inversely proportional to the amount of cAMP present and was converted to the cAMP concentration per well using a cAMP standard curve, and then the amount of cAMP generated per well was converted to a percentage of the observed maximum response. The relative EC 50 value and the upper percentage limit (E max ) were obtained by nonlinear regression analysis, fitting the percentage of the maximum response to the concentration of the added compound to a four-parameter logistic equation.

[0750] Table 1. Endogenous cAMP response in hGIPR-HEK293 immortalized cells

[0751] Example compound <![CDATA[EC 50 (nM) and SEM (n = 4)]]> <![CDATA[E max (%) ± SEM (n = 4)]]> 1 6.5(21.5) 88.4±1.8 2 44.7(7.6) 96.4±4.0 3 13.8(13.9) 90.8±5.9 4 35.5(16.5) 84.0±8.5 5 21.6(5.2) 100.0±8.6 6 15.6(10.9) 90.8±9.5 7 13.5(4.1) 100.9±1.2 8 22.2(15.0) 94.5±5.0 9 34.1(3.4) 84.3±4.9 10 19.3(8.2) 102.4±5.5 11 17.7(9.4) 101.7±8.1 12 11.1(21.6) 86.2±9.4 13 24.6(1.9) 99.0±3.3 14 48.3(7.1) 93.7±7.2 15 5.6(11.0) 98.0±1.3 16 14.6(17.7) 83.6±8.4 17 54.1(9.4) 83.5±8.0

[0752] Evaluation of the agonistic activity of the human GIP receptor

[0753] The functional activity of the GIP receptor (GIPR) was determined by cAMP formation in the Flp-In-293-GIPR HEK293 immortalized cell line expressing human GIPR.

[0754] Flp-In-293-GIPR immortalized cells were seeded in a 384-well plate supplemented with DMEM medium containing 10% FBS, 1× penicillin-streptomycin, and 200 μg / mL HB and incubated overnight to allow cell attachment. A 4× working solution of the test compound was prepared with assay buffer (1× HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX). 5 μL of the 4× working solution of the test compound was added to the cell plate and incubated at 37 °C for 30 min. The increase in intracellular cAMP was quantitatively measured using the CisBio cAMP Dynamic 2HTRF assay kit. Briefly, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 μL), followed by addition of anti-CAMP-Eu 3+ -Cryptate antibody in cell lysis buffer (10 μL). The resulting competitive assay system was incubated at room temperature for at least 60 min and then detected using a microplate reader with an excitation wavelength of 320 nm and emission wavelengths of 665 nm and 620 nm. The peak area of the emitted light is inversely proportional to the amount of cAMP present and was converted to the cAMP concentration per well using a cAMP standard curve, and then the amount of cAMP generated per well was converted to a percentage of the observed maximum response. Relative EC 50 values and upper percentage limits (E max ) were determined by non-linear regression analysis, fitting the percentage of maximum response against the concentration of the added compound to a four-parameter logistic equation. The EC 50 values for the agonist activity of the compounds in some of the examples against human GIPR are shown in the table below:

[0755] Table 2. Agonist activity of the compounds of the present disclosure against human GIPR

[0756]

[0757]

[0758] EC 50 value: A: EC 50 < 10 nM; B: 10 nM ≤ EC 50 < 100 nM; C: 100 nM ≤ EC 50 < 1000

[0759] nM; D: 1000 nM ≤ EC 50

[0760] Conclusion: The compounds of the present disclosure have strong agonist activity against human GIPR.

[0761] Evaluation of agonist activity of human GLP-1 receptor

[0762] The functional activity of the GLP-1 receptor (GLP-1R) was determined by cAMP formation in the Flp-In-293-GLP1R HEK293 immortalized cell line expressing human GLP-1R.

[0763] Flp-In-293-GLP1R immortalized cells were seeded in a 384-well plate with DMEM medium supplemented with 10% FBS, 1× penicillin-streptomycin, and 200 μg / mL HB and incubated overnight for attachment. A 4× working solution of the test compound was prepared with the assay buffer (1× HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX). 5 μL of the 4× working solution of the test compound was added to the cell plate and incubated at 37 °C for 30 min. The increase in intracellular cAMP was quantitatively determined using the CisBio cAMP Dynamic 2HTRF assay kit. Briefly, the intracellular cAMP level was detected by adding the cAMP-d2 conjugate in the cell lysis buffer (10 μL), followed by adding the anti-CAMP-Eu 3+ -Cryptate antibody in the cell lysis buffer (10 μL). The resulting competitive assay system was incubated at room temperature for at least 60 min and then detected using a microplate reader with an excitation wavelength of 320 nm and emission wavelengths of 665 nm and 620 nm. The peak area of the emitted light is inversely proportional to the amount of cAMP present and was converted to the cAMP concentration per well using a cAMP standard curve, and then the amount of cAMP generated per well was converted to a percentage of the observed maximum response. The relative EC 50 value and the upper percentage limit (E max ) were obtained by non-linear regression analysis, fitting the percentage of the maximum response against the concentration of the added compound to a four-parameter logistic equation. The EC 50 values of the compounds in some of the examples for the agonist activity on human GLP-1R are shown in the following table:

[0764] Table 3 Agonist activity of the compounds of the present disclosure on human GLP-1R

[0765] Example compound <![CDATA[EC 50 (nM)]]> Example compound <![CDATA[EC 50 (nM)]]> 19 B 21 B 2b B 23 B 27 B 28 A 29 B 30 B 32 B 33 B 38 B 40 B 42 B 43 B 48 B 49 B 52 B 53 B 54 B 57 B 59 B 62 B 63 B 64 B 67 B 71 B 79 B 81 B 82 B 83 B 85 B 88 B 89 B 97 B 98 B

[0766] EC 50 value: A: EC 50 < 50 nM; B: 50 nM ≤ EC 50 < 500 nM; C: 500 nM ≤ EC 50 < 5000

[0767] nM; D: 5000 nM ≤ EC 50

[0768] Conclusion: The compounds of the present disclosure have strong agonist activity on human GLP-1R.

[0769] Evaluation of the agonist activity of human GCG receptor

[0770] The functional activity of the GCG receptor (GCGR) was determined by cAMP formation in the CHO cell line Flp-In-CHO-GCGR expressing human GCGR.

[0771] Flp-In-CHO-GCGR cells were seeded in a 384-well plate containing F12K medium supplemented with 10% FBS, 1× penicillin-streptomycin, and 800 μg / mL HB and incubated overnight to allow cell attachment. A 4× working solution of the test compound was prepared in assay buffer (1× HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX). 5 μL of the 4× working solution of the test compound was added to the cell plate and incubated at 37 °C for 30 min. The increase in intracellular cAMP was quantified using the CisBio cAMP Dynamic 2HTRF assay kit. Briefly, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 μL), followed by addition of the anti-CAMP-Eu 3+ -Cryptate antibody in cell lysis buffer (10 μL). The resulting competitive assay system was incubated at room temperature for at least 60 min and then detected using a microplate reader with an excitation wavelength of 320 nm and emission wavelengths of 665 nm and 620 nm. The peak area of the emitted light is inversely proportional to the amount of cAMP present and was converted to the cAMP concentration per well using a cAMP standard curve, and then the amount of cAMP generated per well was converted to a percentage of the observed maximum response. Relative EC 50 values and upper percentage limits (E max ) were determined by non-linear regression analysis, fitting the percentage of maximum response to the concentration of the added compound to a four-parameter logistic equation. The EC 50 values of the compounds in some examples for the agonist activity of human GCGR are shown in the following table:

[0772] Table 4 Agonist activity of the compounds of the present disclosure against human GCGR

[0773] Example compound <![CDATA[EC 50 (nM)]]> Example compound <![CDATA[EC 50 (nM)]]> 19 B 21 B 2b B 23 B 25 B 28 A 29 B 30 B 40 B 41 B 47 B 51 B 52 B 54 B 85 B

[0774] EC 50 value: A: EC 50 < 100 nM; B: 100 nM ≤ EC 50 < 1000 nM; C: 1000 nM ≤

[0775] EC 50 < 10000 nM; D: 10000 nM ≤ EC 50

[0776] Conclusion: The compounds of the present disclosure have strong agonist activity against human GCGR.

[0777] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A biaryl compound having the structure shown in Formula I, its stereoisomers, pharmaceutically acceptable salts or deuterated compounds: A, B, and C are each independently selected from N and CR a ; where R a is selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , -(CO)R aa , -O-(CO)R aa , where C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with substituents selected from -OH, -NH2, a halogen, a pseudohalogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, a 4- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group; where R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; X, Y, and Z are each independently selected from N or CR b ; where R b is selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , -(CO)R bb , -O-(CO)R bb , where C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, a halogen, a pseudohalogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, a 4- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group; where R bb is selected from H, a halogen, a pseudohalogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; D is selected from optionally -OH, NH2, halogen, pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl-substituted C 3-10 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl or bridged ring; R 1 selected from C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -S(O)2C 1-6 alkyl, -S(O)2C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group; R 2 Selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OR 2a , R 2a Selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein C 1-6 alkyl or C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl may be optionally substituted by -OH, -NH2, halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl, 4-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl; R 3 and R 3’ each independently selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, a 4- to 6-membered heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group may optionally be substituted by -OH, -NH2, a halogen, oxo or C 1-6 alkyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C=S, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may optionally be substituted by -OH, -NH2, a halogen, pseudohalogen, cyano, oxo, C 1-6 alkyl; R 4 and R 4’ each independently selected from a hydrogen atom, C 1-6 alkyl or a halogen; And the compound of Formula 1 does not include the following compounds:

2. The compound according to claim 1, wherein A, B, and C are each independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with a substituent selected from OH, -NH2, a halogen, a 6-membered aryl, and a 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; X, Y, and Z are each independently selected from N and CR b ; wherein R b is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein the C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, and a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl.

3. The compound according to claim 2, R a is selected from a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -OCH3, -OCH2CH3, F, Cl.

4. The compound according to claim 2, R b is selected from a hydrogen atom, F, Cl, a cyano group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -(SO2)F, -O-(SO2)F.

5. The compound according to any one of claims 1-4, wherein D is selected from optionally -OH, -NH2, halogen, pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 a 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring substituted with cycloalkyl.

6. The compound according to claim 5, wherein D is selected from or bridged ring, wherein R c is selected from a hydrogen atom, -OH, -NH2, halogen, pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl.

7. The compound according to claim 6, wherein R c is selected from a hydrogen atom, -OH, -NH2, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, and cyclobutyl.

8. The compound according to claim 6, wherein D is preferably selected from 9. The compound according to any one of claims 1-8, wherein R 1 is selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl may optionally be substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl.

10. The compound according to claim 9, wherein R 1 is selected from C 1-6 alkyl optionally substituted with halogen.

11. The compound according to claim 10, R 1 is selected from 12. The compound according to any one of claims 1-11, R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a selected from C 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted with -OH, -NH2, halogen.

13. The compound according to claim 12, R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with F.

14. The compound according to claim 13, wherein R 2 is selected from methyl, -OCH3 or -OCF3.

15. The compound according to any one of claims 1-14, R 3 , R 3’ are each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4-6 membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group may optionally be substituted by -OH, -NH2, halogen, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4-6 membered heterocyclic group may optionally be substituted by -OH, -NH2, halogen or C 1-6 alkyl.

16. The compound according to claim 15, R 3 and R 3’ each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C═O, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group.

17. The compound according to claim 15, wherein R 3 is H; R 3’ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl.

18. The compound according to any one of claims 1-17, R 4 and R 4’ are independently selected from a hydrogen atom or a halogen.

19. The compound according to claim 1, having the structure shown in Formula II: Among them, R a1 selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with a substituent selected from OH, NH2, a halogen, a 6-membered aryl, a 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; R b1 selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein the C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; B and C are each independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with a substituent selected from OH, -NH2, a halogen, a 6-membered aryl, and a 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; Y and Z are each independently selected from N and CR b ; wherein R b is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein the C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, and a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; D is selected from optionally -OH, -NH2, halogen, pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 a 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring substituted with cycloalkyl; R 1 selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group may optionally be substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl; R 2 Selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein the C 1-6 alkyl may optionally be substituted by -OH, -NH2, halogen; R 3 and R 3’ are each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4-6 membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group may be optionally substituted with -OH, -NH2, halogen, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4-6 membered heterocyclic group may be optionally substituted with -OH, -NH2, halogen or C 1-6 alkyl; R 4 and R 4’ are independently selected from a hydrogen atom or a halogen; And the compound of Formula II does not include the following compounds:

20. The compound according to claim 19, wherein R a1 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl,; R b1 is selected from a hydrogen atom, a halogen, a cyano group, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -O-(SO2)F.

21. The compound according to claim 19, wherein each of B and C is independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl; Y and Z are each independently selected from N and CR b ; where R b is selected from a hydrogen atom, a halogen, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -(SO2)F, -O-(SO2)F.

22. The compound according to any one of claims 19-21, wherein D is selected from or bridged ring, wherein R c is selected from a hydrogen atom, -OH, -NH2, halogen, pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl.

23. The compound according to claim 22, wherein R c is selected from a hydrogen atom, -OH, -NH2, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, and cyclobutyl.

24. The compound according to claim 22, wherein D is selected from 25. The compound according to any one of claims 19-24, wherein R 1 is selected from C 1-6 alkyl optionally substituted by halogen.

26. The compound according to claim 25, wherein R 1 is selected from 27. The compound according to any one of claims 19 - 26, wherein R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with F.

28. The compound according to claim 27, wherein R 2 is selected from methyl, -OCH3 or -OCF3.

29. The compound according to any one of claims 19-28, wherein R 3 and R 3’ are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4-6 membered heterocyclic group.

30. The compound according to claim 29, wherein R 3 is H; R 3’ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl.

31. The compound according to claim 1, having the structure shown in Formula III: Among them, R a1 selected from H, halogen, -NH2, C 1-6 alkyl, -OC 1-6 alkyl, wherein the C 1-6 alkyl may optionally be substituted by halogen, 6-membered aryl or 5-6-membered heteroaryl; R b1 Selected from a hydrogen atom, a halogen, C 1-6 alkyl, -(SO2)R bb , -O(SO2)R bb , wherein the C 1-6 alkyl may optionally be substituted by a halogen; R bb is selected from H, a halogen, C 1-6 alkyl; B, C, Y, Z are each independently selected from N or CH; R c Selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl; R 1 selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl; R 2 Selected from cyano, C 1-6 alkyl, -OR 2a , R 2a Selected from C 1-6 alkyl, wherein the C 1-6 alkyl may optionally be substituted by -OH, -NH2, -halogen; R 3 and R 3’ are each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may be optionally substituted by OH, NH2, halogen, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may be optionally substituted by OH, NH2, halogen or C 1-6 alkyl; And the compound of Formula III does not include the following compounds:

32. The compound according to claim 31, wherein R a1 is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl; R b1 is selected from a hydrogen atom, a halogen, a cyano group, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -O-(SO2)F.

33. The compound according to any one of claims 31-32, wherein R c is selected from a hydrogen atom, -OH, -NH2, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl.

34. A compound according to any one of claims 31-33, wherein R 1 is selected from C1-6 alkyl optionally substituted with halogen.

35. The compound according to claim 34, wherein R 1 is selected from 36. A compound according to any one of claims 31 - 35, wherein R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with F.

37. The compound according to claim 36, wherein R 2 is selected from methyl, -OCH3 or -OCF3.

38. A compound according to any one of claims 31 - 37, wherein R 3 and R 3’ are each independently selected from H, methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, tert - butyl, cyclopropyl, cyclobutyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C═O, C 3-6 cycloalkyl, 4 - 6 - membered heterocyclic group.

39. The compound according to claim 38, wherein R 3 is H, and R 3’ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl.

40. The compound according to claim 1, having the structure shown in Formula IV: wherein R a1 is selected from H, F, Cl, -NH2, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3; R b1 selected from H, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -(SO2)F; R 1 selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group may optionally be substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl; R 2 Selected from cyano, C 1-6 alkyl, -OR 2a , R 2a Selected from C 1-6 alkyl, wherein the C 1-6 alkyl may optionally be substituted by -OH, -NH2, halogen; R 3 and R 3’ are each independently selected from a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may be optionally substituted by OH, NH2, halogen, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C═O, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group may be optionally substituted by OH, NH2, halogen or C 1-6 alkyl; And the compound of Formula IV does not include the following compounds:

41. The compound according to claim 40, R a1 is selected from -OCH3, R b1 is selected from F.

42. The compound according to claim 40 or 41, R 1 selected from 43. The compound according to any one of claims 40 - 42, R 2 is selected from methyl, -OCH3 or -OCF3.

44. The compound according to any one of claims 40-43, R 3 is H, R 3’ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or R 3 and R 3’ optionally together with the carbon atom to which they are attached form C=O, C 3-6 cycloalkyl, 4-6 membered heterocyclic group.

45. The compound according to claim 1, having the structure shown in Formula V: Among them, R a1 selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with a substituent selected from OH, NH2, a halogen, a 6-membered aryl, a 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; R b1 selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , wherein the C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, and a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; B and C are each independently selected from N and CR a ; wherein R a is selected from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R aa , -O-(SO2)-R aa , wherein C 1-6 alkyl, C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, a halogen, a 6-membered aryl, a 5-6-membered heteroaryl; R aa is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; Y and Z are each independently selected from N and CR b ; where the selection is from a hydrogen atom, -OH, -NH2, a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -(SO2)R bb , -O(SO2)R bb , where C 1-6 alkyl or C 3-6 cycloalkyl may optionally be substituted with a substituent selected from -OH, -NH2, a halogen; R bb is selected from H, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl; D is selected from optionally -OH, -NH2, halogen, pseudohalogen, oxo, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 a 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring substituted with cycloalkyl; R 1 selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group may be optionally substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl; R 2 Selected from cyano, C 1-6 alkyl, -OR 2a , R 2a Selected from C 1-6 alkyl, wherein the C 1-6 alkyl may optionally be substituted by -OH, -NH2, halogen; R 4 and R 4’ are independently selected from a hydrogen atom or a halogen.

46. The compound according to claim 45, wherein R a1 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl; R b1 is selected from a hydrogen atom, a halogen, a cyano group, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -(SO2)F, -O-(SO2)F.

47. The compound according to claim 45, wherein each of B and C is independently selected from N and CR a ; wherein R a is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, F, Cl; Y and Z are each independently selected from N and CR b ; wherein R b is selected from a hydrogen atom, a halogen, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, —(SO2)F, —O(SO2)F.

48. The compound according to any one of claims 45-47, wherein D is selected from or bridged ring, wherein R c is selected from a hydrogen atom, -OH, -NH2, halogen, pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl.

49. The compound according to claim 48, wherein R c is selected from a hydrogen atom, -OH, -NH2, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, and cyclobutyl.

50. The compound according to claim 48, wherein D is selected from 51. A compound as claimed in any one of claims 45 - 51, wherein R1 is selected from C 1-6 alkyl optionally substituted by halogen.

52. The compound according to claim 51, wherein R 1 is selected from 53. A compound according to any one of claims 45 - 52, wherein R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by F.

54. The compound according to claim 53, wherein R 2 is selected from methyl, -OCH3 or -OCF3.

55. The compound according to claim 1, having the structure shown in Formula VI: Among them, R a1 selected from H, halogen, -NH2, C 1-6 alkyl, -OC 1-6 alkyl, wherein C 1-6 alkyl may optionally be substituted by halogen, 6-membered aryl or 5-6-membered heteroaryl; R b1 selected from a hydrogen atom, a halogen, C 1-6 alkyl, -(SO2)R bb , -O(SO2)R bb , wherein the C 1-6 alkyl may optionally be substituted by a halogen; R bb is selected from H, a halogen, C 1-6 alkyl; B, C, Y, Z are each independently selected from N or CH; R c selected from a hydrogen atom, -OH, -NH2, a halogen, a pseudohalogen, -CN, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl; R 1 selected from C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group may optionally be substituted by -OH, -NH2, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, C 1-6 haloalkyl, C 3-6 halocycloalkyl, -OC 1-6 haloalkyl, -OC 3-6 halocycloalkyl; R 2 Selected from cyano, C 1-6 alkyl, -OR 2a , R 2a Selected from C 1-6 alkyl, wherein the C 1-6 alkyl may optionally be substituted by -OH, -NH2, halogen.

56. The compound according to claim 55, wherein R a1 is selected from a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -OCH3, -OCH2CH3, F, Cl.

57. The compound according to claim 55, R b1 is selected from a hydrogen atom, a halogen, a cyano group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, -(SO2)F, -O-(SO2)F.

58. The compound according to any one of claims 55-57, wherein R c is selected from a hydrogen atom, -OH, -NH2, a halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl.

59. The compound according to any one of claims 55 - 57, wherein R 1 is selected from C1 - 6 alkyl optionally substituted by halogen.

60. The compound according to claim 59, wherein R 1 is selected from 61. The compound according to any one of claims 55 - 60, wherein R 2 is selected from cyano, C 1-6 alkyl, -OR 2a , R 2a is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with F.

62. The compound according to claim 61, wherein R 2 is selected from methyl, -OCH3 or -OCF3.

63. The compound of Formula I according to claim 1 is selected from: And its stereoisomers, pharmaceutically acceptable salts or deuterated compounds.

64. A composition comprising the compound of Formula I according to any one of claims 1 - 63, its stereoisomers, pharmaceutically acceptable salts or deuterated compounds, and a pharmaceutically acceptable excipient.

65. A method for treating a disease or symptom mediated by GIPR / GLP1R / GCGR: comprising the following steps: Administering to a subject an effective amount of the compound of Formula I according to any one of claims 1 - 63, its stereoisomers, pharmaceutically acceptable salts or deuterated compounds or an effective amount of the composition according to claim 64.

66. Use in a medicament for treating diseases or symptoms mediated by GIPR / GLP1R / GCGR, comprising the following steps: Administering to a subject an effective amount of the compound of Formula I according to any one of claims 1 - 63, its stereoisomers, pharmaceutically acceptable salts or deuterated compounds or an effective amount of the composition according to claim 64.

67. The method according to any one of claims 65-66, wherein the GIPR / GLP1R / GCGR-mediated diseases or symptoms include: T1DM, 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, long-term weight management, obesity, eating disorders, weight gain due to other medications, excessive sugar craving, 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, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, 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, hyperapolipoprotein B lipoproteinemia, 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.

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