CN115872982A

CN115872982A - Polycyclic compound, pharmaceutical composition containing polycyclic compound, preparation method and application of polycyclic compound

Info

Publication number: CN115872982A
Application number: CN202111151997.7A
Authority: CN
Inventors: 易磊; 王太津; 刘谦; 田强; 龙冬; 宋宏梅; 葛均友; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2021-09-29
Filing date: 2021-09-29
Publication date: 2023-03-31

Abstract

The invention relates to a polycyclic compound, a pharmaceutical composition containing the polycyclic compound, a preparation method and application of the polycyclic compound. Specifically, the invention relates to a compound with a structure shown in a formula I, which shows better GLP-1R agonistic activity and can be used as a high-efficiency GLP-1R agonist for preventing and/or treating GLP-1R related diseases.

Description

Polycyclic compound, pharmaceutical composition containing polycyclic compound, preparation method and application of polycyclic compound

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a small molecule regulator used as GLP-1R (glucagon-like peptide-1 receptor), a preparation method and a medical application thereof.

Background

Diabetes mellitus is a metabolic disease caused by insufficient insulin secretion or insulin action, and is classified into types I and II according to its pathogenesis. Type 1 diabetes is caused by insufficient insulin secretion resulting from autoimmune destruction of the islet beta cells. In order to survive, type I diabetic patients require insulin therapy, including external injections of insulin. Type II diabetes is caused by decreased islet beta cell function and insulin resistance, and is the major type of onset of diabetes. The treatment of type II diabetic patients requires the use of therapeutic drugs, either alone or in combination, or the use of insulin therapy depending on the progression of the disease.

Currently known oral diabetes drugs include insulin secretagogues, biguanides, α -glucosidase inhibitors, thiazolidinediones, sodium-glucose co-transporter 2 (SGLT-2) selective inhibitors, and the like. Insulin secretagogues include sulfonylureas (e.g., glipizide, glimepiride, glyburide), meglitinide (e.g., nateglinide, rapaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors such as sitagliptin, vildagliptin, alogliptin, duloxetine (dulagliptin), linagliptin (linagliptin), saxagliptin (saxogliptin)), and glucagon-like peptide-1receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide), exenatide (exendide), lixiduluride (lixitusside), insulin beta (insulin β), which act primarily on insulin cells by increasing insulin secretion. Biguanides (e.g., metformin) act primarily by reducing hepatic glucose production. Alpha-glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. Thiazolidinediones (e.g. pioglitazone (pioglitazone), rosiglitazone (rosiglitazone)) act on specific receptors (peroxisome proliferator-activated receptor γ) in liver, muscle and adipose tissue. Sodium-glucose linked transporter cotransporter 2 (SGLT 2) inhibitors (e.g., dapagliflozin (dapagliflozin), empagliflozin (empagliflozin), canagliflozin (canagliflozin), egagliflozin (ertugliflozin)) inhibit glucose reabsorption in the kidney and thereby reduce the glucose content of the blood.

However, in addition to their positive effects in maintaining normal blood glucose levels, currently used oral diabetic drugs in clinical use often have limited efficacy and tolerability when taken for a long period of time or cause various side effects such as weight gain, hypoglycemia, gastrointestinal disorders, hepatotoxicity, cardiovascular problems, and the like. In addition, the administration of insulin as the last treatment is inconvenient, requires subcutaneous injections two to three times a day, and may cause hypoglycemia, which is the most serious side effect.

To overcome these problems, glucagon-like peptide-1 (GLP-1) receptor agonists have become the next generation of diabetes drugs.

Glucagon-like peptide 1 (GLP-1) is a peptide hormone encoded by the human glucagon gene and secreted by L cells of the intestinal tract. GLP-1 acts on islet beta cells in a glucose-dependent manner, promotes the transcription of insulin genes, and increases the biosynthesis and secretion of insulin; stimulating the proliferation and differentiation of beta cells, inhibiting beta cell apoptosis, increasing the number of pancreatic beta cells, inhibiting glucagon secretion, suppressing appetite and ingestion, delaying gastric content emptying, etc. GLP-1 mediates intracellular signal transduction through a GLP-1 receptor (GLP-1R), wherein the GLP-1R belongs to a G protein coupled receptor family existing on a cell membrane, and can cause the accumulation of the secondary messenger cyclic adenosine monophosphate (cAMP) when activated, so that downstream signal pathways such as PKA, PI3K, MAPK and the like are further activated to play a biological role.

GLP-1 receptor agonists developed in the early period are GLP-1 analogues, which all belong to peptide substances, including liraglutide, somaglutide and the like, and long-acting and orally-administrable polypeptide medicaments have been developed through genetic engineering methods, preparation improvement and other ways, but oral administration of polypeptides is still limited by administration time, dosage, gastrointestinal disturbance and other disadvantages. Thus, there remains a need for compounds, such as GLP-1R small molecule agonists, that have desirable therapeutic, metabolic, and/or easy to administer properties in the treatment of metabolic and related diseases of the heart, including but not limited to NASH, obesity, and type 2 diabetes. We surprisingly find a small molecular compound in research, which has higher GLP-1R agonistic activity and shows good application prospect.

Disclosure of Invention

The invention aims to provide GLP-1R small molecule regulators with novel structures, a preparation method and pharmaceutical application thereof.

In an embodiment of the invention, the invention provides a compound having the structure of formula I or a pharmaceutically acceptable form thereof:

wherein

X ¹ 、X ⁴ 、X ⁵ Each independently selected from N or CR ³ ；X ² 、X ³ Each is independently selected from N or C and is not N at the same time; x ⁶ 、X ⁷ Each independently selected from N or CR ³ ；X ⁸ Is selected from N or C;

ring B is selected from 3-7 membered heterocycloalkyl or C _4-7 A cycloalkyl group;

the C ring is selected from 4-6 membered heterocycloalkyl or C _4-6 A cycloalkyl group;

d ring is selected from C _6-10 Aryl or 5-10 membered heteroaryl;

ring E is selected from C _6-14 Aryl or 5-14 membered heteroaryl;

v is selected from-O-, -S-, -C (O) -, -CR ^7a R ^7b -or-NR ^7a -；

U is selected from-O-, -C (O) -, -CR ^8a R ^8b -or-NR ^8a -；

W is selected from the group consisting of a bond, -O-, -NR ^9a -、-S-、-C(O)-、-CR ^9a R ^9b -or-C (O) NR ^9a -；

m, n, p, q are each independently selected from 0, 1, 2, 3, 4 or 5;

R ¹ selected from hydrogen, halogen, -CN, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C _6-10 Aryl or 5-10 membered heteroaryl; each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R ^x Substitution;

R ^x selected from hydrogen, halogen, -CN, -NH ₂ 、-NO ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-12 Cycloalkyl, -O (4-12 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, -COC _1-6 Alkyl, -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-NHC(O)C _1-6 Alkyl radical, C _6-10 Aryl, 5-to 10-membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Haloalkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl radicals or-N(C _1-6 Alkyl) (C _3-6 Cycloalkyl) substituted with a substituent;

R ² selected from-COOH, -CONH ₂ 、-CONHOH、-CONH-S(O) ₂ C _1-6 Alkyl, -CONH-S (O) ₂ C _3-6 Cycloalkyl, -P (O) (OH) ₂ 、-B(OH) ₂ 、-CONH-CN、-C _1-6 alkylene-COOH, -C _1-6 alkylene-P (O) (OH) ₂ 、-C _2-4 alkenylene-COOH, -C _2-4 alkynylene-COOH, 5-6 membered heterocycloalkyl, C _3-6 Cycloalkyl, phenyl or 5-10 membered heteroaryl; said alkyl, alkenyl, alkynyl, alkylene, alkenylene or alkynylene each optionally substituted with one or more substituents selected from halogen, hydroxy or-CN, said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl each optionally substituted with one or more hydroxy or-COOH;

each R ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Alkyl, -C _1-6 Haloalkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

R ^4a 、R ^4b each independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl)) or-NO ₂ Said alkyl, cycloalkyl or heterocycloalkyl being each optionally substituted by one or more groups chosen from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Haloalkyl or-OC _1-6 Alkyl substituent substitution;

each R ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, -CONH ₂ 、-NO ₂ 、C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C) _3-6 Cycloalkyl), -C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

or any two R ^4a Two R ^4b Two R ⁵ Together with the atom to which they are attached form C _4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -C _1-6 Haloalkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

R ^7a 、R ^7b 、R ^8a 、R ^8b 、R ^9a 、R ^9b each independently selected fromHydrogen, halogen, -C _1-6 Alkyl, -OC _1-6 Alkyl, -C _1-6 Haloalkyl or-C _1-6 A hydroxyalkyl group;

or R ^7a And R ⁵ 、R ^8a And R ⁵ 、R ^7a And R ^7b Together with the atom to which they are attached form C _5-10 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -C _1-3 Haloalkyl, -C _1-6 Hydroxyalkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NO ₂ 、-NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C (O) (4-6 membered heterocycloalkyl), -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-CONHC _3-6 Cycloalkyl, -CONH (4-6 membered heterocycloalkyl), -NHCOC _1-6 Alkyl, -NHCOOC _1-6 Alkyl, -NHCOC _3-6 Cycloalkyl, -NHCOO (4-6 membered heterocycloalkyl), -N = S (O) (CH) ₃ ) ₂ 、-P(O)(CH ₃ ) ₂ 、C _6-10 Aryl, 5-to 10-membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; said substitutionSaid alkyl, cycloalkyl or heterocycloalkyl in (A) are each optionally substituted by one or more groups selected from halogen, hydroxy, -CN, -NH ₂ Oxo, -C _1-3 Haloalkyl or-OC _1-6 Alkyl substituent substitution;

or any two of R ⁶ 、R ⁶ And R ^8a Together with the atom to which they are attached form C _5-10 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable form thereof selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.

In an embodiment of the invention, the invention provides the use of a compound of formula I or a pharmaceutically acceptable form thereof selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopic label, metabolite or prodrug, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the prevention and/or treatment of a disease or condition for which a GLP-1R agonist is indicated.

In an embodiment of the present invention, the present invention provides a method for the prevention and/or treatment of a disease or condition for which a GLP-1R agonist is indicated, said method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable form thereof selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopic label, metabolite or prodrug, or a pharmaceutical composition of the invention.

In embodiments of the invention, the disease or condition for which a GLP-1R agonist is useful is a disease or condition that is medically sensitive or responsive to GLP-1R activation, potentiation or agonism, for example: type II diabetes.

General terms and definitions

Unless otherwise defined, terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The technical intent used herein is to refer to techniques commonly understood in the art, including variations or equivalents of techniques that would be apparent to those of ordinary skill in the art. Although the following terms are readily understood by those skilled in the art, they are set forth below in order to better explain the present invention.

The terms "comprising," "including," "having," or "involving," and other variations thereof herein, refer to an inclusive or open-ended collection of concepts and do not exclude additional unrecited elements or method steps. It will be understood by those skilled in the art that terms such as "including" and "comprising" are intended to have the meaning of "… composition".

The term "one or more" or similar expressions "at least one" mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more(s).

When the lower and upper limits of a range of values are disclosed, any value or any sub-range falling within the range is intended to be specifically disclosed. In particular, each numerical range of the parameters disclosed herein (e.g., in the form of "about a to b," or equivalently, "about a to b," or equivalently "about a-b") is to be understood to encompass each number and subrange therein. For example, "C _1-6 "is to be understood to coverAnd each point value, e.g. C _2-5 、C _3-4 、C _1-2 、C _1-3 、C _1-4 、C _1-5 Etc. and C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ And so on. Also for example, "3-10 membered" is understood to encompass any subrange therein as well as each point value, e.g., 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7, 4-8, 5-7, 5-8, 6-7, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10, etc.

The term "alkyl", when used herein alone or in combination with other groups, refers to a straight or branched chain saturated aliphatic hydrocarbon group. For example, the term "C" as used in the present invention _1-6 Alkyl "refers to a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). E.g. "C _1-6 Alkyl "may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, and the like.

The term "alkylene" as used herein, alone or in combination with other groups, refers to a saturated, straight or branched chain, divalent hydrocarbon radical. For example, the term "C" as used herein _1-6 The alkylene group "means a saturated straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms, such as methylene, ethylene, propylene or butylene, and the like.

The term "hydroxyalkyl", when used herein alone or in combination with other groups, refers to an alkyl group substituted with one or more (such as 1 to 3) hydroxy groups. For example, the term "C" as used in the present invention _1-6 Hydroxyalkyl "refers to hydroxyalkyl groups having 1 to 6 carbon atoms, e.g.

And the like.

The term "cycloalkyl", when used herein alone or in combination with other groups, refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group; for example monocyclic rings, e.g. cyclopropyl,Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic rings, including spiro, fused or bridged rings (such as bicyclo [ 1.1.1)]Pentyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl, bicyclo [5.2.0]Nonyl or decalinyl, etc.). For example, the term "C _3-12 Cycloalkyl "refers to cycloalkyl groups having 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) ring carbon atoms.

The term "heterocycloalkyl", as used herein alone or in combination with other groups, refers to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic) non-aromatic group having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) in the ring and one or more heteroatoms (e.g., 1, 2, 3, or 4) each independently selected from N, O, P, and S. The term also covers the case where the C atom, N atom and/or P atom in the ring may be substituted by oxo (= O) and/or the S atom in the ring may be substituted by 1 or 2 oxo (= O). The ring systems in heterocycloalkyl groups may be fused, bridged or spiro ring systems. The heterocycloalkyl group may be attached to other groups (or moieties) through any one of the carbon or heteroatom atoms in the ring if the valence requirement is met. For example, 3-12 membered, 3-8 membered, 3-6 membered heterocycloalkyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The term "aryl" as used herein, alone or in combination with other groups, refers to an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) aromatic group having a conjugated pi-electron system. As used herein, the term "C _6-10 Aryl "means an aromatic group having 6 to 10 carbon atoms, such as phenyl or naphthyl, and the like.

The term "heteroaryl" as used herein, alone or in combination with other groups, refers to a monocyclic or fused ring aromatic group having a conjugated pi-electron system, which has one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) in the ring and one or more (e.g., 1, 2, 3, or 4) heteroatoms each independently selected from N, O, P, and S. Heteroaryl groups can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group may contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 9, 10 ring atoms. The heterocycloalkyl group, if required for a valence, may be attached to the parent molecular moiety through any one of the ring atoms. Examples of heteroaryl groups are, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridine, pyrimidine, pyrazine, pyridazine and the like. The term also encompasses the case where a heteroaryl group may optionally be further fused to an aryl or heteroaryl ring to form a fused ring system.

The term "fused ring system (fused ring)" refers to a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbocyclic or heterocyclic rings that share ring edges, the carbocyclic rings including cycloalkyl and aryl groups, and the heterocyclic rings including heteroaryl and heterocycloalkyl groups. The condensed ring system is, for example, a condensed ring system formed from a cycloalkyl group and a cycloalkyl group, a condensed ring system formed from a cycloalkyl group and a heterocycloalkyl group, a condensed ring system formed from a cycloalkyl group and an aryl group, a condensed ring system formed from a cycloalkyl group and a heteroaryl group, a condensed ring system formed from a heterocycloalkyl group and an aryl group, a condensed ring system formed from a heteroaryl group and a heteroaryl group, a condensed ring system formed from a heteroaryl group and an aryl group, or the like.

The term "alkenyl", when used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C" as used herein _2-6 Alkenyl "refers to alkenyl groups having 2 to 6 carbon atoms and one, two, or three (preferably one) carbon-carbon double bonds (e.g., ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like), which are optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

Herein either alone or in combinationThe term "alkenylene", when used in combination with other groups, refers to a straight or branched chain divalent aliphatic hydrocarbon radical having one or more carbon-carbon double bonds, where the two groups (or segments) to which it is attached may be attached to either the same carbon atom or to different carbon atoms. For example, the term "C" as used herein _2-4 Alkenylene "refers to alkenylene having 2-4 carbon atoms (e.g.

Etc.) which are optionally substituted with one or more (e.g., 1-3) substituents described herein.

The term "alkynyl", as used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein _2-6 Alkynyl "refers to alkynyl groups having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds (e.g., ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), optionally substituted with one or more (e.g., 1 to 3) of the substituents described herein.

The term "alkynylene", as used herein alone or in combination with other groups, refers to a straight or branched chain divalent aliphatic hydrocarbon radical having one or more carbon-carbon triple bonds, with the two radicals (or segments) to which it is attached each being attached to a different carbon atom. For example, the term "C" as used herein _2-4 Alkynyl "refers to alkynyl radicals having 2-4 carbon atoms (e.g.

Etc.) optionally substituted with one or more (e.g., 1-3) substituents described herein.

The term "haloalkyl", as used herein, alone or in combination with other groups, refers to an alkyl group as described aboveWherein one or more hydrogen atoms are replaced by halogen. For example, the term "C _1-6 Haloalkyl "refers to C optionally substituted with one or more (e.g., 1-3) halogens _1-6 An alkyl group. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl are, for example, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CCl ₃ 、-C ₂ F ₅ 、-C ₂ Cl ₅ 、-CH ₂ CF ₃ 、-CH ₂ Cl or-CH ₂ CH ₂ CF ₃ And the like.

The term "halo" or "halogen" group, when used herein alone or in combination with other groups, denotes F, cl, br or I.

The term "hydroxy" when used herein alone or in combination with other groups means-OH.

The term "cyano," when used herein alone or in combination with other groups, refers to — CN.

The term "nitro" as used herein, alone or in combination with other groups, refers to-NO ₂ 。

The term "amino" as used herein, alone or in combination with other groups, refers to-NH ₂ 。

The term "oxo" when used herein alone or in combination with other groups means = O.

The term "independently" or "independently" as used herein means that at least two groups (or fragments) present in a structure in the same or similar range of values can have the same or different meanings in a particular instance. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, -CN, alkyl or aryl, and when substituent X is hydrogen, substituent Y may be either hydrogen or halogen, hydroxy, -CN, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be either hydrogen or halogen, hydroxy, -CN, alkyl or aryl.

The term "substituted" and other variations thereof herein mean that one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on the designated atom is replaced with other equivalents, provided that the designated atom or group of atoms does not exceed the normal valence under the current circumstances and that a stable compound can be formed. If an atom or group of atoms is described as "optionally substituted with \8230;" substituted ", it may be substituted or unsubstituted. Unless otherwise indicated, the attachment site of a substituent herein may be from any suitable position of the substituent. When a bond in a substituent is shown as crossing a chemical bond between two atoms attached to each other in a ring system, it means that the substituent may be attached to any one of the ring system atoms.

Whenever the term "alkyl" or "aryl" or any of its prefix roots appears in the name of a substituent, by itself or as part of another substituent, unless otherwise stated, it should be construed as including the limitations given above for "alkyl" and "aryl". Number of carbon atoms specified (e.g. C) _l-6 ) Shall independently refer to the number of carbon atoms in the alkyl moiety or the number of carbon atoms in the alkyl moiety of the larger substituent in which the alkyl group is the prefix.

The term "chemical bond" refers to the strong force that binds two or more adjacent atoms (or ions) within a pure molecule or crystal to each other, and includes mainly covalent bonds, ionic bonds, metallic bonds, coordination bonds, and the like. Unless otherwise indicated, the chemical bonds in the compounds of the invention in free form are mostly covalent bonds.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic acid/organic acid/acidic amino acid or inorganic base/organic base/basic amino acid, such salts also being referred to as acid addition salts or base addition salts. For a review of suitable Salts see, for example, jusiak, soczewinski, et al, remington's Pharmaceutical Sciences [ M ], mack Publishing Company,2005 and Stahl, wermuth, handbook of Pharmaceutical Salts: properties, selection, and Use [ M ], wiley-VCH,2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and that hydrolyzes in vivo to a compound of the invention or a salt thereof. In addition, the compounds of the present invention may themselves be esters.

The term "isomers" refers to compounds having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms, due to the same number and type of atoms.

The term "stereoisomer" (or "optical isomer") refers to a stable isomer having a perpendicular plane of asymmetry due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) that enables rotation of plane polarized light. Since the compounds of the present invention contain asymmetric centers as well as other chemical structures that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds may be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity ≥ 99%, ≥ 98%, ≥ 97%, ≥ 96%, ≥ 95%, ≥ 90%, > 85%, ≥ 80%, ≥ 75%, > 70%, > 65% or ≥ 60%). As described hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. The starting compounds of a particular stereochemistry are either commercially available or may be prepared according to the methods described hereinafter and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

Solid line (-), solid wedge shape are used herein

Or a virtual wedge>

To depict the covalent chemical bonds of the compounds of the present invention. When a solid line is used to depict a bond to a chiral atom, all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) at that chiral atom are meant to be included. When a solid or dotted wedge is used to depict the bond to the chiral atom, it indicates that the stereoisomer shown is present. Unless otherwise indicated, stereoisomers of the compounds of the invention may encompass specific enantiomers, diastereomers, racemates or mixtures thereof in any proportion.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, nitroso-oxime isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of multiple polymorphs mixed in any ratio.

The term "solvate" refers to a substance formed by the binding of a compound of the present invention (or a pharmaceutically acceptable salt thereof) to at least one solvent molecule by non-covalent intermolecular forces. The compounds of the invention may exist in the form of solvates, which contain polar solvents as lattice structural elements. The amount of polar solvent may be present in stoichiometric or non-stoichiometric proportions.

The term "isotopic label" refers to a derivatized compound formed by replacing a particular atom in a compound of the invention with its isotopic atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, cl, such as ² H(D)、 ³ H(T)、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ³⁷ Cl and ¹²⁵ I. for example, ¹² c can be covered ¹³ C or ¹⁴ C, replacing; ¹ h can be covered ² H (D, deuterium) or ³ H (T, tritium) substitution; ¹⁶ o can be ¹⁸ O substitution, and the like.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, since the available lone pair of electrons is required for oxidation to the oxide. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: t.l.gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750 (a.r.katritzky and a.j.boulton, eds., academic Press); and g.w.h.cheeseman and e.s.g.werstink, advances in Heterocyclic Chemistry, vol.22, pp 390-392 (a.r.kattritzky and a.j.boulton, eds., academic Press).

The term "metabolite" refers to a derivative compound formed by the metabolism of a compound of the present invention, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like. For further information on metabolism see Goodman and Gilman's The Pharmacological Basis of Therapeutics [ M ], mcGraw-Hill International Editions,1996. The present invention encompasses all possible metabolite forms of the compounds of the invention, i.e. substances formed in the body of the individual to whom the compounds of the invention are administered. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by assays.

The term "prodrug" refers to a derivative compound that, upon administration to a subject, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are those that increase the bioavailability of the compounds of the invention when administered to a subject (e.g., more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, see, e.g., T.Higuchi, V.Stella, pro-drugs as Novel Drug Delivery Systems [ J ], american Chemical Society, vol.14,1975. Furthermore, the present invention also encompasses compounds of the present invention containing protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, such as those described in t.w.greene, p.g.m.wuts, protective Groups in Organic Synthesis [ M ], john Wiley & Sons, 2006. These protecting groups may be removed at a suitable subsequent stage using methods known in the art.

The invention also encompasses methods of making the compounds described herein. It is to be understood that the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as would be understood by one of skill in the art. Preferred methods include, but are not limited to, those described below. The reaction may be carried out in a solvent or solvent mixture suitable for the reagents and materials used and for effecting the conversion.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.

The term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") as used herein refers to an amount of active ingredient that will achieve the desired effect to some extent upon administration, e.g., to alleviate one or more symptoms of the treated condition or to prevent the occurrence of the condition or symptoms thereof.

As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, ameliorating the progression of a disorder or condition to which such term applies or one or more symptoms of such disorder or condition.

The term "prevention" refers to inhibiting and delaying the onset of a disease, and includes not only prevention prior to the development of the disease, but also prevention of recurrence of the disease after treatment.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) with a disease (e.g., a disease described herein) or normal individuals. "non-human animal" in the context of the present invention includes all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, domestic and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.)

Detailed Description

Compounds of the invention

wherein

d ring is selected from C _6-10 Aryl or 5-10 membered heteroaryl;

ring E is selected from C _6-14 Aryl or 5-14 membered heteroaryl;

v is selected from-O-, -S-, -C (O) -, -CR ^7a R ^7b -or-NR ^7a -；

U is selected from-O-, -C (O) -, -CR ^8a R ^8b -or-NR ^8a -；

W is selected from the group consisting of a bond, -O-, -NR ^9a -、S、-C(O)-、-CR ^9a R ^9b -or-C (O) NR ^9a -；

m, n, p, q are each independently selected from 0, 1, 2, 3, 4 or 5;

R ¹ selected from hydrogen, halogen, -CN, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C _6-10 Aryl or 5-10 membered heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groupEach optionally substituted by one or more R ^x Substitution;

R ^x selected from hydrogen, halogen, -CN, -NH ₂ 、-NO ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-12 Cycloalkyl, -O (4-12 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, -COC _1-6 Alkyl, -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-NHC(O)C _1-6 Alkyl radical, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Haloalkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl or-N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl) groups;

each R ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Alkyl, -C _1-6 Haloalkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C) _3-6 Cycloalkyl), -C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

R ^4a 、R ^4b each independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl) or-NO ₂ Said alkyl, cycloalkyl or heterocycloalkyl being each optionally substituted by one or more groups chosen from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Haloalkyl or-OC _1-6 Alkyl substituent substitution;

each R ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, -CONH ₂ 、-NO ₂ 、C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

R ^7a 、R ^7b 、R ^8a 、R ^8b 、R ^9a 、R ^9b each independently selected from hydrogen, halogen, -C _1-6 Alkyl, -OC _1-6 Alkyl, -C _1-6 Haloalkyl or-C _1-6 A hydroxyalkyl group;

each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NO ₂ 、-NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C) _3-6 Cycloalkyl), -C (O) (4-6 membered heterocycloalkyl), -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-CONHC _3-6 Cycloalkyl, -CONH (4-6 membered heterocycloalkyl), -NHCOC _1-6 Alkyl, -NHCOOC _1-6 Alkyl, -NHCOC _3-6 Cycloalkyl, -NHCOO (4-6 membered heterocycloalkyl), -N = S (O) (CH) ₃ ) ₂ 、-P(O)(CH ₃ ) ₂ 、C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; said alkyl, cycloalkyl or heterocycloalkyl of said substituents being each optionally substituted by one or more substituents selected from halogen, hydroxy, -CN, -NH ₂ Oxo, -C _1-3 Haloalkyl or-OC _1-6 Alkyl substituent;

or any two R ⁶ 、R ⁶ And R ^8a Together with the atom to which they are attached form C _5-10 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

In some embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable form thereof:

wherein

X ¹ 、X ⁴ 、X ⁵ Each independently selected from N or CR ³ ；

Ring B is selected from 4-6 membered heterocycloalkyl or C _4-6 A cycloalkyl group;

the D ring is selected from 6-membered aryl or 6-membered heteroaryl, in which 6-membered aryl Y is ¹ 、Y ² 、Y ³ 、Y ⁴ 、Y ⁵ Each independently is CR ⁵ In the 6-membered heteroaryl group, Y ¹ 、Y ² 、Y ³ 、Y ⁴ 、Y ⁵ Each independently selected from N or CR ⁵ No more than 3N atoms and no 3 consecutive N atoms are present in the D ring;

ring E is selected from phenyl or 5-10 membered heteroaryl;

u is-CR ^8a R ^8b -；

V is selected from-O-, -S-, -CR ^7a R ^7b -or-NR ^7a -；

W is selected from the group consisting of a bond and-CR ^9a R ^9b -；

m, p, q are each independently selected from 0, 1, 2, 3, 4 or 5;

each R ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Haloalkyl, -C _1-6 Alkyl, -OC _1-6 Alkyl, -C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

R ^4a 、R ^4b each independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ Oxo or-C _1-6 Alkyl, each of which is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Haloalkyl or-OC _1-6 Alkyl substituent substitution;

or any two R ^4a Two R ^4b Together with the atom to which they are attached form C _4-10 Cycloalkyl or 4-10 membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl or-C _1-6 Substituted with a substituent of haloalkyl;

each R ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, phenyl, 5-6 membered heteroaryl, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

R ^7a 、R ^7b 、R ^8a 、R ^8b 、R ^9a 、R ^9b each independently selected from hydrogen, halogen, -C _1-3 Alkyl, -OC _1-3 Alkyl, -C _1-3 Haloalkyl or-C _1-3 A hydroxyalkyl group;

or R ^7a And R ⁵ 、R ^8a And R ⁵ Together with the atom to which they are attached form C _5-6 Cycloalkyl or 5-6 membered heterocycloalkyl; said cycloalkyl or heterocycloalkyl being each optionally substituted by one or more groups chosen from halogen, -CN, oxo, hydroxy, -C _1-3 Alkyl, -C _1-3 Haloalkyl, -OC _1-3 Alkyl or-C _1-3 Substituted with a substituent of hydroxyalkyl;

R ¹ 、R ⁶ as defined by formula I;

In some embodiments, the invention provides a compound of formula II-1, II-2, II-3, or a pharmaceutically acceptable form thereof:

wherein

Each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-CONHC _3-6 Cycloalkyl, -CONH (4-6 membered heterocycloalkyl), -N = S (O) (CH) ₃ ) ₂ 、-P(O)(CH ₃ ) ₂ 、C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

Y ¹ 、Y ² 、Y ³ 、Y ⁴ 、Y ⁵ 、X ¹ 、X ⁴ 、X ⁵ ring B, ring C, ring D, ring E, ring R ¹ 、R ^4a 、R ^4b 、R ^8b M, p, q are as defined for formula II;

In some embodiments, the present invention provides compounds of formulae II-A, II-B, II-C, or pharmaceutically acceptable forms thereof:

wherein

Each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C) _3-6 Cycloalkyl), -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-CONHC _3-6 Cycloalkyl, -CONH (4-6 membered heterocycloalkyl), -N = S (O) (CH) ₃ ) ₂ 、-P(O)(CH ₃ ) ₂ 、C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl radical、-N(C _1-6 Alkyl radical) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

w is selected from the group consisting of a bond and-CR ^9a R ^9b -；

Ring B is a 4-6 membered heterocycloalkyl;

Y ¹ 、Y ² 、Y ³ 、Y ⁴ 、Y ⁵ 、X ¹ 、X ⁴ 、X ⁵ c ring, D ring, E ring, R ¹ 、R ^4a 、R ^4b 、R ^8b 、R ^9a 、R ^9b M, p, q are as defined for formula II;

In some embodiments of the present invention, the present invention provides compounds of formula II, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C,

selected from:

preferably selected from +>

Wherein R is ³ As defined in formula II, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B or formula II-C; preferably selected from->

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein R is ¹ Selected from hydrogen, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-10 membered heterocycloalkyl, benzeneOr 5-6 membered heteroaryl; each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one or more R ^x Substitution; r ^x Selected from hydrogen, halogen, -CN, -NH ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-8 Cycloalkyl, -O (4-10 membered heterocycloalkyl), -COC _1-6 Alkyl, -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-NHC(O)C _1-6 Alkyl, phenyl, 5-6 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Haloalkyl or-OC _1-6 Alkyl substituents.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein R is ¹ Selected from hydrogen, -C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5 membered heteroaryl; each of said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally substituted with one or more R ^x Substitution; r ^x Selected from hydrogen, halogen, -CN, -NH ₂ Oxo, -C _1-4 Alkyl, -OC _1-4 Alkyl, -COC _1-4 Alkyl, -CONH ₂ or-NHC (O) C _1-4 Alkyl, each of which is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-4 Haloalkyl or-OC _1-4 Alkyl substituents.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein R is ¹ Selected from:

preferably, R ¹ Is selected from

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein each R is ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl or C _3-8 Cycloalkyl, each of said alkyl, alkenyl, alkynyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Haloalkyl, -C _1-6 Alkyl or-OC _1-6 Alkyl substituents.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein each R is ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-4 Alkyl, -OC _1-4 Alkyl, -OC _3-6 Cycloalkyl, -C _2-4 Alkenyl or-C _2-4 Alkynyl, said alkyl, alkenyl, alkynyl or cycloalkyl each optionally substituted with one or more groups selected from halo, hydroxy, oxo, -NH ₂ 、-CN、-C _1-4 Alkyl or-OC _1-4 Alkyl substituents.

In some embodiments of the present invention, the present invention provides compounds of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein each R is ³ Independently selected from hydrogen, F, hydroxy, -CN, methyl, ethyl, -OCH ₃ -O-cyclopropyl, ethenyl or ethynyl; each of said cyclopropyl, ethenyl or ethynyl groups being optionally substituted with one or more methyl or ethyl groups; preferably, each R ³ Independently selected from hydrogen, F, methyl or-CN; preferably, each R ³ Independently selected from hydrogen.

In some embodiments of the invention, the invention provides a compound of formula I, formula II-1, formula II-2, or formula II-3In the compound, the B ring is selected from 4-6-membered nitrogen-containing heterocycloalkyl or C _4-6 A cycloalkyl group; preferably, the B ring is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, or formula II-3 wherein the C ring is selected from 4-6 membered nitrogen containing heterocycloalkyl or C _4-6 A cycloalkyl group; preferably, the C ring is selected from 4-membered nitrogen-containing heterocycloalkyl or C _4-6 A cycloalkyl group; preferably, the C ring is selected from cyclobutyl or azetidinyl.

In some embodiments of the present invention, the present invention provides compounds of formula I, formula II-1, formula II-2, or formula II-3,

selected from:

wherein R is ^4a 、R ^4b P and q are as defined in formula I, formula II-1, formula II-2 or formula II-3.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein R is ^4a 、R ^4b Each independently selected from hydrogen, halogen, hydroxy, -CN, oxo or-C _1-3 Alkyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, oxo, or-CN; preferably, R ^4a 、R ^4b Each independently selected from hydrogen or oxo; preferably, R ^4a 、R ^4b Each independently hydrogen.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein the D ring is selected from phenyl, pyridinyl, or pyrimidinyl.

In some embodiments of the present invention, the present invention provides compounds of formula I, formula II wherein the substituted D ring is selected from:

wherein R is ⁵ As defined in formula I or formula II.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, or formula II-a wherein the substituted D ring is selected from:

wherein R is ⁵ As defined in formula I, formula II-1 or formula II-A.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-2, or formula II-B wherein the substituted D ring is selected from:

wherein R is ⁵ As defined in formula I, formula II-2 or formula II-B.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-3, or formula II-C wherein the substituted D ring is

Wherein R is ⁵ As defined in formula I, formula II-3 or formula II-C.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein each R is ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -CONH ₂ 、-NO ₂ Or C _3-8 Cycloalkyl, each of said alkyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl or-C _3-6 Cycloalkyl substituents.

In some embodiments of the present invention, the present invention provides compounds of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein each R is ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-4 Alkyl, -OC _1-4 Alkyl or C _3-6 Cycloalkyl, each of said alkyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ or-C _1-4 Alkyl substituents.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein each R is ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ Methyl, ethyl, cyclopropyl, -OCH ₃ 、-CF ₃ Or CHF ₂ (ii) a Preferably, each R ⁵ Independently hydrogen.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein ring E is selected from phenyl or pyridyl.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C,

selected from: />

Wherein R is ⁶ And m is as defined for formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B or formula II-C.

In some embodiments of the invention, the invention provides compounds of formula I, formula II-1, formula II-2, formula II-3, formulaIn the compounds of formula II-A, formula II-B or formula II-C, each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -CONH ₂ 、-N＝S(O)(CH ₃ ) ₂ 、-P(O)(CH ₃ ) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; each of said alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ Methyl, -OCH ₃ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

In some embodiments of the present invention, there is provided a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-A, formula II-B, or formula II-C wherein each R is ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-4 Alkyl, -OC _1-4 Alkyl, -CONH ₂ Or C _3-6 A cycloalkyl group; each of said alkyl or cycloalkyl groups being optionally substituted by one or more groups selected from halogen, -CN, oxo, hydroxy, -NH ₂ Methyl, -OCH ₃ Or C _3-6 Cycloalkyl substituents; preferably, each R ⁶ Independently selected from hydrogen, fluorine, chlorine, hydroxyl, -CN, -NH ₂ Methyl, -CHF ₂ 、-CF ₃ 、-OCH ₃ 、-CONH ₂ Or cyclopropyl; preferably, each R ⁶ Independently selected from hydrogen, fluorine, chlorine or-CN.

In some embodiments of the present invention, the compounds of formula II provided herein,

is selected from->

Ring B is selected from 4-6 membered nitrogen containing heterocycloalkyl or C _4-6 A cycloalkyl group;

the C ring is selected from 4-6 membered nitrogen-containing heterocycloalkyl or C _4-6 Cycloalkyl radicals；

Ring D is selected from phenyl, pyridyl or pyrimidinyl;

ring E is selected from phenyl or pyridyl;

u is-CH ₂ -；

V is selected from-O-, -S-, -CH ₂ -or-NH-;

w is selected from a chemical bond or-CH ₂ -；

m, p, q are each independently selected from 0, 1, 2, 3, 4 or 5;

R ¹ selected from hydrogen, -C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5 membered heteroaryl; each of said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally substituted with one or more R ^x Substitution; r ^x Selected from hydrogen, halogen, -CN, -NH ₂ Oxo, -C _1-4 Alkyl, -OC _1-4 Alkyl, -COC _1-4 Alkyl, -CONH ₂ or-NHC (O) C _1-4 Alkyl, each of which is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-4 Haloalkyl or-OC _1-4 Alkyl substituent substitution;

R ^4a 、R ^4b each independently selected from hydrogen or oxo;

each R ⁶ Independently selected from hydrogen, fluorine, chlorine, hydroxyl, -CN, -NH ₂ Methyl, -CHF ₂ 、-CF ₃ 、-OCH ₃ 、-CONH ₂ Or a cyclopropyl group.

In some embodiments of the present invention, the present invention provides compounds of formula II,

is->

Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl;

the C ring is selected from cyclobutyl or azetidinyl;

ring D is selected from phenyl, pyridyl or pyrimidinyl;

ring E is selected from phenyl or pyridyl;

u is-CH ₂ -；

V is selected from-O-;

w is selected from-CH ₂ -；

m, p, q are each independently selected from 0, 1, 2, 3, 4 or 5;

R ¹ is selected from

R ^4a 、R ^4b Each independently is hydrogen;

each R ⁶ Independently selected from hydrogen, fluorine, chlorine or-CN.

It will be understood by those skilled in the art that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from a combination of technical features or preferred technical features in one embodiment with technical features or preferred technical features in another embodiment are also included in the scope of the present invention.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable form thereof, selected from:

/>

The preparation method of the invention

The compounds of the present invention may be prepared by any method known in the art. Reagents and starting materials are readily available to those of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (See, e.g., see, e.g., selectric for example, et al, "enertiomers, racemates, and solutions," John ey and Sons, inc.,1981, and e.l. eil and s.h. wilen).

The present invention provides a method for preparing a compound represented by formula II-A, formula II-B or formula II-C, comprising:

step 1: using S1 as initial material, substituting, reducing, condensing, cyclizing, and deprotecting to obtain fragment S1.5

Step 1-1: carrying out substitution reaction on raw materials S1 and A1 in a polar solvent in the presence of inorganic base to obtain a fragment S1.1;

step 1-2: the fragment S1.1 is subjected to reduction reaction in a polar solvent with the participation of a reducing agent to obtain a fragment S1.2;

step 1-3: carrying out condensation reaction on the segment S1.2 and the segment B1 in a polar solvent under the participation of a condensation reagent and organic alkali to obtain a segment S1.3;

step 1-4: dehydrating and closing the segment S1.3 in an organic solvent under the catalysis of acid to obtain a segment S1.4;

step 1-5: and removing the protecting group of the segment S1.4 under the participation of acid or alkali to obtain a segment S1.5.

In some embodiments of the present invention, the polar solvent in step 1-1 above is selected from dioxane or THF, and the inorganic base is selected from potassium carbonate or potassium tert-butoxide.

In some embodiments of the present invention, the polar solvent in step 1-2 is selected from methanol or THF, and the reducing agent is selected from Pd/C (in the presence of hydrogen), zinc powder/ammonium chloride, iron powder/acetic acid, sodium hydrosulfite.

In some embodiments of the present invention, the polar solvent in steps 1-3 above is selected from dichloroethane, THF, DMF, or mixtures thereof, the condensation reagent is selected from HATU, HBTU, EDCI, and the organic base is selected from Et ₃ N or DIPEA.

In some embodiments of the present invention, the organic solvent in steps 1-4 above is selected from acetic acid, toluene or dioxane, and the acid is selected from acetic acid or p-toluenesulfonic acid.

In some embodiments of the present invention, the acid in steps 1-5 above is selected from hydrochloric acid or TFA and the base is selected from piperidine or ethylenediamine.

Step 2: preparation of fragment M1.1, fragment M1.2 and fragment M1.3

Step 2-1: carrying out substitution reaction on starting materials M1 and N1 in a polar solvent in the presence of inorganic base to obtain a fragment M1.1;

step 2-2: carrying out substitution reaction on starting materials M1 and N2 in a polar solvent in the presence of inorganic base to obtain a fragment M1.2;

step 2-3: reacting an initial raw material N3 with M2, M3, M4 and M5 respectively to obtain a fragment M1.3;

step 2-3-1: preparing a fragment M1.3 by refluxing the starting materials diphenol (N3) and ketone or aldehyde (M2) with a catalytic amount of a mild acid catalyst in an aprotic solvent and separating water in a water separator;

step 2-3-2: an acetal or ketal (M3) of acyclic (no dashed line present) or cyclic (dashed line present) structure can be reacted with a diphenol (N3) in the presence of an acid or a base to prepare a fragment M1.3;

step 2-3-3: thioacetal or thioketal (M4) of acyclic (no dashed line present) or cyclic (dashed line present) structure can be reacted with diphenol (N3) in the presence of a mercury salt, a mild oxidizing agent to prepare the fragment M1.3;

step 2-3-4: alkyne (M5) can be reacted with diphenol (N3) with heating in the presence of triruthenium dodecacarbonyl in an aprotic solvent under inert gas protection to prepare the segment M1.3.

In some embodiments of the present invention, the polar solvent in step 2-1 above is selected from dioxane or DMF, and the inorganic base is selected from potassium carbonate or potassium tert-butoxide.

In some embodiments of the present invention, the polar solvent in step 2-2 above is selected from dioxane or DMF, and the inorganic base is selected from potassium carbonate or potassium tert-butoxide.

In some embodiments of the present invention, the acid catalyst in step 2-3-1 above is, for example, p-toluenesulfonic acid, and the aprotic solvent is selected from benzene, toluene or xylene.

In some embodiments of the present invention, the acid in step 2-3-2 above is, for example, p-toluenesulfonic acid, and the base is, for example, potassium carbonate.

In some embodiments of the invention, the mercury salt in steps 2-3-3 above is, for example, mercury acetate and the oxidizing agent is, for example, NCS.

In some embodiments of the present invention, the aprotic solvent in steps 2-3-4 above is, for example, toluene, and the inert gas is selected from argon or nitrogen.

And step 3: and carrying out substitution reaction or metal coupling reaction on the fragment S1.5 and the fragments M1.1, M1.2 and M1.3 respectively to obtain an intermediate, and then carrying out deprotection by acid or alkali to obtain the compound shown in the formula II-A, the formula II-B or the formula II-C.

In some embodiments of the present invention, the substitution reaction in step 3 above is carried out in a polar solvent (e.g., DMF, NMP, etc.) in the presence of a base (e.g., potassium carbonate), and the metal coupling reaction is carried out in a polar solvent (e.g., DMF, dioxane, etc.), a base (e.g., cesium carbonate), a ligand (e.g., BINAP), palladium or copper catalyst (e.g., palladium acetate, pd, etc.) ₂ (dba) ₃ CuI) is carried out in the presence of a catalyst.

In some embodiments of the invention, deprotection of the intermediate in step 3 above with an acid (e.g., TFA) or a base (e.g., lithium hydroxide) affords compounds of formula II-A, formula II-B, or formula II-C.

In the above preparation method:

x is halogen, preferably F, cl;

r is a carboxyl protecting group, preferably C _1-6 Alkyl, benzyl;

Pg ₁ a protecting group which is an amino group (e.g., methyl, t-butoxycarbonyl, t-butyldimethylsilyl, triisopropylsilyl, benzyl, methoxymethyl, etc.);

R ^8b’ selected from hydrogen, halogen, -C _1-5 Alkyl, -OC _1-5 Alkyl, -C _1-5 Haloalkyl or-C _1-5 A hydroxyalkyl group;

R ^8b ＝CH ₂ R ^8b '；

the remaining groups are defined by the general formula II-A, formula II-B or formula II-C;

it will be appreciated by those skilled in the art that one or more steps in the above-described preparation method may be omitted, the order of the reaction steps may be appropriately adjusted, and the protection/deprotection reaction step may be added or omitted as necessary, depending on the structure of the product desired to be obtained.

Pharmaceutical compositions, formulations and kits

The present invention also provides a pharmaceutical composition comprising a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-a, formula II-B, or formula II-C, or a pharmaceutically acceptable form thereof selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.

It is a further object of the present invention to provide a process for preparing a pharmaceutical composition of the present invention, said process comprising combining a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-a, formula II-B or formula II-C, or a pharmaceutically acceptable form thereof, or a mixture thereof, selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs, with one or more pharmaceutically acceptable carriers.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Pharmaceutically acceptable carriers include pharmaceutical excipients. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

The pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms in a human or animal patient. For example, various suitable dosage forms can be prepared according to the administration route.

When administered orally, the pharmaceutical composition may be formulated in any orally acceptable dosage form.

When administered transdermally or topically, the pharmaceutical compositions may be formulated into suitable ointment, lotion, or liniment forms, in which the active ingredient may be suspended or dissolved in one or more carriers.

The pharmaceutical composition can also be used in the form of injection, including injection, sterile powder for injection and concentrated solution for injection.

Yet another aspect of the present invention relates to a pharmaceutical formulation comprising a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-a, formula II-B or formula II-C, a pharmaceutically acceptable form thereof selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs, or a mixture thereof, as an active ingredient, or a pharmaceutical composition of the present invention. In some embodiments, the formulation is in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

It is a further object of the invention to provide an article of manufacture, for example in the form of a kit. Articles of manufacture as used herein are intended to include, but are not limited to, kits and packages. The article of the present invention comprises: (a) a first container; (b) A pharmaceutical composition in a first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-a, formula II-B, or formula II-C, or a pharmaceutically acceptable form thereof selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopic label, metabolite, or prodrug, or a mixture thereof; and (c) optionally, packaging instructions that indicate that the pharmaceutical composition can be used to treat a disease or condition that is sensitive or responsive to GLP-1R activation, potentiation or agonism, such as: type II diabetes.

The package insert is a trademark, label, logo, etc. that lists information related to the pharmaceutical composition located in the first container. The listed information is typically determined by a regulatory agency (e.g., the U.S. food and drug administration) that governs the area in which the article is to be sold. Preferably the package insert specifically lists the indications for which the pharmaceutical composition is approved for use. The package insert may be made of any material from which information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (e.g., printed or applied).

Methods of treatment and uses

It is another object of the present invention to provide a method of preventing or treating a disease or condition for which a GLP-1R agonist is indicated, said method comprising administering to a subject in need thereof an effective amount of a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-a, formula II-B or formula II-C, or a pharmaceutically acceptable form thereof selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs, or a mixture thereof, or a pharmaceutical composition of the present invention.

In an embodiment of the invention, the invention provides the use of a compound of formula I, formula II-1, formula II-2, formula II-3, formula II-a, formula II-B or formula II-C, or a pharmaceutically acceptable form thereof, selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopic label, metabolite or prodrug, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the prevention and/or treatment of a disease or condition for which a GLP-1R agonist is indicated.

According to some embodiments of the invention, the disease or condition for which a GLP-1R agonist is useful is a disease sensitive or responsive to GLP-1R activation, potentiation or agonism, for example: type II diabetes.

The dosing regimen may be adjusted to provide the best desired response. For example, when administered as an injection, a single bolus, bolus and/or continuous infusion may be administered, and the like. For example, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. Generally, the dosage of treatment will vary depending on considerations such as, for example: the age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; duration of symptoms; and other variables that can be adjusted by the individual physician. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition. The amount and regimen of administration of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical art. For example, the composition or compound of the present invention may be administered in divided doses 4 times per day to 1 time per 3 days, and the amount administered may be, for example, 0.01 to 1000 mg/time. The desired dose may be administered in one or more administrations to achieve the desired result. The pharmaceutical compositions according to the invention may also be provided in unit dosage form.

Advantageous effects

The invention provides a novel GLP-1R agonist which can realize at least one of the following technical effects:

(1) High agonistic activity against GLP-1R.

(2) Excellent physicochemical properties (e.g. solubility, physical and/or chemical stability).

(3) Excellent pharmacokinetic properties (e.g. good bioavailability, suitable half-life and duration of action).

(4) Excellent safety (lower toxicity and/or fewer side effects, wider therapeutic window), etc.

Detailed Description

Examples

The present invention will be described in more detail below by referring to examples and test examples, which are not intended to limit the scope of the present invention and may be modified without departing from the scope of the present invention.

Determination of Mass Spectra (MS) an Agilent (ESI) mass spectrometer was used, manufacturer: agilent, model: agilent 6120B.

Determination of Nuclear Magnetic (NMR) Bruker NMR spectrometer was used, manufacturer: bruker, model number: AVANCE III HD-400.

Preparative High Performance Liquid Chromatography (HPLC) Using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250X 20mm column).

The thin layer chromatography purification adopts a silica gel plate of GF 254 (0.4-0.5 nm) produced by a cigarette bench.

The reaction is monitored by Thin Layer Chromatography (TLC) or liquid chromatography mass spectrometry (LC-MS) using a developer system including, but not limited to: the volume ratio of the solvent is adjusted according to different polarities of the compounds, or triethylamine and the like are added for adjustment.

Column chromatography generally uses Qingdao ocean silica gel with 200-300 meshes as a stationary phase. The eluent system includes but is not limited to dichloromethane and methanol system and n-hexane and ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of triethylamine and the like can be added for adjustment.

Unless otherwise specified in the examples, the reaction temperature was room temperature (20 ℃ C. To 30 ℃ C.).

Unless otherwise indicated, reagents used in the examples were purchased from Acros Organics, aldrich Chemical Company, nanjing pharmacosome technology, shanghai Shuyao, or other companies.

The abbreviations used herein have the following meanings:

the specific embodiment is as follows:

intermediate preparation example 1 preparation of 4- ((6-bromopyridin-2-yl) oxy) methyl) -3-fluorobenzonitrile (compound Int 1)

Compound A-1 (1.72g, 11.36mmol) and 2-bromo-6-fluoropyridine (2.00g, 11.36mmol) are added into 1, 4-dioxane (20 mL), potassium tert-butoxide (1.53g, 13.64mmol) is added in portions, after the addition, the system is heated to 40 ℃, the reaction is 30min, and LC-MS monitors the completion of the reaction. Cooled to room temperature, extracted by addition of water and ethyl acetate, and the organic phase washed with saturated sodium chloride, dried over sodium sulfate, and concentrated to give Int1 (2.5 g, yield 72%) as a pale yellow compound.

Example 1: preparation of (S) -2- (2- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) -2-azaspiro [3.3] heptan-6-yl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (compound 1).

The first step is as follows: preparation of methyl (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoate (Compound 1-2)

Compounds 1-1 (3.00g, 15.07mmol) and K ₂ CO ₃ (3.12g, 22.60mmol) was added to THF (60 mL), and (S) -oxetane-2-methanamine (1.64g, 18.83mmol) was dissolved in THF (20 mL) and added dropwise to the reaction system, which was warmed to 30 ℃ for 16 hours, LC-MS monitors the reaction completion. Cooled to room temperature, filtered over celite, concentrated, and purified by column chromatography to give compound 1-2 (3.7 g, 92% yield).

The second step is that: preparation of methyl (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoate (Compounds 1-3):

compound 1-2 (2.20g, 8.26mmol) and 10% Pd/C (220 mg) were added to THF (25 mL) and MeOH (75 mL), vacuum was applied, hydrogen gas was replaced three times, the reaction was carried out at 25 ℃ for 3 hours, and the completion of the reaction was monitored by LC-MS. Filtration through celite, concentration, and column chromatography purification afforded the pale yellow compounds 1-3 (1.3 g, 67% yield).

The third step: preparation of methyl (S) -tert-butyl-6- ((4- (methoxycarbonyl) -2- ((oxetan-2-ylmethyl) amino) phenyl) carbamoyl) -2-azaspiro [3.3] heptane-2-carboxylate (compounds 1-4):

compound 1-3 (444mg, 1.69mmol), 2-Boc-2-azaspiro [3.3] heptane-6-carboxylic acid (340mg, 1.41mmol), DIPEA (911mg, 7.05mmol), HATU (2.14g, 5.64mmol) were added to a mixed solution of DCE (10 mL) and DMF (5 mL), the system was warmed to 50 ℃ for 16 hours and LC-MS monitored for completion of the reaction. Water and ethyl acetate were added, and extraction, drying, filtration, concentration and column chromatography purification were carried out to obtain 1 to 4 (300 mg, yield 46%) as a yellow viscous compound.

The fourth step: preparation of methyl (S) -2- (2- (tert-butoxycarbonyl) -2-azaspiro [3.3] heptan-6-yl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate (Compounds 1-5):

compound 1-4 (300mg, 652.84. Mu. Mol) was added to acetic acid (10 mL), warmed to 100 ℃ for 1 hour, and LC-MS monitored for completion. Extraction with water and ethyl acetate, concentration, and column chromatography gave pale yellow compounds 1-5 (65 mg, yield 23%).

The fifth step: preparation of (S) -methyl 1- (oxetan-2-ylmethyl) -2- (2-azaspiro [3.3] heptan-6-yl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (Compound 1-6):

compound 1-5 (65mg, 147.22. Mu. Mol) was dissolved in dichloromethane (2 mL) and TFA (1 mL) and reacted at 25 ℃ for 1 hour, LC-MS monitored the completion of the reaction, and the reaction solution was concentrated to dryness to give a trifluoroacetate salt of compound 1-6 (67 mg, yield 99%).

And a sixth step: preparation of (S) -methyl 2- (2- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) -2-azaspiro [3.3] heptan-6-yl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate (compounds 1-7):

trifluoroacetic acid salts of compounds 1-6 (44.49mg, 97.68. Mu. Mol), int1 (30mg, 97.68. Mu. Mol), cesium carbonate (127.31mg, 390.73. Mu. Mol), BINAP (24.33mg, 39.07. Mu. Mol) and Pd ₂ (dba) ₃ (17.89mg, 19.54. Mu. Mol) was added to 1, 4-dioxane (10 mL), and the mixture was purged with nitrogen, microwave-heated at 125 ℃ for 3.5 hours, and LC-MS monitored the completion of the reaction. Cooling to room temperature, filtering to remove solid, concentrating the filtrate, and performing column chromatography to obtain yellow viscous compound 1-7 (10 mg, yield 18%)

The seventh step: preparation of (S) -2- (2- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) -2-azaspiro [3.3] heptan-6-yl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (compound 1):

compound 1-7 (15mg, 26.43. Mu. Mol), lithium hydroxide monohydrate (21.65mg, 528.53. Mu. Mol) was added to ACN (4 mL) and water (1 mL), followed by warming to 55 ℃ for 2 hours, and LC-MS monitored the completion of the reaction. The pH of the system was adjusted to about 3 with aqueous citric acid, extracted with ethyl acetate, and concentrated to give a crude product, which was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid) to give compound 1 (3 mg, yield 18%).

MS(ESI):m/z 554.2[M+H] ⁺ 。 ¹ H-NMR(400MHz,DMSO-d ₆ ):δ8.18(s,1H),7.92-7.87(m,1H),7.80(dd,J＝8.4Hz,1.6Hz,1H),7.74-7.66(m,2H),7.62(d,J＝8.4Hz,1H),7.44(t,J＝8.0Hz,1H),6.10(d,J＝8.0Hz,1H),5.92(d,J＝8.0Hz,1H),5.41(s,2H),5.02-4.94(m,1H),4.55(dd,J＝15.2Hz,6.8Hz,1H),4.49-4.38(m,2H),4.34-4.27(m,1H),4.04(s,2H),3.93-3.87(m,1H),3.86(s,2H),2.72-2.62(m,5H),2.38-2.31(m,1H)。

Example 2: preparation of (S) -2- (7- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) -7-azaspiro [3.5] non-2-yl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 21).

Compound 21 was synthesized in a similar manner to that described in the third to seventh steps of example 1, except that 7-Boc-7-azaspiro [3.5] nonane-2-carboxylic acid was used in the first step in place of 2-Boc-2-azaspiro [3.3] heptane-6-carboxylic acid in the third step of example 1.

MS(ESI):m/z 582.3[M+H] ⁺ 。 ¹ H-NMR(400MHz,DMSO-d ₆ ):δ8.18(d,J＝1.2Hz,1H),7.91(dd,J＝10.0Hz,1.6Hz,1H),7.78(dd,J＝8.4Hz,1.6Hz,1H),7.71(dd,J＝8.0Hz,1.6Hz,1H),7.68-7.61(m,2H),7.45(t,J＝8.0Hz,1H),6.37(d,J＝8.0Hz,1H),6.08(d,J＝8.0Hz,1H),5.41(s,2H),5.02-4.93(m,1H),4.54(dd,J＝15.2Hz,6.8Hz,1H),4.49-4.37(m,2H),4.35-4.27(m,1H),4.02-3.90(m,1H),3.52-3.44(m,2H),3.43-3.25(m,2H),2.72-2.65(m,1H),2.39-2.16(m,5H),1.71-1.64(m,2H),1.57-1.50(m,2H)。

Example 3: preparation of (S) -2- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) -6-azaspiro [3.4] octan-2-yl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 17)

Compound 17 was synthesized in a similar manner to that described in the third step to the seventh step in example 1, except that 6-Boc-6-azaspiro [3.4] octane-2-carboxylic acid was used in the first step in place of 2-Boc-2-azaspiro [3.3] heptane-6-carboxylic acid in the third step in example 1.

MS(ESI):m/z 568.2。 ¹ H NMR(400MHz,DMSO d ₆ )δ8.20(s,1H),7.88(d,J＝10.4Hz,1H),7.79(dd,J＝8.4,1.2Hz,1H),7.73–7.62(m,3H),7.40(t,J＝8.0Hz,1H),6.01(d,J＝8.0Hz,1H),5.95(d,J＝8.0Hz,1H),5.44(s,2H),5.03–4.94(m,1H),4.58(dd,J＝15.2,7.2Hz,1H),4.51–4.39(m,2H),4.36–4.26(m,1H),3.99(p,J＝8.4,8.6Hz,1H),3.40(t,J＝6.4Hz,2H),3.36(s,2H),2.73–2.62(m,1H),2.60–2.51(m,2H),2.47–2.29(m,3H),2.16(t,J＝6.4Hz,2H).

Biological assay

Test example 1: HEK293/GLP-1R/CRE-Luc cell CRE luciferase reporter gene assay.

1. The test system comprises:

cell: HEK293/GLP-1R/CRE-Luc (Bai Kyoto Ke Bai);

detection reagent: bright-Glo ^TM Luciferase assay system (Promega).

2. Test parameters are as follows:

cell number: 3X 10 ⁴ Cells/well;

plating a culture medium: DMEM (high sugar) +10% FBS;

adding a culture medium: DMEM (high sugar) +10% FBS;

compound incubation conditions: 37 ℃ C., 5% CO ₂ ；

Incubation time: 24h;

and (3) detecting the temperature: room temperature;

BMG PHERAStar FS detects the fluorescence signal.

3. The test steps are as follows:

culturing the cells in a medium containing 10% fetal bovine serum, incubating at 37 deg.C and 5% CO ₂ Culturing is carried out under culture conditions. Cells (90. Mu.l/well, cell concentration 3.33X 10) were plated into 96-well plates ⁴ Individual cells/ml), cultured overnight in an incubator to allow the cells to adhere to the wall. The next day, 10. Mu.l/well of complete medium containing prediluted compound (10 mM compound stock concentration), 50. Mu.M maximum assay concentration, 10 concentration points diluted in 5-fold gradients, 1 well per concentration, were added and incubated at 37 ℃ for 24h. The next day, 100. Mu.l of detection reagent Bright-Glo was added to each well ^TM The mixture was placed on a microplate shaker (650 RPM) and mixed for 5min at room temperature, and then the relative fluorescence units of each well were measured at BMG PHORAStar FS.

4. Data processing:

positive control wells and DMSO control wells were set up using GLP-1 (7-36) amide (manufacturer: TOCRIS) as a positive control at a final concentration of 100. Mu.M/well, and DMSO control wells were filled with complete medium at the same concentration of DMSO (0.5%) as the test compound wells. According to%Response＝(Lum _{Test hole} -Lum _{DMSO control wells} )/(Lum _{Positive control well} -Lum _{DMSO control wells} ) X 100% for data processing. Half the Effective Concentration (EC) of the compound was calculated according to a four parameter model fitting curve ₅₀ )。

5. And (3) test results:

following the above procedure, the CRE luciferase reporter gene agonism levels of the compounds of the invention on HEK293/GLP-1R/CRE-Luc cells were determined, CRE being the cAMP response element, and elevation of intracellular cAMP levels activates the cAMP response element binding protein (CREB) to bind CRE and induce luciferase expression, with the results shown in Table 1.

TABLE 1

6. And (4) conclusion:

the compound can activate the expression of a CRE luciferase reporter gene of a HEK293/GLP-1R/CRE-Luc cell, and shows that the compound has agonistic activity on GLP-1R.

In conclusion, the invention provides a series of GLP-1R small molecule regulators with novel structures and high activity, and has great potential to be developed into medicaments aiming at GLP-1R related diseases.

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including all patents, patent applications, journal articles, books, and any other publications) cited in this application is hereby incorporated by reference in its entirety.

Claims

1. A compound having the structure of formula I:

wherein

X ¹ 、X ⁴ 、X ⁵ Each independently selected from N or CR ³ ；X ² 、X ³ Each independently selected from N or C and not simultaneously N; x ⁶ 、X ⁷ Each independently selected from N or CR ³ ；X ⁸ Is selected from N or C;

d ring is selected from C _6-10 Aryl or 5-10 membered heteroaryl;

ring E is selected from C _6-14 Aryl or 5-14 membered heteroaryl;

v is selected from-O-, -S-, -C (O) -, -CR ^7a R ^7b -or-NR ^7a -；

U is selected from-O-, -C (O) -, -CR ^8a R ^8b -or-NR ^8a -；

m, n, p, q are each independently selected from 0, 1, 2, 3, 4 or 5;

R ^x selected from hydrogen, halogen, -CN, -NH ₂ 、-NO ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-12 Cycloalkyl, -O (4-12 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, -COC _1-6 Alkyl, -CONH ₂ 、-CONH(C _1-6 Alkyl radicals),-CON(C _1-6 Alkyl radical) ₂ 、-NHC(O)C _1-6 Alkyl radical, C _6-10 Aryl, 5-to 10-membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Haloalkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl or-N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl) substituted with a substituent;

each R ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Alkyl, -C _1-6 HalogenatedAlkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C _3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

R ^4a 、R ^4b each independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl) or-NO ₂ Each of said alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Haloalkyl or-OC _1-6 Alkyl substituent;

or any two R ^4a Two R ^4b Two R ⁵ Together with the atom to which they are attached form C _4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, each of which is optionally substitutedOne or more groups selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -C _1-6 Haloalkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NO ₂ 、-NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、-NHC _3-6 Cycloalkyl, -N (C) _1-6 Alkyl) (C _3-6 Cycloalkyl), -C (O) (4-6 membered heterocycloalkyl), -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-CONHC _3-6 Cycloalkyl, -CONH (4-6 membered heterocycloalkyl), -NHCOC _1-6 Alkyl, -NHCOOC _1-6 Alkyl, -NHCOC _3-6 Cycloalkyl, -NHCOO (4-6 membered heterocycloalkyl), -N = S (O) (CH) ₃ ) ₂ 、-P(O)(CH ₃ ) ₂ 、C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl each optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl radical) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; said alkyl, cycloalkyl or heterocycloalkyl of said substituents being each optionally substituted by one or more substituents selected from halogen, hydroxy, -CN, -NH ₂ Oxo, -C _1-3 Haloalkyl or-OC _1-6 Alkyl substituent substitution;

2. A compound according to claim 1, or a pharmaceutically acceptable form thereof, of formula II:

wherein

X ¹ 、X ⁴ 、X ⁵ Each independently selected from N or CR ³ ；

the D ring is selected from 6-membered aryl or 6-membered heteroaryl, in which 6-membered aryl Y ¹ 、Y ² 、Y ³ 、Y ⁴ 、Y ⁵ Each independently is CR ⁵ In the 6-membered heteroaryl group, Y ¹ 、Y ² 、Y ³ 、Y ⁴ 、Y ⁵ Each independently selected from N or CR ⁵ No more than 3N atoms in the D ring and no 3 consecutive N atoms are present;

ring E is selected from phenyl or 5-10 membered heteroaryl;

u is-CR ^8a R ^8b -；

V is selected from-O-, -S-, -CR ^7a R ^7b -or-NR ^7a -；

W is selected from the group consisting of a bond and-CR ^9a R ^9b -；

m, p, q are each independently selected from 0, 1, 2, 3, 4 or 5;

R ^4a 、R ^4b each independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ Oxo or-C _1-6 Alkyl, each of which is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Haloalkyl or-OC _1-6 Substitution of alkyl groupsSubstituted by radicals;

or any two R ^4a Two R ^4b Together with the atom to which they are attached form C _4-10 Cycloalkyl or 4-10 membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from halogen, -CN, oxo, hydroxy, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl or-C _1-6 Substituted with a haloalkyl;

or R ^7a And R ⁵ 、R ^8a And R ⁵ Together with the atom to which they are attached form C _5-6 Cycloalkyl or 5-6 membered heterocycloalkyl; said cycloalkyl or heterocycloalkyl being each optionally substituted by one or more groups chosen from halogen, -CN, oxo, hydroxy, -C _1-3 Alkyl, -C _1-3 Haloalkyl, -OC _1-3 Alkyl or-C _1-3 Substituted with a hydroxyalkyl group;

R ¹ 、R ⁶ as defined in claim 1.

3. A compound according to claim 2, or a pharmaceutically acceptable form thereof, which is a compound of formula II-1, II-2, II-3, or a pharmaceutically acceptable form thereof:

wherein

Y ¹ 、Y ² 、Y ³ 、Y ⁴ 、Y ⁵ 、X ¹ 、X ⁴ 、X ⁵ ring B, ring C, ring D, ring E, ring R ¹ 、R ^4a 、R ^4b 、R ^8b M, p, q are as defined in claim 2.

4. A compound or pharmaceutically acceptable form thereof according to claim 2 or 3, wherein

Selected from: />

Preferably selected from->

Wherein R is ³ As defined in claim 2 or 3.

5. A compound or pharmaceutically acceptable form thereof according to any one of claims 1-4, wherein

R ¹ Selected from hydrogen, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one or more R ^x Substitution; r ^x Selected from hydrogen, halogen, -CN, -NH ₂ Oxo, -C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-8 Cycloalkyl, -O (4-to 10-membered heterocycloalkyl), -COC _1-6 Alkyl, -CONH ₂ 、-CONH(C _1-6 Alkyl), -CON (C) _1-6 Alkyl radical) ₂ 、-NHC(O)C _1-6 Alkyl, phenyl, 5-6 membered heteroaryl, C _3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, each of said alkyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Haloalkyl or-OC _1-6 Alkyl substituent substitution;

preferably, R ¹ Selected from hydrogen, -C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5 membered heteroaryl; each of said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally substituted with one or more R ^x Substitution; r ^x Selected from hydrogen, halogen, -CN, -NH ₂ Oxo, -C _1-4 Alkyl, -OC _1-4 Alkyl, -COC _1-4 Alkyl, -CONH ₂ or-NHC (O) C _1-4 Alkyl, each of which is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-4 Haloalkyl or-OC _1-4 Alkyl substituent;

more preferably, R ¹ Selected from:

particularly preferably, R ¹ Is selected from

6. A compound or pharmaceutically acceptable form thereof according to any one of claims 1-5, wherein

Each R ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl or C _3-8 Cycloalkyl, each of said alkyl, alkenyl, alkynyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-C _1-6 Haloalkyl, -C _1-6 Alkyl or-OC _1-6 Alkyl substituent substitution;

preferably, each R ³ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-4 Alkyl, -OC _1-4 Alkyl, -OC _3-6 Cycloalkyl, -C _2-4 Alkenyl or-C _2-4 Alkynyl, said alkyl, alkenyl, alkynyl or cycloalkyl each optionally substituted with one or more groups selected from halo, hydroxy, oxo, -NH ₂ 、-CN、-C _1-4 Alkyl or-OC _1-4 Alkyl substituent substitution;

more preferably, each R ³ Independently selected from hydrogen, F, hydroxy, -CN, methyl, ethyl、-OCH ₃ -O-cyclopropyl, ethenyl or ethynyl; each of said cyclopropyl, ethenyl or ethynyl groups being optionally substituted with one or more methyl or ethyl groups;

particularly preferably, each R ³ Independently selected from hydrogen, F, methyl or-CN.

7. A compound or pharmaceutically acceptable form thereof according to any one of claims 1-6, wherein

Selected from:

wherein R is ^4a 、R ^4b P and q are as defined in any one of claims 1 to 6.

8. A compound or pharmaceutically acceptable form thereof according to any one of claims 1-7, wherein

R ^4a 、R ^4b Each independently selected from hydrogen, halogen, hydroxy, -CN, oxo or-C _1-3 Alkyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, oxo, or-CN;

preferably, R ^4a 、R ^4b Each independently selected from hydrogen or oxo.

9. A compound or pharmaceutically acceptable form thereof according to claim 1 or 2, wherein the substituted D ring is selected from:

R ⁵ as defined in claim 1 or 2.

10. A compound or pharmaceutically acceptable form thereof according to any one of claims 1-9, wherein

Each R ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -CONH ₂ 、-NO ₂ Or C _3-8 Cycloalkyl, each of said alkyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl or-C _3-6 Cycloalkyl substituents;

preferably, each R ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-4 Alkyl, -OC _1-4 Alkyl or C _3-6 Cycloalkyl, each of said alkyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, -NH ₂ 、-CN、-NO ₂ or-C _1-4 Alkyl substituent substitution;

more preferably, each R ⁵ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ Methyl, ethyl, cyclopropyl, -OCH ₃ 、-CF ₃ Or CHF ₂ 。

11. A compound or pharmaceutically acceptable form thereof according to any one of claims 1-10, wherein

Selected from: />

R ⁶ And m is as defined in any one of claims 1 to 10.

12. A compound or pharmaceutically acceptable form thereof according to any one of claims 1-11, wherein

Each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-6 Alkyl, -OC _1-6 Alkyl, -OC _3-6 Cycloalkyl, -O (4-6 membered heterocycloalkyl), -CONH ₂ 、-N＝S(O)(CH ₃ ) ₂ 、-P(O)(CH ₃ ) ₂ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; said alkyl, cycloalkyl or heterocycloalkyl being each optionally substituted by one or more groups chosen from halogen, -CN, oxo, hydroxy, -NH ₂ Methyl, -OCH ₃ 、C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

preferably, each R ⁶ Independently selected from hydrogen, halogen, hydroxy, -CN, -NH ₂ 、-C _1-4 Alkyl, -OC _1-4 Alkyl, -CONH ₂ Or C _3-6 A cycloalkyl group; each of said alkyl or cycloalkyl groups being optionally substituted by one or more groups selected from halogen, -CN, oxo, hydroxy, -NH ₂ Methyl, -OCH ₃ Or C _3-6 Cycloalkyl substituents;

more preferably, each R ⁶ Independently selected from hydrogen, fluorine, chlorine, hydroxyl, -CN, -NH ₂ Methyl, -CHF ₂ 、-CF ₃ 、-OCH ₃ 、-CONH ₂ Or a cyclopropyl group.

13. A compound or pharmaceutically acceptable form thereof, wherein the compound is selected from:

/>

14. A pharmaceutical composition comprising a compound of any one of claims 1 to 13, or a pharmaceutically acceptable form thereof selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.

15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable form thereof, selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for the prevention or treatment of a disease or condition for which a GLP-1R agonist is indicated,

preferably, the disease for which a GLP-1R agonist is indicated is type II diabetes.