WO2018171698A1 - Heteroaryl pyrimidone derivative, and preparation method therefor and uses thereof - Google Patents

Abstract

A heteroaryl pyrimidone derivative represented by formula (I), a preparation method therefor, and uses thereof in serving as a therapeutic agent and especially uses thereof in serving as an acetyl coenzyme A carboxylase (ACC) inhibitor, definitions of substituent groups in formula (I) being the same as those in the specifications.

Description

Heteroarylpyrimidinone derivative, preparation method and use thereof

The present application claims priority to Chinese Patent Application No. 200910182530.6, entitled "Heteroarylpyrimidinone Derivatives, Preparation Methods and Uses thereof", filed on March 24, 2017, all of which are incorporated herein by reference. The content is incorporated herein by reference.

Technical field

The present invention relates to a heteroarylpyridinone derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as a therapeutic agent, particularly as an acetyl-CoA carboxylase (ACC) inhibitor.

Background technique

Acetyl-CoA carboxylase (ACC) is one of the important proteins involved in fatty acid metabolism. It uses biotin as a coenzyme to catalyze the production of malonyl-CoA from acetyl-CoA. This irreversible reaction (malonyl-CoA), in turn, provides a substrate for the synthesis of subsequent fatty acids or modulates the fatty acid oxidation signal, which is the first step of fatty acid metabolism and is a rate limiting step. The catalytic reaction can be divided into two steps, depending on the biotin carboxylase (BC) and carboxyltransferase (CT) activities of ACC.

There are two subtypes of ACC in human body, namely ACC1 and ACC2, which are separately encoded by two genes, ACACA and ACACB. There are differences in tissue distribution and intracellular distribution. ACC1 is a cytosolic enzyme that is mainly expressed in fat synthesis tissues (such as fat and breast tissue); ACC2 is localized in the mitochondrial membrane and is mainly enriched in oxidized tissues (such as the heart). In skeletal muscle, both are expressed at high levels in the liver. Therefore, ACC1 is mainly involved in the regulation of fatty acid synthesis, and ACC2 is mainly responsible for the regulation of the oxidation process of fatty acids. The activity of ACC is regulated by a variety of proteins, cytokines, endocrine hormones and receptors. Among them, AMPK is the main substance regulating ACC activity, which can inhibit the activity by direct phosphorylation of ACC; and protein phosphorylase 2 can dephosphorylate ACC, thereby enhancing the effect of ACC. Under physiological conditions, free fatty acids synthesized in the cytosol are transported to the mitochondria via the mitochondrial membrane on carnitine palmitoyltransferase 1 (CPT1) for oxidative energy supply. Malonyl-CoA in the cytosol allosterically inhibits CPT1, leaving its activity at a lower level, thereby limiting fatty acid oxidation. When the body is under stress or increased energy consumption, the AMPK pathway can be activated immediately, and the downstream ACC is inactivated. The level of malonyl-CoA is rapidly decreased, further inhibiting the inhibition of CPT1, promoting the oxidation of fatty acids, and providing the body with More adenosine triphosphate ATP.

Increased fatty acid synthesis and fatty acid metabolism disorders caused by impaired fatty acid oxidation are common features of many metabolic diseases, including liver steatosis, dyslipidemia, obesity, metabolic syndrome, nonalcoholic fatty Hepatitis (NASH), type 2 diabetes (T2DM) and atherosclerosis. In addition, abnormal fatty acid metabolism is also one of the characteristics of tumor diseases, and participates in the cell proliferation process that regulates abnormal malignant tumors. Since ACC is a key regulatory protein of lipid metabolism, drug inhibition of ACC can stimulate the synthesis of fatty acids in lipid-derived tissues while stimulating the oxidation of fatty acids in oxidized tissues, thus providing treatment for the above-mentioned diseases with abnormal lipid metabolism. A very attractive treatment.

A series of ACC inhibitor patents have been published, including WO2014182943, WO2014182945, WO2014182950, etc. The drugs currently in clinical phase II are mainly GS-0976, but the compounds disclosed in the prior art and the test drugs are effective, Safety or applicability is still unsatisfactory. At present, research on ACC inhibitors is not enough. It is still necessary to research and develop new ACC inhibitors to meet the growing medical and health needs.

Summary of the invention

The present inventors have unexpectedly found through experimental research that the compound of the following formula (I) can effectively inhibit ACC.

Accordingly, in a first aspect, the present invention provides a novel class of heteroaryl-pyrimidinone derivatives of the following formula (I):

among them:

X is selected from -NH-, -O- or -S-; preferably -S-;

L ^{1 is} selected from an alkylene group, a cycloalkylene group or a heterocyclic group;

R ^{1 is} selected from a hydrogen atom, an alkyl group or a halogen, wherein the alkyl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclic, Aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O)R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , Substituted by a substituent of -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

R ² is -C(O)NR ^a R ^b ;

R ^{a is} selected from a hydrogen atom or an alkyl group;

R ^{b is} selected from cyano or -OR ⁷ ;

R ^{3 is} selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted with one or more substituents selected from R ⁸ ;

R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, -OR ¹¹ , -SR ¹¹ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC (O) R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

Alternatively, R ⁴ and R ⁵ together with the atom to which they are attached form a 3 to 8 membered saturated or partially unsaturated cycloalkyl group, or form a hetero atom having one or more selected from N, O, S(O) _n a 4 to 8 membered saturated or partially unsaturated heterocyclic group, wherein said cycloalkyl or heterocyclic group is further optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, and an alkoxy group. , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O)R ¹¹ , -S Substituting (O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

R ^{6 is} selected from the group consisting of halogen, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O) R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ , preferably a heteroaryl group;

Alternatively, R ¹ and R ⁶ together with the atom to which they are attached form a 3 to 8 membered saturated or partially unsaturated cycloalkyl group, or form a hetero atom having one or more selected from N, O, S(O) _n . a 4 to 8 membered saturated or partially unsaturated heterocyclic group, or a 5 to 10 membered aryl or heteroaryl group, wherein said cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further subjected to one or A plurality selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ^{10, -C (O) R 11} , -OC (O) R 11, -S (O) n NR 9 R 10, -C (O) oR 11 or -NR ⁹ C (O) R ¹⁰ substituents Replace

R ^{7 is} selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optional Further one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹² R ¹³ , -C(O Substituting a substituent of NR ¹² R ¹³ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ or -NR ¹² C(O)R ¹³ ;

R ^{8 is} each independently selected from the group consisting of hydroxyl, halogen, alkyl, cyano, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O) NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O)R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹² R ^{13, -C (O) NR 12} R 13, -C (O) R 14, -C (O) oR 14 or -NR ¹² C (O) R ^13, substituted with a substituent;

Alternatively, R ⁹ and R ¹⁰ together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S(O) _n atoms, and 4 The ～8 membered heterocyclic ring is further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =0, - Substituted by a substituent of NR ¹² R ¹³ , -C(O)NR ¹² R ¹³ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ or -NR ¹² C(O)R ¹³ ;

R ¹² , R ¹³ and R ¹⁴ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxy Substituted by a substituent of the acid ester;

n is 0, 1, or 2.

Herein, the compound of the formula (I) (and the compound of the formula (II) to the formula (IV)) also includes, in scope, stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

In some preferred embodiments of the invention, the compound of formula (I) has the structure of formula (II):

among them:

m is 1, 2, 3, 4 or 5;

The definitions of L ¹ , R ¹ , R ² , R ⁶ , R ⁸ and R ¹¹ are as described in the formula (I).

In some preferred embodiments of the invention, the compound of formula (II) has a specific stereo configuration, ie, has the structure of formula (III):

among them:

m is 1, 2, 3, 4 or 5;

The definitions of L ¹ , R ¹ , R ² , R ⁶ , R ⁸ and R ¹¹ are as described in the formula (I).

In some preferred embodiments of the invention, the compound of formula (II) has a specific stereo configuration, ie, has the structure of formula (IV):

among them:

m is 1, 2, 3, 4 or 5;

The definitions of L ¹ , R ¹ , R ² , R ⁶ , R ⁸ and R ¹¹ are as described in the formula (I).

In some preferred embodiment of the present invention, there is provided a compound of formula (I), (II), (III) or the compound (IV), in which R ¹ is selected from methyl or trifluoromethyl.

In some preferred embodiments of the invention there is provided a compound of formula (I), (II), (III) or (IV), wherein:

R ^{2 is} selected from -C(O)NR ^a R ^b ;

R ^{a is} selected from a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a hydrogen atom or a methyl group;

The definition of R ^b is as described in the formula (I).

In some preferred embodiments of the invention there is provided a compound of formula (I), (II), (III) or (IV), wherein:

R ^{2 is} selected from -C(O)NR ^a R ^b ;

R ^{b is} selected from cyano or -OR ⁷ , and R ⁷ is an alkyl group, wherein the alkyl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a cycloalkyl group, a phenyl group; more preferably, R ⁷ is C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxyl group, a cyclopropyl group, and a phenyl group;

The definition of ^Ra is as described in the general formula (I).

In some preferred embodiments of the invention there is provided a compound of formula (I), (II), (III) or (IV) wherein R ^{6 is} selected from the group consisting of halogen, -C(O)R ¹¹ , -C ( O) NR ⁹ R ¹⁰ or oxazolyl, wherein R ⁹ , R ¹⁰ and R ¹¹ are as defined in the general formula (I).

In some preferred embodiments of the invention there is provided a compound of formula (I), (II), (III) or (IV), wherein L ¹ is:

In some preferred embodiment of the present invention, there is provided a compound of formula (I), (II), (III) or the compound (IV), wherein R ⁸ is selected from methoxy and halo.

In some preferred embodiments of the invention there is provided a compound of formula (I), (II), (III) or (IV), wherein R ¹¹ is tetrahydropyranyl.

Typical compounds of the invention include, but are not limited to:

Typical compounds described above include stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

Further, the present invention provides a process for the preparation of a compound of formula (I), which process comprises:

Reaction of ^a compound of formula (IA) with NHR ^a R ^b or a salt thereof to provide a compound of formula (I);

Wherein: X, L ¹ , R ^a , R ^b , and R ¹ to R ⁶ are as defined in the formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), including stereoisomers, tautomers thereof or pharmaceutically acceptable thereof The salt or the like), and optionally a pharmaceutically acceptable carrier, excipient or combination thereof.

In yet another aspect, the invention provides a method of inhibiting ACC comprising contacting ACC with a compound of formula (I) of the invention, or a pharmaceutical composition thereof. The invention accordingly also provides a method of preventing or treating a disease or condition associated with ACC comprising administering a compound or pharmaceutical composition according to the invention to a subject in need thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutical composition thereof for the manufacture of a medicament for use as an ACC inhibitor.

The invention also provides the use of a compound of formula (I) or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with ACC, wherein the disease or condition is preferably a metabolic disease, a cancer, a fungus a parasitic or bacterial infection; wherein the metabolic disease is preferably hepatic steatosis, nonalcoholic fatty liver, obesity, dyslipidemia, hyperlipidemia, type II diabetes or metabolic syndrome, wherein the obesity is preferred Is Prader-Willi syndrome, Bardet-Biedl syndrome or Cohen syndrome or MOMO syndrome, wherein the cancer is preferably liver Cell carcinoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colorectal cancer, head and neck cancer, melanoma, ovarian cancer or cervical cancer, more preferably hepatocellular carcinoma and non-small cell lung cancer.

Detailed description of the invention

Unless otherwise stated, some of the terms used in the specification and claims of the invention are defined as follows:

"Alkyl" as a group or a part of a group means a straight or branched C ₁ -C ₂₀ aliphatic hydrocarbon group, preferably a C ₁ -C ₁₀ alkyl group, more preferably C ₁ -C ₆ alkyl, particularly preferably C ₁ -C ₄ alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. The alkyl group can be substituted or unsubstituted.

"Alkylene" is a divalent alkyl group. It is preferably a C ₁ -C ₁₀ alkylene group, more preferably a C ₁ -C ₆ alkylene group, and particularly preferably a C ₁ -C ₄ alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene,

Acetylene and so on. The alkylene group may be substituted or unsubstituted.

"Alkenyl" refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. A C ₂ -C ₄ alkylene group is preferred. The alkenyl group can be optionally substituted or unsubstituted.

"Alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond which may be straight or branched. Preference is given to C ₂ -C ₁₀ alkynyl, more preferably C ₂ -C ₆ alkynyl, most preferably C ₂ -C ₄ alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be substituted or unsubstituted.

"Cycloalkyl" means a saturated or partially saturated monocyclic, fused, bridged or spiro carbon ring. It is preferably a C ₃ -C ₁₂ cycloalkyl group, more preferably a C ₃ -C ₈ cycloalkyl group, and most preferably a C ₃ -C ₆ cycloalkyl group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene The alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.

"Cycloalkylene" is a divalent cycloalkyl group. It is preferably a C ₃ -C ₁₂ cycloalkylene group, more preferably a C ₃ -C ₈ cycloalkylene group, and most preferably a C ₃ -C ₆ cycloalkylene group. Examples of alkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and the like. A cycloalkylene group can be substituted or unsubstituted.

"Cyclopropylene" means

"Cyclopentylene" means

"Spirocycloalkyl" means a 5- to 18-membered polycyclic group having two or more cyclic structures and sharing a carbon atom (called a spiro atom) with each other, and the ring may contain 1 One or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.

"Fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group having two or more cyclic structures that share a pair of carbon atoms with each other, wherein one or more of the rings may contain one or more A double bond, but none of the rings have a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.

"Bridge cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two non-directly bonded carbon atoms, wherein one or more rings may contain One or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into bicyclic, tricyclic, pyridone or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or pyridone, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group can be optionally substituted or unsubstituted.

"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged, and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine , 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl. The heterocyclic group may be substituted or unsubstituted.

"Spiroheterocyclyl" means a 5- to 18-membered polycyclic group having two or more cyclic structures and sharing one atom between the single rings, and having one or more double bonds in the ring. , but none of the rings have a fully conjugated π-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _q (where q is selected from 0, 1 or 2) heteroatoms, the remainder The ring atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings have A fully conjugated π-electron aromatic system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _q (where q is selected from 0, 1 or 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic fused heterocyclic group, preferably a bicyclic ring or a tricyclic ring, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine.

"Bridge heterocyclyl" refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 members, containing two or more cyclic structures and sharing two atoms which are not directly bonded to each other, one or more of which A ring may contain one or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _q (where q is selected from 0 a hetero atom of 1 or 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted.

"Heterocyclylene" means a divalent heterocyclic group. It preferably has a 5- to 7-membered monocyclic heterocyclic group or a 7 to 10 membered bicyclic heterocyclic group or a tricyclic heterocyclic group which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. . The heterocyclylene group may be substituted or unsubstituted.

"Aryl" means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner. The term "aryl" includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably, the aryl group is a C ₆ -C ₁₀ aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group. The aryl group can be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:

"Heteroaryl" means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinolyl, oxazolyl, benzisothiazolyl, benzene And oxazolyl and benzoisoxazolyl. Heteroaryl groups can be substituted or unsubstituted. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:

"Alkoxy" means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. The C ₁ -C ₆ alkoxy group is preferred, and a C ₁ -C ₄ alkoxy group is particularly preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"Hydroxy" refers to an -OH group.

"Halogen" means fluoro, chloro, bromo and iodo, preferably chloro, bromo and iodo.

"Amino" means -NH ₂ .

"Cyano" means -CN.

"Nitro" means -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Carboxy" refers to -C(O)OH.

"Carboxylic acid ester group" means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.

"DMSO" refers to dimethyl sulfoxide.

"巯基" means -SH.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are replaced by a corresponding number of substituents independently of one another. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an ethylenic bond.

As used herein, "substituted" or "substituted", unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy. , alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Base, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =0, -OR ¹¹ , -SR ¹¹ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O)R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ , wherein n is 0, 1 or 2;

"Pharmaceutically acceptable salt" refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound of the formula (I) may be a metal salt, an amine salt formed with a suitable acid, a metal salt preferably an alkali metal or an alkaline earth metal salt, and suitable acids including inorganic acids and organic acids such as acetic acid and benzenesulfonate. Acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid , methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and most preferred is the hydrochloride salt.

"Pharmaceutical composition" means containing one or more of the compounds described herein, including pharmaceutically acceptable salts or stereoisomers, tautomers or prodrugs thereof, and optionally other pharmaceutically active ingredients. A mixture, which may contain other optional ingredients such as pharmaceutically acceptable carriers and/or excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

As used herein, the term "plurality" includes two or more, such as two, three, four, and the like.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

The preparation method of the compound of the formula (I) of the invention comprises the following steps:

Reaction of ^a compound of formula (IA) with NHR ^a R ^b or a salt thereof to give a compound of formula (I),

Wherein: X, L ¹ , R ^a , R ^b , and R ¹ to R ⁶ are as defined in the formula (I).

detailed description

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

The examples give the preparation of representative compounds represented by formula (I) and related structural identification data. It is to be understood that the following examples are intended to illustrate the invention and not to limit the invention. ^{The 1} H NMR spectrum was measured using a Bruker instrument (400 MHz) and the chemical shift was expressed in ppm. The internal standard of tetramethylsilane (0.00 ppm) was used. ¹ H NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublet, dt = triple The double peak of the peak. If a coupling constant is provided, its unit is Hz.

Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are either commercially available or synthesized according to known methods, and the commercially available starting materials and reagents are not further purified. For direct use, unless otherwise indicated, commercial manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd., and the like.

D ₃ OD: deuterated methanol

CDCl ₃ : Deuterated chloroform

DMSO-d ₆ : deuterated dimethyl sulfoxide

The argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.

There is no particular description in the examples, and the solution in the reaction means an aqueous solution.

The compound is purified by silica gel column chromatography and thin layer chromatography, wherein the eluent or developer system is selected from the group consisting of: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloro Methane: ethyl acetate; wherein the volume ratio of the solvent varies depending on the polarity of the compound, and it may be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.

Example 1

N-Methoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-A -6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methyl Propionamide

first step

(2-methoxyphenyl) ethylene oxide

2-Methoxybenzaldehyde 1a (20.0 g, 146.9 mmol) was dissolved in 100 mL of dimethyl sulfoxide, followed by t-butylthiohypoiodate (36.0 g, 173.3 mmol) and sodium hydroxide (24.7 g). , 441.0 mmol), heated to 80 ° C for 1.5 hours. The reaction solution was cooled to room temperature, and then added with EtOAc (EtOAc) (EtOAc (EtOAc) Purification by silica gel column chromatography (eluent: A) afforded (2-methoxyphenyl) hexanes 1b (13.1 g, colorless oil).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 (t, J = 1.2 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 1.2 Hz, 1H), 6.89 (d) , J = 7.6 Hz, 1H), 4.22 (t, J = 0.4 Hz, 1H), 3.87 (s, 3H), 2.71 (dd, J = 5.6, 2.4 Hz, 1H) 3.14 (dd, J = 5.6, 2.4 Hz, 1H).

Second step

2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol 1d

(S)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol 1e

(R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol 1f

(2-Methoxyphenyl)oxirane 1b (26.0 g, 173.0 mmol) was added to tetrahydro-2H-pyran-4-ol 1c (53.1 g, 519.7 mmol) and aluminum trifluoromethanesulfonate ( 4.10 g, 8.65 mmol) was dissolved and allowed to react at room temperature for 3 hours. To the reaction mixture, 200 mL of dichloromethane and 200 mL of water were added, and the mixture was separated, and the organic layer was evaporated. mjjjjjjjj 2-((Tetrahydro-2H-pyran-4-yl)oxy)ethanol 1d (13.0 g, white solid), yield: 30%.

1d ¹ H NMR (400MHz, CDCl ₃ ) δ 7.42 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 6.87 ( d, J = 8.0 Hz, 1H), 5.07 (dd, J = 8.0, 4.0 Hz, 1H), 3.87-4.00 (m, 2H), 3.83 (s, 3H), 3.62-3.72 (m, 1H), 3.46 -3.58 (m, 2H), 3.32-3.43 (m, 2H), 2.35-2.37 (m, 1H), 1.99-2.03 (m, 1H), 1.77-1.80 (m, 1H), 1.60-1.70 (m, 2H).

third step

(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol 1d (9.0 g) was further passed by using a supercritical fluid chromatography (SFC) method. Separation preparative HPLC and chiral column chiral isomers were resolved (chiral column Pheno Lux Cellulose- ₂ , 250 x 30 mm ID, 60 mL/min; mobile phase A: CO ₂ , mobile phase B: isopropanol) for resolution (S)-2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol 1e (4.00 g, white solid). 44.4%, 100% ee, retention time: 1.521 min; (R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol 1f (4.74 g, white solid), Yield: 52.7%, 100% ee, retention time: 1.679 min.

the fourth step

2-(tributylstannyl)oxazole

Oxazole 1 g (500 mg, 7.24 mmol) was dissolved in 12 mL of tetrahydrofuran. Under nitrogen, the mixture was cooled to -78 ° C for 5 minutes, and n-butyllithium (4.56 mL, 7.29 mmol) was slowly added. After the addition, the mixture was stirred at -78 ° C for 30 minutes. Then, tributyltin chloride (1.96 mL, 7.24 mmol) was added, and the mixture was stirred at -78 ° C for 10 minutes, and allowed to react to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. 15 mL of hexane was evaporated, and the filtrate was concentrated under vacuo to give 2-(tributylstannyl) oxazole 1 h (1.8 g, pale yellow liquid), yield: 70%.

^{1 H NMR (400MHz, CDCl3)} : 7.84 (1H, s), 7.18 (1H, s), 1.67-1.53 (6H, m), 1.42-1.29 (6H, m), 1.20 (6H, m), 0.89 ( 9H, t, J = 7Hz).

the fifth step

2-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl- Tert-butyl 2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoate

2-(6-Bromo-5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-protected under nitrogen tert-Butyl 2-methylpropionate 1i (700 mg, 1.74 mmol, prepared according to published patent application WO2013071169), 2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran) 4-yl)oxy)ethanol 1d (834 mg, 3.30 mmol) and triphenylphosphine (912 mg, 3.48 mmol) were dissolved in 20 mL anhydrous tetrahydrofuran. After cooling to 0 ° C for 3 minutes, a solution of diisopropyl azodicarboxylate (0.69 mL, 3.48 mmol) in 4 mL of tetrahydrofuran was added. After the addition was completed, the mixture was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjj -((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d] Pyrimidine-3(4H)-yl)-2-methylpropanoic acid tert-butyl ester 1j (960 mg, off-white solid), yield: 87%. MS m/z (ESI): 636.7 [M+1]

Step 6

2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-) Zin-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid tert-butyl ester

2-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl))-protected under nitrogen 5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid tert-butyl ester 1j (970mg 1.52 mmol), 2-(tributylstannyl)oxazole 1h (817 mg, 2.28 mmol) and tetrakistriphenylphosphine palladium (245 mg, 0.21 mmol) were dissolved in 12 mL of toluene. The reaction was heated to 110 ° C for 7 hours. The reaction solution was cooled to room temperature, then added with 40 mL of water, EtOAc (EtOAc) Deprotection: A system) purification to give 2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 - tert-butyl methacrylate 1k (400 mg, pale yellow solid), yield: 42%.

MS m/z (ESI): 625.8 [M+1]

Seventh step

2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-) Zin-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid

2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-) Oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid tert-butyl ester 1k (337 mg, 0.54 mmol) was dissolved in 10 mL dichloromethane. 2 mL of trifluoroacetic acid was added dropwise at 0 ° C, and after the addition was completed, the reaction was allowed to proceed to room temperature for 3 hours. 25 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (10 mL × 3). Purification: B system) purification to give 2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 Methylpropionic acid 1 m (43 mg, pale yellow solid), yield: 14%.

MS m/z (ESI): 591.8 [M+1]

Eighth step

N-Methoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-A -6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methyl Propionamide

2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-) Oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid 1m (30mg , 0.0526 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (48 mg, 0.1262 mmol) and N,N-diiso The propyl ethylamine (86 μL, 0.526 mmol) was dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 10 minutes. O-methylhydroxylamine hydrochloride (28 mg, 0.316 mmol) was added and allowed to react at room temperature for 15 hours. 2 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (4 mL×3). The residue obtained is purified by silica gel thin-plate chromatography (developing solvent: B system) to give N-methoxy-2-(1-(2-(2-methoxyphenyl)-2-((4) Hydrogen-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothiophene [2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 1 (30 mg, white solid), yield: 95.2%.

MS m/z (ESI): 598.8 [M+1]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.24 (s, 1H), 7.69 (s, 1H), 7.56 (d, J = 7.5Hz, 1H), 7.27 (t, J = 7.4Hz, 1H), 7.21 (s, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.37 (dd, J = 8.4, 5.1 Hz, 1H), 4.19-4.09 (m, 1H), 4.05–3.95 (m, 1H), 3.82 (d, J=6.9 Hz, 6H), 3.78-3.66 (m, 2H), 3.43 (dd, J=11.9, 4.1 Hz, 1H), 3.39-3.28 (m, 2H), 2.82 (s, 3H), 1.84 (s, 3H), 1.79 (s, 3H), δ 1.75-1.67 (m, 2H), 1.55 (ddd, J = 13.8, 8.8, 4.6 Hz , 1H), 1.47-1.38 (m, 1H).

Example 2

N-Cyano-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropane Amide

first step

N-Cyano-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropane Amide

2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-) Oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid 1m (35mg , 0.061 mmol) dissolved in 1 mL of N,N-dimethylformamide, cooled down, and added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (56 mg, 0.148 mmol) and N,N-diisopropylethylamine (100 μL, 0.61 mmol) were stirred for 10 minutes, and cyanamide 2a (15.4 mg, 0.368 mmol) was added and allowed to react at room temperature for 15 hours. 5 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (5 mL × 3). The residue was purified by silica gel thin-plate chromatography (developing solvent: B system) to give N-cyano-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H) -pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2, 3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 2 (9 mg, white solid).

MS m/z (ESI): 615.8 [M+23]

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.53 (d, J = 6.6 Hz, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.20 (s, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 5.41-5.34 (m, 1H), 4.13-4.00 (m, 2H), 3.86 (s, 3H), 3.80- 3.66 (m, 2H), 3.48-3.38 (m, 1H), 3.36-3.25 (m, 2H), 2.81 (s, 3H), 1.80 (d, J = 11.1 Hz, 6H), 1.74-1.66 (m, 2H), 1.62-1.49 (m, 2H).

Example 3

(R)-N-methoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)- 2-methylpropionamide

first step

(R)-2-(6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid tert-butyl ester

2-(6-Bromo-5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-protected under nitrogen tert-Butyl 2-methylpropionate 1i (1.00 g, 2.48 mmol), (R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl) Ethyloxyl 1f (1.19 g, 4.71 mmol) and triphenylphosphine (1.30 g, 4.96 mmol) were dissolved in 25 mL of anhydrous tetrahydrofuran. After cooling to 0 ° C for 3 minutes, a solution of diisopropyl azodicarboxylate (1.0 mL, 4.96 mmol) in 6 mL of tetrahydrofuran was added. After the addition, the mixture was allowed to react to room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjj 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1,2-dihydrothieno[2, 3-d]pyrimidine-3(4H)-yl)-2-methylpropanoic acid tert-butyl ester 3a (1.35 g, white solid), yield: 85%.

MS m/z (ESI): 636.8 [M+1]

Second step

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl- 6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid Tert-butyl ester

(R)-2-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)) Ethyl)-5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid tert-butyl Ester 3a (1.35 g, 2.12 mmol), 2-(tributylstannyl)oxazole 1 h (1.14 g, 3.18 mmol) and tetratriphenylphosphine palladium (343 mg, 0.30 mmol) were dissolved in 17 mL of toluene. The mixture was heated to 110 ° C for 4.5 hours. The reaction solution was cooled to room temperature, 50 mL of 10% potassium fluoride solution was added, and the mixture was extracted with ethyl acetate (15 mL × 3). Column chromatography (eluent: A system) was purified to give (R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4) -yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidine -3(4H)-yl)-2-methylpropanoic acid tert-butyl ester 3b (600 mg, white solid), yield: 45%.

MS m/z (ESI): 625.8 [M+1]

third step

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl- 6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 - tert-Butyl methacrylate 3b (600 mg, 0.96 mmol) was dissolved in 15 mL dichloromethane. After stirring at 0 ° C for 3 minutes, 3 mL of trifluoroacetic acid was added dropwise, and after the addition, the mixture was allowed to react to room temperature for 3 hours. 20 mL of ethyl acetate and 30 mL of saturated brine were added to the reaction mixture, the aqueous layer was separated, and extracted with ethyl acetate (10 mL×2), and the organic phase was combined and washed with water (50 mL) and brine (50 mL) The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, evaporated. 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo- 1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid 3c (145 mg, white solid), yield: 26%.

MS m/z (ESI): 591.8 [M+1]

the fourth step

(R)-N-methoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)- 2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropane Acid 3c (10 mg, 0.0175 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19.8 mg, 0.0526 mmol) and N , N-diisopropylethylamine (22.6 mg, 0.1756 mmol) was dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 10 min, and then added with O-methylhydroxylamine hydrochloride (14.6 mg, 0.01756 mmol) ), reacted at room temperature for 42 hours. 3 ml of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (2 mL × 3). The residue was purified by silica gel chromatography (developing solvent: B system) to give (R)-N-methoxy-2-(1-(2-(2-methoxyphenyl)-2-( (tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydro Thio[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 3 (5 mg, white solid), yield: 47.6%.

MS m/z (ESI): 620.8 [M+23]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.19 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.37-7.23 (t, J = 7.4Hz, 1H) , 7.21 (s, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 5.37 (dd, J = 8.3, 5.0 Hz, 1H), 4.13 (s, 1H), 4.00 (s, 1H), 3.83 (d, J = 6.0 Hz, 6H), 3.73 (dd, J = 18.5, 11.7 Hz, 2H), 3.43 (s, 1H), 3.35 (dd, J = 17.0) , 8.4 Hz, 2H), 2.83 (s, 3H), 1.85 (s, 3H), 1.80 (s, 3H), δ 1.75-1.67 (m, 2H), 1.55 (ddd, J = 13.8, 8.8, 4.6 Hz, 1H), 1.47–1.38 (m, 1H).

Example 4

(R)-N-Cyano-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionamide

first step

(R)-N-Cyano-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionic acid 3c (20 mg, 0.035 mmol), cyanamide 2a (7.5 mg, 0.175 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetra The ureido hexafluorophosphate (20 mg, 0.053 mmol) and N,N-diisopropylethylamine (20 μL, 0.11 mmol) were dissolved in 2 mL of N,N-dimethylformamide and allowed to react at room temperature for 18 hours. TLC detection of raw materials was not completely reacted, supplemented with cyanamide 2a (7.5mg, 0.175mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluoro Phosphate (20 mg, 0.053 mmol) and N,N-diisopropylethylamine (20 [mu]L, 0.11 mmol). 15 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (7 mL × 3). Purification by the method (developing agent: B system) gives (R)-N-cyano-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran)- 4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d] Pyrimidine-3(4H)-yl)-2-methylpropanamide 4 (5.0 mg, white solid), yield: 25%.

MS m/z (ESI): 551.9 [M-42+1]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.69 (s, 1H), 7.54 (d, J = 7.4Hz, 1H), 7.31-7.27 (m, 1H), 7.20 (s, 1H), 7.05-6.97 ( m,1H), 6.86 (d, J = 8.2 Hz, 1H), 5.41-5.31 (m, 1H), 4.18-3.93 (m, 2H), 3.86 (s, 3H), 3.77-3.65 (m, 2H) , 3.40 (dd, J = 15.7, 7.0 Hz, 1H), 3.36-3.25 (m, 2H), 2.80 (s, 3H), 2.00 (dd, J = 18.5, 11.0 Hz, 1H), 1.80 (s, 3H) ), 1.77 (s, 3H), 1.68-1.49 (m, 3H).

Example 5

(R)-N-ethoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)- 2-methylpropionamide

first step

(R)-N-ethoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)- 2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionic acid 3c (15 mg, 0.026 mmol), O-ethylhydroxylamine hydrochloride 5a (13 mg, 0.13 mmol), 2-(7-azobenzotriazole)-N,N,N', N'-tetramethyluronium hexafluorophosphate (20 mg, 0.053 mmol) and N,N-diisopropylethylamine (35 μL, 0.21 mmol) were dissolved in 1 mL of N,N-dimethylformamide at room temperature. 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjj Phenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo -1,2-Dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 5 (5.0 mg, off-white solid), yield: 30%.

MS m/z (ESI): 634.9 [M+23]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.20 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 7.4Hz, 1H), 7.29 (d, J = 7.6Hz, 1H), 7.21 (s, 1H), 7.02 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.41-5.32 (m, 1H), 4.22-4.05 (m, 2H), 4.03 ( Dd, J = 13.4, 6.5 Hz, 2H), 3.84 (s, 3H), 3.79-3.65 (m, 2H), 3.49-3.40 (m, 1H), 3.34 (dd, J = 16.4, 7.8 Hz, 2H) , 2.83 (s, 3H), 1.85 (s, 3H), 1.80 (s, 3H), 1.76-1.67 (m, 2H), 1.59-1.50 (m, 1H), 1.48-1.40 (m, 1H), 1.33 -1.29(m,3H).

Example 6

(R)-N-isopropoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-Methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl) -2-methylpropionamide

first step

(R)-N-isopropoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-Methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl) -2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionic acid 3c (25 mg, 0.044 mmol), O-isopropylhydroxylamine hydrochloride 6a (15 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (17 mg, 0.066 mmol) and N,N-diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in 1.5 mL of tetrahydrofuran and allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to silica gel chromatography (yield: B system) to give (R)-N-isopropoxy-2-(1-(2-(2- methoxy) Phenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo Generation-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 6 (6.0 mg, white solid), yield: 22%.

MS m/z (ESI): 649.9 [M+23]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.21 (s, 1H), 7.06 -6.98 (m, 1H), 6.84 (d, J = 5.8 Hz, 1H), 5.39 - 5.31 (m, 1H), 4.24 - 4.15 (m, 1H), 4.15 - 3.99 (m, 2H), 3.84 (s , 3H), 3.78-3.65 (m, 2H), 3.43 (dt, J = 11.0, 9.7 Hz, 1H), 3.34 (ddd, J = 13.8, 10.8, 5.1 Hz, 2H), 2.82 (s, 3H), 1.85 (s, 3H), 1.81 (s, 3H), 1.59-1.50 (m, 2H), 1.47-1.39 (m, 2H), 1.28 (d, J = 6.3 Hz, 6H).

Example 7

(R)-N-isobutoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-Methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl) -2-methylpropionamide

first step

(R)-N-isobutoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-Methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl) -2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionic acid 3c (25 mg, 0.044 mmol), O-isobutylhydroxylamine hydrochloride 7a (17 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (17 mg, 0.066 mmol) and N,N-diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in 1.5 mL of tetrahydrofuran and reacted at 28 ° C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to silica gel chromatography (yield: B system) to give (R)-N-isobutoxy-2-(1-(2-(2-methoxy) Phenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo Generation-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 7 (5.0 mg, off-white solid), yield: 20%.

MS m/z (ESI): 662.9 [M+23]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.20 (d, J = 14.2Hz, 1H), 7.70 (s, 1H), 7.55 (t, J = 7.8Hz, 1H), 7.21 (s, 1H), 7.05 -6.97 (m, 1H), 6.85 (d, J = 8.1 Hz, 1H), 5.40 - 5.30 (m, 1H), 4.08 (ddd, J = 20.5, 16.3, 9.1 Hz, 2H), 3.84 (s, 3H) ), 3.79 (dd, J = 13.5, 5.6 Hz, 2H), 3.76-3.73 (m, 2H), 3.43 (ddd, J = 9.4, 7.7, 4.3 Hz, 1H), 3.34 (dt, J = 11.6, 6.5) Hz, 2H), 2.83 (s, 3H), 1.84 (s, 3H), 1.80 (s, 3H), 1.77-1.67 (m, 3H), 1.60-1.48 (m, 2H), 0.97 (d, J = 6.6Hz, 6H).

Example 8

(R)-N-(benzyloxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl -2-methylpropionamide

first step

(R)-N-(benzyloxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl -2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionic acid 3c (25 mg, 0.044 mmol), O-benzylhydroxylamine hydrochloride 8a (21 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (17 mg, 0.066) Methyl) and N,N-diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in 1.5 mL of tetrahydrofuran and reacted at 28 ° C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified mjjjjjjjjjjjj Oxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-di Oxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 8 (5.0 mg, white solid), yield: 20%.

MS m/z (ESI): 697.9 [M+23]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.10 (s, 1H), 7.70 (s, 1H), 7.53 (dd, J = 15.0,6.8Hz, 3H), 7.41-7.34 (m, 3H), 7.21 ( s, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.41-5.34 (m, 1H), 4.97 (s, 2H), 4.20 - 3.95 (m) , 2H), 3.78 (d, J = 19.1 Hz, 3H), 3.71 (dd, J = 16.5, 8.1 Hz, 2H), 3.49-3.39 (m, 1H), 3.33 (dd, J = 13.3, 7.5 Hz, 2H), 2.84 (s, 3H), 1.79 (s, 3H), 1.74 (s, 3H), 1.62-1.51 (m, 2H), 1.51-1.38 (m, 2H).

Example 9

(R)-N-(tert-butoxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)- 2-methylpropionamide

first step

(R)-N-(tert-butoxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)- 2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionic acid 3c (25 mg, 0.044 mmol), O-tert-butylhydroxylamine hydrochloride 9a (17 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (17 mg, 0.066 mmol) and N,N-diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in 1.5 mL of tetrahydrofuran and allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to silica crystals (yield: B system) to give (R)-N-(tert-butoxy)-2-(1-(2-(2-) Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4- Dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 9 (5.0 mg, off-white solid), yield: 20% .

MS m/z (ESI): 662.9 [M+23]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.85 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 6.8Hz, 1H), 7.34-7.28 (m, 1H), 7.21 (s, 1H), 7.05-6.99 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.40-5.33 (m, 1H), 4.15-4.01 (m, 2H), 3.85 (s, 3H), 3.78 -3.67 (m, 2H), 3.47-3.40 (m, 1H), 3.34 (dt, J = 15.2, 4.0 Hz, 2H), 2.83 (s, 3H), 1.87 (s, 3H), 1.84 (s, 3H) ), 1.63-1.49 (m, 2H), 1.49-1.36 (m, 2H), 1.31 (s, 9H).

Example 10

(R)-N-(allyloxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)- 2-methylpropionamide

first step

(R)-N-(allyloxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)- 2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -methylpropionic acid 3c (25 mg, 0.044 mmol), O-allyl hydroxylamine hydrochloride 10a (15 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (17 mg, 0.066 mmol) and N,N-diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in 1.5 mL of tetrahydrofuran and allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to silica crystals (yield: B system) to give (R)-N-(allyloxy)-2-(1-(2-(2-) Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4- Dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 10 (5.0 mg, white solid), yield: 20% .

MS m/z (ESI): 646.9 [M+23]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.20 (s, 1H), 7.70 (s, 1H), 7.57 (d, J = 7.0Hz, 1H), 7.33-7.28 (m, 1H), 7.21 (s, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.08-5.98 (m, 1H), 5.47 (d, J = 17.6 Hz, 1H), 5.37 ( t, J = 8.7 Hz, 2H), 4.46 (d, J = 6.1 Hz, 2H), 4.19 - 4.10 (m, 1H), 4.05 - 3.93 (m, 1H), 3.84 (s, 3H), 3.71 (dt , J = 15.5, 8.8 Hz, 2H), 3.50-3.40 (m, 1H), 3.34 (dd, J = 16.2, 7.6 Hz, 2H), 2.83 (s, 3H), 1.84 (s, 3H), 1.79 ( s, 3H), 1.55 (dd, J = 12.9, 7.5 Hz, 2H), 1.51-1.38 (m, 2H).

Example 11

(R)-N-(cyclopropylmethoxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidine-3 (4H )-yl)-2-methylpropionamide

first step

(R)-N-(cyclopropylmethoxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidine-3 (4H )-yl)-2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -Methylpropionic acid 3c (25 mg, 0.044 mmol), O-(cyclopropylmethyl)hydroxylamine hydrochloride 11a (16 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphinus The acid chloride (17 mg, 0.066 mmol) and N,N-diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in 1.5 mL of tetrahydrofuran and allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjj 2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2, 4-Dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 11 (5.0 mg, white solid) 20%.

MS m/z (ESI): 660.9 [M+23]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.40 - 5.34 (m, 1H), 4.17 - 3.99 (m, 2H), 3.85 (s, 3H), 3.80 ( d, J = 7.3 Hz, 2H), 3.77-3.65 (m, 2H), 3.47-3.40 (m, 1H), 3.34 (dd, J = 16.9, 8.6 Hz, 2H), 2.82 (s, 3H), 1.85 (s, 3H), 1.81 (s, 3H), 1.62-1.51 (m, 2H), 1.51-1.37 (m, 2H), 1.16 (dd, J = 14.3, 3.8 Hz, 1H), 0.85 (dd, J = 9.1, 4.8 Hz, 2H), 0.60 (d, J = 7.2 Hz, 2H).

Example 12

(R)-N-methoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)- N,2-dimethylpropanamide

first step

(R)-N-methoxy-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl) -5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)- N,2-dimethylpropanamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -Methylpropionic acid 3c (25 mg, 0.044 mmol), N,O-dimethylhydroxylamine hydrochloride 12a (13 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride ( 17 mg, 0.066 mmol) and N,N-diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in 1.5 mL of tetrahydrofuran and reacted at 30 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjj Phenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo -1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-N,2-dimethylpropanamide 12 (5.0 mg, off-white solid), yield: 20% .

MS m/z (ESI): 612.9 [M+1]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.71 (s, 1H), 7.56 (d, J = 6.6Hz, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.87 (d, J = 7.0 Hz, 1H), 5.49 - 5.33 (m, 1H), 4.21 (q, J = 16.4 Hz, 1H), 3.89 (s, 1H), 3.88 (d, J = 10.4 Hz, 3H), 3.72 (ddd, J = 26.0, 17.5, 9.2 Hz, 2H), 3.55 (s, 3H), 3.47-3.38 (m, 1H), 3.31 (dd, J = 18.0, 9.5 Hz) , 2H), 3.18 (s, 3H), 2.86 (s, 3H), 1.88 (s, 3H), 1.83 (s, 3H), 1.75-1.64 (m, 3H), 1.57-1.48 (m, 1H).

Example 13

(R)-N-(2-hydroxyethoxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidine-3 (4H )-yl)-2-methylpropionamide

first step

(R)-N-(2-hydroxyethoxy)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy) Ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidine-3 (4H )-yl)-2-methylpropionamide

(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-) 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2 -Methylpropionic acid 3c (45 mg, 0.079 mmol), 2-(aminooxy)ethanol hydrochloride 13a (30 mg, 0.40 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride ( 60 mg, 0.24 mmol) and N,N-diisopropylethylamine (70 μL, 0.40 mmol) were dissolved in 1.5 mL of tetrahydrofuran and reacted at 30 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to silica crystals (yield: B system) to give (R)-N-(2-hydroxyethoxy)-2-(1-(2-() 2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2, 4-Dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanamide 13 (5.0 mg, white solid) 10%.

MS m/z (ESI): 651.8 [M+23]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.40 (s, 1H), 7.71 (d, J = 5.8Hz, 1H), 7.60-7.51 (m, 1H), 7.22 (s, 1H), 7.08-6.98 ( m,1H), 6.87 (d, J = 6.4 Hz, 1H), 5.37 (dt, J = 12.0, 6.4 Hz, 1H), 4.36-4.26 (m, 1H), 4.22-4.11 (m, 1H), 4.04 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.82-3.77 (m, 2H), 3.77-3.66 (m, 2H), 3.44 (s, 1H), 3.35 (s, 2H), 2.84(s,3H), 1.87(s,3H),1.82(s,3H),1.75-1.69(m,2H),1.60-1.52(m,2H).

Biological evaluation

Test Example 1. Determination of IC ₅₀ of inhibition of enzymatic activity of ACC1 and ACC2 by the compound of the present invention

The following method was used to determine the degree of inhibition of the enzymatic activity of recombinant human ACC1, ACC2 protein by the preferred compounds of the invention under in vitro conditions.

The principle of the method is based on the reaction of AMC-catalyzed acetyl-CoA to form malonyl-CoA. ATP is consumed during this reaction and ADP is produced. The resulting reaction can be reconverted to ADP by the kinase using ADP-Glo ^TM kit from Promega (Promega) to ATP, which may be part of the kit in the ATP luciferase - luciferin reaction, and generates a chemical Illuminated signal. Therefore, by measuring the intensity of the chemiluminescent signal, the amount of ADP produced in the catalytic reaction can be reflected, thereby indirectly determining the enzymatic activity of the ACC protein and the effect of the test compound on the enzyme activity. The main reagents used were: ACC1, ACC2 protein (purchased from BPS bioscience, ACC1 Cat. No. 50200, ACC2 Cat. No. 50201), Acetyl CoA (acetyl-CoA, purchased from Sigma, Cat. No. A2056), NaHCO3 (purchased from Sigma, Cat. No. S6014). ), ADP-Glo ^TM Kinase assay kit (purchased from Promega, Cat. No. V9102).

The test procedure is briefly described as follows: First, the 1x buffer required for the reaction was prepared, and its composition was as follows: 50 mM HEPES (pH 7.4 purchased from Invitrogen, Cat. No. 15630), 2 mM magnesium chloride (MgCl ₂ , purchased from Sigma, article number M1028), 2 mM lemon Potassium citrate (purchased from Sigma, Cat. No. 89306), 0.01% Brij-35 detergent (available from Merck, Cat. No. 203728), 2 mM DTT (purchased from Sigma, Cat. No. D0632). The test compound powder was dissolved in DMSO to prepare a stock solution having a concentration of 10 mM, and then subjected to a 3-fold dilution to prepare a concentration required for the test, and each compound was set at 10 concentration points in a concentration range of 10 μM to 0.5 nM. First, add appropriate amount of ACC protein (2nM) to the 384-well microplate, and then add diluted test compound solutions to each well. Each concentration is provided with a duplicate well control and a solvent control (blank group) ), negative control group (DMSO group). The 384-well plates were then shaken on a microplate shaker and incubated for 15 minutes at room temperature. Thereafter, a mixture of substrates containing ATP, acetyl-CoA and NaHCO3 diluted with the aforementioned buffer was added to each well to start the reaction, and the final concentrations of the three components were ATP 20 μM, acetyl-CoA 10 μM, and NaHCO ₃ 30 mM, respectively. After the reaction at room temperature for 30 minutes in accordance with the ADP-Glo ^TM Kinase assay kit instructions in the kit, the reaction solution was added to each well and the liquid corresponding to the detection (refer to the specific method of operation instructions of the kit), and finally the Envision 2104 Relative light unit (RLU) values for each well were determined on a multi-plate reader (Perkin Elmer). The percent inhibition of a compound's inhibition of ACC enzyme activity at a concentration is calculated by the following formula:

Inhibition rate % = [(negative control well RLU mean - blank well RLU average) - (test well RLU mean - blank well RLU mean)] / (negative control well RLU mean - blank well RLU mean) * 100

Finally, a non-linear regression analysis was performed on the logarithm of the concentration of the compound and the percent inhibition of the corresponding concentration in the GraphPad Prism 5 software to obtain the half-inhibitory concentration value (IC ₅₀ ) of the compound.

Table 1 IC ₅₀ data for inhibition of ACC1 and ACC2 enzyme activities by the compounds of the present invention

Example number	IC 50 (nM)/ACC1	IC 50 (nM)/ACC2
1	0.75	ND
2	0.91	ND
3	0.72	1.6
4	1.15	ND
5	1.66	ND
6	2.05	ND
7	2.03	ND
8	0.26	ND
9	1.03	ND
10	0.30	ND
11	0.22	1.6
12	1.76	ND
13	0.83	1.7

Note: ND means not measured.

Conclusion: The compounds of the present invention have a good inhibitory effect on ACC1 and ACC2.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (18)

1. a compound of formula (I):

   

   Including or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

   among them:

   X is selected from -NH-, -O- or -S-; preferably -S-;

   L ^{1 is} selected from an alkylene group, a cycloalkylene group or a heterocyclic group;

   R ^{1 is} selected from a hydrogen atom, an alkyl group or a halogen, wherein the alkyl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclic, Aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O)R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , Substituted by a substituent of -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

   R ² is -C(O)NR ^a R ^b ;

   R ^a is selected from a hydrogen atom or an alkyl group;

   R ^{b is} selected from cyano or -OR ⁷ ;

   R ^{3 is} selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted with one or more substituents selected from R ⁸ ;

   R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, -OR ¹¹ , -SR ¹¹ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC (O) R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

   Alternatively, R ⁴ and R ⁵ together with the atom to which they are attached form a 3 to 8 membered saturated or partially unsaturated cycloalkyl group, or form a hetero atom having one or more selected from N, O, S(O) _n a 4 to 8 membered saturated or partially unsaturated heterocyclic group, wherein said cycloalkyl or heterocyclic group is further optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, and an alkoxy group. , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O)R ¹¹ , -S Substituting (O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

   R ^{6 is} selected from the group consisting of halogen, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O) R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ , preferably a heteroaryl group;

   Alternatively, R ¹ and R ⁶ together with the atom to which they are attached form a 3 to 8 membered saturated or partially unsaturated cycloalkyl group, or form a hetero atom having one or more selected from N, O, S(O) _n . a 4 to 8 membered saturated or partially unsaturated heterocyclic group, or a 5 to 10 membered aryl or heteroaryl group, wherein said cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further subjected to one or A plurality selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ^{10, -C (O) R 11} , -OC (O) R 11, -S (O) n NR 9 R 10, -C (O) oR 11 or -NR ⁹ C (O) R ¹⁰ substituents Replace

   R ^{7 is} selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optional Further one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹² R ¹³ , -C(O Substituting a substituent of NR ¹² R ¹³ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ or -NR ¹² C(O)R ¹³ ;

   R ^{8 is} each independently selected from hydroxy, alkyl, halo, cyano, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O) NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -OC(O)R ¹¹ , -S(O) _n NR ⁹ R ¹⁰ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

   R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹² R ^{13, -C (O) NR 12} R 13, -C (O) R 14, -C (O) oR 14 or -NR ¹² C (O) R ^13, substituted with a substituent;

   Alternatively, R ⁹ and R ¹⁰ together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S(O) _n atoms. And the 4-8-membered heterocyclic ring is further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =0. Substituting a substituent of -NR ¹² R ¹³ , -C(O)NR ¹² R ¹³ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ or -NR ¹² C(O)R ¹³ ;

   R ¹² , R ¹³ and R ¹⁴ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxy Substituted by a substituent of the acid ester;

   n is 0, 1, or 2.
2. The compound of claim 1 having the structure of formula (II):

   

   among them:

   m is 1, 2, 3, 4 or 5;

   The definitions of L ¹ , R ¹ , R ² , R ⁶ , R ⁸ and R ¹¹ are as set forth in claim 1.
3. A compound according to claim 2 having the structure of formula (III):

   

   among them:

   m is 1, 2, 3, 4 or 5;

   The definitions of L ¹ , R ¹ , R ² , R ⁶ , R ⁸ and R ¹¹ are as set forth in claim 1.
4. A compound according to claim 2 having the structure of formula (IV):

   

   among them:

   m is 1, 2, 3, 4 or 5;

   The definitions of L ¹ , R ¹ , R ² , R ⁶ , R ⁸ and R ¹¹ are as set forth in claim 1.
5. The compound according to any one of claims 1 to 4, wherein R ^{1 is} selected from methyl or trifluoromethyl.
6. The compound according to any one of claims 1 to 5, wherein:

   R ² is -C(O)NR ^a R ^b ;

   R ^{a is} selected from a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a hydrogen atom or a methyl group;

   The definition of R ^b is as set forth in claim 1.
7. The compound according to any one of claims 1 to 6, wherein:

   R ² is -C(O)NR ^a R ^b ;

   R ^{b is} selected from cyano or -OR ⁷ , and R ⁷ is alkyl, wherein the alkyl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, cycloalkyl, phenyl;

   The definition of ^Ra is as set forth in claim 1.
8. The compound according to claim 7, wherein R ⁷ is a C ₁ -C ₆ alkyl group, wherein said C ₁ -C ₆ alkyl group is further further selected from one or more selected from the group consisting of a hydroxyl group, a cyclopropyl group, and a phenyl group. Substituted by a substituent.
9. The compound according to any one of claims 1 to 8, wherein R ^{6 is} selected from the group consisting of halogen, -C(O)R ¹¹ , -C(O)NR ⁹ R ¹⁰ or oxazolyl, wherein R ⁹ , R ¹⁰ and The definition of R ¹¹ is as set forth in claim 1.
10. The compound according to any one of claims 1 to 9, wherein L ₁ is:

    
11. The compound according to any one of claims 1 to 10, wherein R ^{8 is} selected from methoxy or halogen.
12. The compound according to any one of claims 1 to 11, wherein R ¹¹ is a tetrahydropyranyl group.
13. The compound of claim 1 wherein said compound is selected from the group consisting of:

    
14. A method of preparing a compound of formula (I) according to claim 1, the method comprising:

    

    Reaction of ^a compound of formula (IA) with NHR ^a R ^b or a salt thereof to provide a compound of formula (I);

    Wherein: X, L ¹ , R ^a , R ^b , R ¹ to R ⁶ are as defined in claim 1.
15. A pharmaceutical composition comprising an effective amount of a compound of formula (I) according to any one of claims 1 to 13, and optionally a pharmaceutically acceptable carrier, excipient or combination thereof.
16. Use of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 for the preparation of a medicament for use as an ACC inhibitor.
17. Use of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 for the preparation of a medicament for preventing or treating a disease or condition associated with ACC, or The condition is preferably a metabolic disease, a cancer, and a fungal, parasitic or bacterial infection; wherein the metabolic disease is preferably hepatic steatosis, nonalcoholic fatty liver, obesity, dyslipidemia, hyperlipidemia, type II diabetes Or metabolic syndrome, wherein the obesity is preferably Prader-Willi syndrome, Bardet-Biedl syndrome or Cohen syndrome or MOMO syndrome, wherein the cancer is preferably hepatocellular carcinoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colorectal cancer, head and neck cancer, melanoma, ovarian cancer or cervical cancer, more preferably hepatocellular carcinoma and Non-small cell lung cancer.
18. A method of preventing or treating a disease or condition associated with ACC, comprising administering a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 to a subject in need thereof.