CN115141215B

CN115141215B - KRAS G12D protein inhibitors and uses thereof

Info

Publication number: CN115141215B
Application number: CN202210358421.6A
Authority: CN
Inventors: 王剑; 杨飞飞; 王星星; 侯冰; 宇文辉; 陈朋; 石钟阳; 单波; 梅建明
Original assignee: Shanghai Deqi Pharmaceutical Technology Co ltd
Current assignee: Shanghai Deqi Pharmaceutical Technology Co ltd
Priority date: 2021-03-30
Filing date: 2022-03-30
Publication date: 2023-09-15
Anticipated expiration: 2042-03-30
Also published as: CN115141215A; CN117659051A

Abstract

The present disclosure relates to novel compounds useful as KRAS protein inhibitors, pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Description

KRAS G12D protein inhibitors and uses thereof

Technical Field

The present disclosure relates generally to novel compounds useful as KRAS protein inhibitors and pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Background

KRAS oncoprotein is a gtpase and is an essential mediator of intracellular signaling pathways involved in tumor cell growth and survival. In normal cells, KRAS acts as a molecular switch alternating between an inactive GDP-binding state and an active GTP-binding state. The transition between these states is facilitated by the guanosine nucleotide exchange factor that loads the GTP and activates KRAS and by the GTP hydrolysis catalyzed by the gtpase activator protein to inactivate KRAS. The binding of GTP to KRAS promotes the binding of effectors to trigger signaling pathways including the RAF-MEK-ERK (MAPK) pathway.

Activating mutations in KRAS are a hallmark of cancer and prevent the association of gtpase activator proteins, thereby stabilizing effector binding and enhancing KRAS signaling. KRAS G12D is present in approximately 36% pancreatic cancer, 12% colorectal cancer, 6% endometrial cancer, and 4% NSCLC. Thus, KRAS, particularly KRAS G12D, are widely recognized as very important oncologic targets.

Although progress has been made in targeting KRAS G12D, targeting this gene with small molecules remains a challenge. Accordingly, there is a need in the art to develop improved small molecule compounds that inhibit KRAS, particularly KRAS G12D.

Disclosure of Invention

The present disclosure provides compounds, pharmaceutically acceptable salts, stereoisomers, tautomers and prodrugs thereof, capable of modulating KRAS G12D protein. Methods of using such compounds for treating various diseases or conditions, such as cancer, are also provided.

In one aspect, the present disclosure provides a compound having formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

V ¹ Is N or CH;

ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

L ² Selected from the group consisting of: bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;

R ¹ selected from the group consisting of: alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more R ^b Substitution;

R ² selected from the group consisting of saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroarylOptionally substituted with one or more groups independently selected from the group consisting of: cyano, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, -S (R) ^a )、-NR ^c R ^d Carboxyl, carbamoyl, aryl and heteroaryl;

R ³ is hydrogen, hydroxy, halogen, C _1-3 Alkyl, C _1-3 Cyanoalkyl, C _1-3 Hydroxyalkyl, -C (O) H, -C (O) OR ^a 、 -C(O)N(R ^d )(R ^e ) Or a 5-6 membered heteroaryl;

R ^a is hydrogen or alkyl;

each R ^b Independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR ^d R ^e 、 -OC(O)NR ^d R ^e Carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

each R ^c Independently selected from the group consisting of: oxo, halogen, cyano, hydroxy, -NR ^d R ^e 、-C(O)OR ^a 、 -C(O)N(R ^d )(R ^e ) Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl;

Each Rd is independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from cyano, halo, hydroxy, or amino; and is also provided with

R ^e Independently hydrogen or C _1-3 An alkyl group.

In another aspect, the present disclosure provides a compound having formula (II):

wherein the method comprises the steps of

V ² Is N or C (R) ⁵ )；

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ² selected from the group consisting of saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with cyano, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, -S (R ^a )、-NR ^c R ^d A carboxyl, carbamoyl, aryl or heteroaryl substitution;

R ⁴ 、R ⁵ and R is ⁶ Each independently is hydrogen, hydroxy, halogen, or trifluoromethyl;

R ^a is hydrogen or alkyl;

each R ^b Independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR ^d R ^e 、 -OC(O)NR ^d R ^e Carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy,Alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

each R ^d Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, or amino; and is also provided with

R ^e Independently hydrogen or C _1-3 An alkyl group.

In another aspect, the present disclosure provides a compound having formula (III):

wherein the method comprises the steps of

V ³ Is N or C (R) ⁴ )；

V ⁴ Is N or C (R) ⁷ )；

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ¹ selected from the group consisting of: alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, arylEach of the radicals, heteroaryl is optionally substituted with one or more R ^b Substitution;

R ⁷ hydrogen, hydroxy, halogen, cyano or trifluoromethyl;

R ^a is hydrogen or alkyl;

each R ^d Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroarylEach of alkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, or amino; and is also provided with

R ^e Independently hydrogen or C _1-3 An alkyl group.

In another aspect, the present disclosure provides a compound having formula (Ia) or formula (Ib), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

L ¹ Is a bond, O, S or N (R ^a )；

R ^a is hydrogen or alkyl;

each R ^b Independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR ^d R ^e 、 -OC(O)NR ^d R ^e Carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^e Independently hydrogen or C _1-3 An alkyl group.

In another aspect, the present disclosure provides a compound having formula (IIa) or formula (IIb), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

Wherein the method comprises the steps of

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ¹ selected from the group consisting of: alkyl group,Alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more R ^b Substitution;

R ⁴ hydrogen, hydroxy or halogen;

R ⁵ hydrogen, hydroxy or halogen;

R ^a is hydrogen or alkyl;

each R ^d Independently selected from the group consisting of: hydrogen, alkylA group, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, or amino; and is also provided with

R ^e Independently hydrogen or C _1-3 An alkyl group.

In another aspect, the present disclosure provides a compound having formula (IIIa) or formula (IIIb) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ⁴ hydrogen, hydroxy or halogen;

R ⁵ hydrogen, hydroxy or halogen;

R ⁷ hydrogen, hydroxy, halogen, cyano or trifluoromethyl;

R ^a is hydrogen or alkyl;

R ^e Independently hydrogen or C _1-3 An alkyl group.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present disclosure provides a method for treating cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising:

(a) Determining that the cancer is associated with a KRAS G12D mutation; and

(b) Administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

In yet another aspect, the present disclosure provides a method for modulating the activity of a KRAS G12D mutein comprising reacting the KRAS G12D mutein with a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

In yet another aspect, the present disclosure provides a method for preparing a labeled KRAS G12D mutein comprising reacting the KRAS G12D mutein with a compound of the present disclosure or a pharmaceutically acceptable salt thereof to produce the labeled KRAS G12D mutein.

In another aspect, the present disclosure provides a method of treating cancer comprising administering to a subject in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides a method of inhibiting tumor metastasis comprising administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating cancer.

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in inhibiting tumor metastasis.

Detailed Description

Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying drawings. While the disclosure will be described in conjunction with the enumerated embodiments, it will be understood that the embodiments are not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present disclosure as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event of a departure or conflict between one or more of the incorporated references and similar materials (including but not limited to the defined terms, term usage, described techniques, etc.) and the present application, the present disclosure controls. All references, patents, patent applications cited in this disclosure are hereby incorporated by reference in their entirety.

It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

Definition of the definition

The definition of specific functional groups and chemical terms is described in more detail below. For purposes of this disclosure, chemical elements are identified according to the periodic Table of elements (Periodic Table of the Elements), CAS version, handbook of physics and chemistry (Handbook of Chemistry and Physics), 75 th edition, inner cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivities are described in the following references: organic chemistry (Organic Chemistry), thomas Sorrell, 2 nd edition, university science book press (University Science Books), assailitot, 2006; smith and March, mach's Advanced Organic Chemistry, 6 th edition, john wili father company (John Wiley & Sons, inc.), new york, 2007; larock, integrated organic transformation (Comprehensive Organic Transformations), 3 rd edition, VCH Press (VCH Publishers, inc.), new York, 2018; carrutthers, some modern methods of organic synthesis (Some Modern Methods of Organic Synthesis), 4 th edition, university of cambridge press (Cambridge University Press), cambridge, 2004; the entire contents of each of the references are incorporated herein by reference.

Throughout this disclosure, linking substituents are described. It is particularly desirable that each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR (CR 'R') -includes both-NR (CR 'R') -and- (CR 'R') NR-. In the case where a linking group is explicitly required for a structure, the Markush variable (Markush variable) listed for the group is understood to be the linking group. For example, if the structure requires a linking group and the markush group definition of the variables lists "alkyl", it is understood that "alkyl" means a linking alkylene.

Where a bond to a substituent is shown to intersect a bond connecting two atoms in a ring, the substituent may be bonded to any atom in the ring. Where a substituent is listed, but it is not specified through which atom the substituent is bonded to the remainder of a given formula compound, the substituent may be bonded through any atom in the formula. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

In any variable (e.g., R ⁱ ) When a compound occurs more than one time in any component or formula, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a display group is substituted with 0 to 2R ⁱ Partially substituted, said groups may optionally be substituted with up to two R ⁱ Partially substituted, and R ⁱ Independently at each occurrence selected from R ⁱ Is defined in (a). Moreover, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, the term "C _i-j "indicates a range of the number of carbon atoms, where i and j are integers, and the range of the number of carbon atoms includes the endpoints (i.e., i and j) and each integer point therebetween, and where j is greater than i. For example, C _1-6 A range of one to six carbon atoms is indicated, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C _1-12 "indicates 1 to 12 carbon atoms, in particular 1 to 10 carbon atoms, in particular 1 to 8 carbon atoms, in particular 1 to 6 carbon atoms, in particular 1 to 5 carbon atoms, in particular 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms or in particular 1 to 2 carbon atoms.

As used herein, the term "acyl" refers to-C (=o) -R, wherein R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein.

As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain hydrocarbon group that may optionally be independently substituted with one or more substituents described below. The term "C _i-j Alkyl "refers to an alkyl group having i to i carbon atoms. In some embodiments, the alkyl groups contain 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C _1-10 Examples of alkyl "include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C _1-6 Examples of alkyl "are methyl, ethyl,Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, and the like.

As used herein, the term "alkenyl", whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond that may be optionally independently substituted with one or more substituents described herein and includes groups having a "cis" orientation and a "trans" orientation or alternatively an "E" orientation and a "Z" orientation. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (ethylene or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

As used herein, the term "alkynyl", whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond that may be optionally independently substituted with one or more substituents described herein. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

As used herein, the term "alkoxy", whether used as part of another term or independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. The term "C _i-j Alkoxy "means that the alkyl portion of the alkoxy group has from i to i carbon atoms. In some embodiments, the alkoxy groups contain 1 to 10 carbon atoms. In some embodiments, the alkoxy groups contain 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C _1-6 Examples of alkoxy groups "include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, neopentyloxy, n-hexyloxy, and the like.

As used herein, the term "alkoxyalkyl" refers to a group of formula-R "OR ', wherein R' and R" are independently alkyl as defined above.

As used herein, the term "amino" refers to-NH ₂ A group. The amino group may also be substituted with one or more groups such as alkyl, aryl, carbonyl, or other amino groups.

As used herein, the term "aryl", whether used as part of another term or independently, refers to mono-and polycyclic ring systems having a total of from 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains from 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes groups in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic system, only one ring need be aromatic (e.g., 2, 3-indoline), but all rings may be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, tetrahydronaphthyl, and the like. Aryl groups may be substituted at one or more ring positions with substituents as described above.

As used herein, the term "carbamoyl" refers to-C (O) NH ₂ 。

As used herein, the term "carboxy" refers to-COOH.

As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups as defined above.

As used herein, the term "cycloalkyl", whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic systems wherein all ring atoms are carbon and the system contains at least three ring-forming carbon atoms. In some embodiments, cycloalkyl groups may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, cycloalkyl groups may be saturated cyclic alkyl groups. In some embodiments, cycloalkyl groups may be partially unsaturated cyclic alkyl groups containing at least one double or triple bond in their ring system. In some embodiments, cycloalkyl groups may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decyl, bicyclo [1, 1] pentenyl, bicyclo [2, 1] heptenyl, and the like.

As used herein, the term "cycloalkylalkyl" refers to a radical of formula-R 'R ", wherein R' is alkyl as defined above, and R" is cycloalkyl as defined above.

As used herein, the term "cyano" refers to-CN.

As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromoo), and iodine (or iodoo).

As used herein, the term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl and the like.

As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur as well as any quaternized form of basic nitrogen (including N-oxides).

As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl groups may be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes polycyclic groups in which the heteroaryl ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein the linking group or point of attachment is on the heteroaryl ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1,3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclic group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen or sulfur and any quaternized form of basic nitrogen. "heterocyclyl" also includes groups in which the heterocyclyl is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclic group may be carbon-linked or nitrogen-linked, where possible. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, the groups derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Furthermore, the group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked).

In some embodiments, the term "3-to 12-membered heterocyclyl" refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1-dioxothietanylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinonyl, pyrazinonyl, pyrimidinonyl, pyridazinonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl condensed rings or pyridyl condensed rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chroenyl, isochroenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1,2-a ] pyridinyl, [1,2,4] triazolo [4,3-a ] pyridinyl, [1,2,3] triazolo [4,3-a ] pyridinyl, and the like. Examples of spiroheterocyclyl groups include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of bridged heterocyclyl groups include, but are not limited to, morphinan, hexamethylenetetramine, 3-aza-bicyclo [3.1.0] hexane, 8-aza-bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO), and the like.

As used herein, the term "hydroxyl" refers to-OH.

As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxyl groups.

As used herein, the term "oxo" refers to an =o substituent.

As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

As used herein, the term "substituted", whether preceded by the term "optional", means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It is to be understood that "substitution" or "substituted" includes implicit preconditions that such substitution is consistent with the permissible valences of the substituted atoms, and that the substitution results in stable or chemically feasible compounds, e.g., compounds that do not spontaneously undergo transformations such as rearrangement, cyclization, elimination, and the like. Unless otherwise indicated, an "optionally substituted" group may have the appropriate substituent at each substitutable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. It will be appreciated by those skilled in the art that the substituents themselves may be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are to be understood as including substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

Compounds of formula (I)

The present disclosure provides novel compounds of formula (I), formula (II) or formula (III), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and various uses of the disclosed compounds.

wherein the method comprises the steps of

V ¹ Is N or CH;

ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ² a member selected from the group consisting of saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of: cyano, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, -S (R) ^a )、-NR ^c R ^d Carboxyl, carbamoyl, aryl and heteroaryl;

R ³ is hydrogen, hydroxy, halogen, C _1-3 Alkyl, C _1-3 Cyanoalkyl, C _1-3 Hydroxyalkyl, -C (O) H, -C (O) OR ^a 、-C(O)N(R ^d )(R ^e ) Or a 5-6 membered heteroaryl;

R ^a is hydrogen or alkyl;

each R ^d Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from cyano, halo, hydroxy, or amino; and is also provided with

R ^e Independently hydrogen or C _1-3 An alkyl group.

wherein the method comprises the steps of

V ² Is N or C (R) ⁵ )；

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ^a is hydrogen or alkyl;

R ^e Independently hydrogen or C _1-3 An alkyl group.

Wherein the method comprises the steps of

V ³ Is N or C (R) ⁴ )；

V ⁴ Is N or C (R) ⁷ )；

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ¹ selected from the group consisting ofGroup: alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more R ^b Substitution;

R ⁷ hydrogen, hydroxy, halogen, cyano or trifluoromethyl;

R ^a Is hydrogen or alkyl;

R ^e Independently hydrogen or C _1-3 An alkyl group.

In some embodiments, ring a is a 6-10 membered heterocyclyl.

In certain embodiments, ring a is selected from the group consisting of:

in some embodiments, L ¹ Is O.

In some embodiments, L ² Is alkyl.

In some embodiments, R ¹ To optionally be covered by one or more R ^b Substituted heterocyclyl groups.

In certain embodiments, R ¹ To optionally be covered by one or more R ^b SubstitutedIn certain embodiments, each R ^b Independently halogen, alkoxy or-OC (O) NR ^d R ^e 。

In some embodiments, R ¹ Is covered by one R ^b SubstitutedIn certain embodiments, R ^b Is halogen. In certain embodiments, R ^b Is fluorine. In certain embodiments, R ^b Is an alkoxy group. In certain embodiments, R ^b Is C _1-3 An alkoxy group. In certain embodiments, R ^b Is methoxy. In certain embodiments, R ^b is-OC (O) NR ^d R ^e Wherein R is ^d And R is ^e Each independently of the otherIs alkyl.

In some embodiments, R ² Aryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxy, alkyl, alkenyl, or alkynyl.

In certain embodiments, R ² Naphthyl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxy, alkyl, alkenyl, or alkynyl.

In some embodiments, R ³ Is hydrogen.

In some embodiments, R ⁴ Is hydrogen or halogen. In certain embodiments, R ⁴ Hydrogen, fluorine or chlorine.

In some embodiments, R ⁵ Is hydrogen or halogen. In certain embodiments, R ⁵ Hydrogen, fluorine or chlorine.

In some embodiments, R ⁶ Is hydrogen or halogen.

In some embodiments, R ⁷ Hydrogen, cyano or halogen.

wherein the method comprises the steps of

L ¹ Is a bond, O, S or N (R ^a )；

R ² selected from saturatedOr a partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with cyano, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, -S (R ^a )、-NR ^e R ^d A carboxyl, carbamoyl, aryl or heteroaryl substitution;

R ^a is hydrogen or alkyl;

each R ^b Independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR ^d R ^e 、-OC(O)NR ^d R ^e Carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^e Independently hydrogen or C _1-3 An alkyl group.

Wherein the method comprises the steps of

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ⁴ hydrogen, hydroxy or halogen;

R ⁵ hydrogen, hydroxy or halogen;

R ^a is hydrogen or alkyl;

each R ^b Independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR ^d R ^e 、 -OC(O)NR ^d R ^e Carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, and alkaneOxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^e Independently hydrogen or C _1-3 An alkyl group.

wherein the method comprises the steps of

Ring A is heterocyclyl;

L ¹ is a bond, O, S or N (R ^a )；

R ² selected from saturation orA partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with cyano, halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, -S (R ^a )、-NR ^c R ^d A carboxyl, carbamoyl, aryl or heteroaryl substitution;

R ⁴ hydrogen, hydroxy or halogen;

R ⁵ hydrogen, hydroxy or halogen;

R ⁷ hydrogen, hydroxy, halogen, cyano or trifluoromethyl;

R ^a is hydrogen or alkyl;

R ^e Independently hydrogen or C _1-3 An alkyl group.

In some embodiments, the present disclosure provides a compound having the formula selected from the group consisting of:

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the compounds provided herein are described with reference to the general formula and specific compounds. Furthermore, the compounds of the present disclosure may exist in a variety of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites) and pharmaceutically acceptable salts thereof, all of which are within the scope of the present disclosure.

As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that upon metabolism under physiological conditions or conversion by solvolysis yields the desired active compound. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates or hydrates of the active compounds. Typically, prodrugs are inactive or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolic breakdown, the ester groups are cleaved to yield the active drug. In addition, some prodrugs are enzymatically activated to produce the active compound or compounds that produce the active compound upon further chemical reaction. The prodrug may be developed from a prodrug form to an active form in a single step, or may have one or more intermediate forms that may or may not be active themselves. The preparation and use of prodrugs is discussed in the following references: higuchi and v.stilla, "Pro-drug as novel delivery system (Pro-drugs as Novel Delivery Systems)", volume 14 of the a.c.s. seminar Series (a.c. Symposium Series), bioreversible carrier in drug design (Bioreversible Carriers in Drug Design), editors Edward b.roche, american pharmaceutical society (American Pharmaceutical Association) and pegamon Press, 1987. Prodrug: challenge and return (Prodrugs: challenges and Rewards), editorial V.Stella, R.Borchardt, M.Hageman, R.Oliyai, H.Maag, J.Tilley, new York Springs Press (Springer Verlag New York), 2007, all of which are hereby incorporated by reference in their entirety.

As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but breaks down into inactive metabolite degradants such that the activity time is limited. See, for example, soft medicine: principles and methods of safe drug design (Soft drugs: principles and methods for the design of safe drugs), nicholas Bodor, drug research review (Medicinal Research Reviews), volume 4, 4 th edition, 449-469, 1984, which references are hereby incorporated by reference in their entirety.

As used herein, the term "metabolite", e.g., an active metabolite, overlaps with the prodrug as described above. Such metabolites are therefore pharmacologically active compounds, or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in the subject. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Wherein the active metabolite is such a pharmacologically active derivative compound. For prodrugs, the prodrug compounds are generally inactive or less active than the metabolite. For active metabolites, the parent compound may be an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using conventional techniques known in the art. See, for example, bertolini et al, 1997, journal of pharmaceutical chemistry (J Med Chem) 40:2011-2016; shan et al, J pharmaceutical science journal (J Pharm Sci) 86:756-757; bagshawe,1995, drug Dev Res 34:220-230; wermuth, supra.

As used herein, the term "pharmaceutically acceptable" means that the substance or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the subject being treated.

As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the indicated compounds and are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, di-, tri-, tetra-salts, and the like. The pharmaceutically acceptable salts are non-toxic in the amount and concentration in which they are administered. The preparation of such salts may facilitate pharmacological use by altering the physical properties of the compound without impeding its performance in terms of its physiology. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administration of higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts, such as those containing: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinic acid salts. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid.

When an acidic functional group such as carboxylic acid or phenol is present, pharmaceutically acceptable salts also include base addition salts, such as those containing: benzathine (benzathine), chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines and zinc. See, for example, remington's pharmaceutical complete book (Remington's Pharmaceutical Sciences), 19 th edition, mark Publishing company (Mack Publishing co.), iston, pennsylvania, volume 2, page 1457, 1995; manual of pharmaceutical salts: properties, selection and Use (Handbook of Pharmaceutical Salts: properties, selection, and Use, stahl and Wermuth, wiley-VCH Press (Wiley-VCH), wei Yinhai m, germany, 2002. Such salts may be prepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound may be dissolved in a suitable solvent (e.g., an aqueous or hydro-alcoholic solution containing a suitable acid) and then isolated by evaporation of the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosyl acid such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, and the like.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids (e.g., L-glycine, L-lysine, and L-arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (e.g., hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine); and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

It is also to be understood that the compounds of the present disclosure may exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polycrystalline forms), and that the present disclosure is intended to cover all such forms.

As used herein, the term "solvate" or "solvated form" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, forming solvates. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alkoxide. The hydrate is produced by maintaining one or more water molecules with water as H ₂ One molecule of the substance in the molecular state of O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the terms "crystalline form," "polymorphic form," and "polymorph" are used interchangeably and refer to a crystalline structure of a compound (or a salt or solvate thereof) that can crystallize in a different crystal packing arrangement, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may dominate one crystal form. Polymorphs of a compound can be prepared by crystallization under different conditions.

The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise indicated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure are intended to also include isotopes thereof, such as, but not limited to ¹ H、 ² H、 ³ H、 ¹¹ C、 ¹² C、 ¹³ C、 ¹⁴ C、 ¹⁴ N、 ¹⁵ N、 ¹⁶ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³² S、 ³³ S、 ³⁴ S、 ³⁶ S、 ¹⁷ F、 ¹⁸ F、 ¹⁹ F、 ³⁵ Cl、 ³⁷ Cl、 ⁷⁹ Br、 ⁸¹ Br、 ¹²⁴ I、 ¹²⁷ I and ¹³¹ I. in some embodiments, the hydrogen includes protium, deuterium, and tritium. In some embodiments, the carbon comprises ¹² C and C ¹³ C。

Those skilled in the art will appreciate that the compounds of the present disclosure may exist in different tautomeric forms, and that all such forms are contemplated as falling within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be converted to each other by a low energy barrier. The existence and concentration of the isomeric forms will depend on the environment in which the compound is located and may vary depending, for example, on whether the compound is solid or in an organic or aqueous solution. For example, proton tautomers (also known as proton-metamorphosing tautomers) include interconversions by proton transfer, such as keto-enol, amide-imide, lactam-lactam, imine-enamine isomerisation, and cyclic forms where a proton may occupy two or more positions of a heterocyclic ring system. Valence tautomers include interconversions by recombination of some of the bond-forming electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Unless otherwise indicated, compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms.

Synthesis of Compounds

The compounds provided herein may be prepared using any known organic synthesis technique and may be synthesized according to any of a number of possible synthetic routes.

The reactions for preparing the compounds of the present disclosure may be carried out in suitable solvents that may be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, a temperature which may range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, the appropriate solvent for the particular reaction step may be selected by one skilled in the art.

The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in the following references: T.W.Greene and P.GM.Wuts, protecting group in organic Synthesis (Protective Groups in Organic Synthesis), 3 rd edition, john Willi parent, new York (1999); P.Kocienski, protecting group (Protecting Groups), george Tami Press (Georg Thieme Verlag), 2003; and Peter g.m. wuts, greene's Protective Groups in Organic Synthesis, 5 th edition, wiley,2014, all of which are incorporated herein by reference in their entirety.

Can be according to any combination known in the artThe reaction is monitored by a suitable method. For example, the radiation may be detected by, for example, nuclear magnetic resonance spectroscopy (e.g., ¹ h or ¹³ C) The product formation is monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or Thin Layer Chromatography (TLC). The compounds can be purified by a variety of methods including High Performance Liquid Chromatography (HPLC) ("preparative LC-MS purification: improved compound specific methods optimize" Karl F. Blom, brian Glass, richard Sparks, andrew P. Combos. J. Combined chemistry J. Combi. Chem.) "2004,6 (6), 874-883, incorporated herein by reference in its entirety) and normal phase silica gel chromatography.

Use of compounds

In one aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, capable of inhibiting KRAS proteins, particularly KRAS G12D proteins.

As used herein, the term "therapy" is intended to have its normal meaning, i.e., treating a disease so as to completely or partially alleviate one, some or all of its symptoms, or correct or compensate for an underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization of disease state (i.e., not worsening), delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "therapy" may also mean an increase in survival compared to the expected survival in the absence of receiving therapy. The condition requiring therapy includes a condition that has suffered from a condition or disorder, a condition that is susceptible to suffering from a condition or disorder, or a condition that is to be prevented from a condition or disorder. The term "therapy" also encompasses prophylaxis unless there is a specific indication to the contrary. The terms "treatment" and "therapeutically" should be interpreted in a corresponding manner.

As used herein, the term "prevention" is intended to have its normal meaning and includes primary prevention for preventing the development of a disease and secondary prevention in which the disease has progressed and the patient is temporarily or permanently protected from exacerbation or worsening of the disease or suffering from new symptoms associated with the disease.

The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" may be regarded as "application of therapy", wherein "therapy" is as defined herein.

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in therapy, e.g., for use in a therapy related to KRAS protein.

In some embodiments, the cancer is mediated by KRAS proteins. In some embodiments, the cancer is mediated by a KRAS-G12D mutein.

Pharmaceutical composition

In another aspect, a pharmaceutical composition is provided comprising one or more molecules or compounds of the present disclosure or a pharmaceutically acceptable salt thereof.

In another aspect, a pharmaceutical composition is provided comprising one or more molecules or compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the present disclosure in a form suitable for administration to a subject.

As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used herein, "pharmaceutically acceptable excipients" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent".

The particular excipients used will depend on the means and purpose for which the compounds of the present disclosure are applied. The solvent is generally selected based on solvents deemed safe by those skilled in the art to be administered to mammals, including humans. Generally, the safe solvent is a non-toxic aqueous solvent such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and the like, and mixtures thereof.

In some embodiments, suitable excipients may include buffers, such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethyldiammonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl p-hydroxybenzoates, such as methyl or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); a low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelation of Agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc-protein complexes); and/or nonionic surfactants, e.g. TWEEN ^TM 、PLURONICS ^TM Or polyethylene glycol (PEG).

In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide an optimal presentation of a drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions, respectively, hydroxymethyl cellulose or gelatin microcapsules and poly- (methyl methacrylate) microcapsules. Such techniques are disclosed in the Lemington's pharmaceutical Specification, 16 th edition, osol, A-edition (1980). A "liposome" is a vesicle comprising various types of lipids, phospholipids, and/or surfactants that can be used to deliver a drug (such as a compound disclosed herein and optionally a chemotherapeutic agent) to a mammal, including a human. The components of liposomes are typically arranged in bilayer form, similar to the lipid arrangement of biological membranes.

The pharmaceutical compositions provided herein may be in any form that allows for administration of the composition to a subject, including but not limited to humans, and allows for formulation of the composition to be compatible with the intended route of administration.

Various routes are contemplated for the pharmaceutical compositions provided herein, and thus the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injectable administration, emulsions and suspensions may be acceptable as liquid dosage forms, and powders suitable for reconstitution with a suitable solution may be acceptable as solid dosage forms. For inhaled administration, solutions, sprays, dry powders and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches may be in acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams, and sprays can be in acceptable dosage forms.

The amount of active ingredient in a unit dosage form of the composition is a therapeutically effective amount and will vary depending upon the particular treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents the identified disease or condition or exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The precise effective amount of the subject will depend on the weight, size, and health of the subject; the nature and extent of the pathology; the rate of application; selecting a therapeutic agent or combination of therapeutic agents for administration; judgment of prescribing doctor. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oral administration formulations.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a tablet formulation. Pharmaceutically acceptable excipients suitable for use in tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binding agents, such as starch; lubricants, such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl parahydroxybenzoate, and antioxidants, such as ascorbic acid. The tablet formulation may be uncoated or coated to regulate its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil, for example peanut oil, liquid paraffin or olive oil.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which generally contains the active ingredient in the form of a fine powder, and one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and gum acacia; dispersants or wetting agents, such as lecithin or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate); or condensation products of ethylene oxide with long chain fatty alcohols, such as heptadecaethyleneoxy cetyl alcohol; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives (e.g. ethyl or propyl parahydroxybenzoate), antioxidants (e.g. ascorbic acid), colouring agents, flavouring agents and/or sweetening agents (e.g. sucrose, saccharin or aspartame).

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oily suspension, typically containing the suspended active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil; or mineral oils such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifying agents may be, for example, naturally-occurring gums, such as acacia or tragacanth; naturally occurring phospholipids, such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents and preservatives.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain a sweetening agent, such as glycerin, propylene glycol, sorbitol, aspartame, or sucrose; a demulcent; a preservative; flavoring and/or coloring agents.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an injectable administration formulation.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1, 3-butanediol or as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an inhalation administration formulation.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. The carrier and stabilizer will vary depending on the requirements of the particular compound, but typically includes nonionic surfactants (Tween, pluronic (Pluronic) or polyethylene glycol), harmless proteinaceous serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of topical or transdermal administration formulations.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which may be formulated, generally, with conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal patches well known to those of ordinary skill in the art.

Pharmaceutically acceptable excipients and carriers, in addition to those representative dosage forms described above, are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described, for example, in the following references: "Leiddint pharmaceutical complete", mark publication Co., ltd (Mack Pub. Co.), new Jersey (1991), "Leiddint: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), editorial university of philadelphia science (University of the Sciences in Philadelphia), 21 st edition, LWW (2005), which is incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated into a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending upon the subject being treated and the particular mode of administration.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated such that 0.001 to 1000mg/kg body weight/day, e.g., 0.01 to 800mg/kg body weight/day, 0.01 to 700mg/kg body weight/day, 0.01 to 600mg/kg body weight/day, 0.01 to 500mg/kg body weight/day, 0.01 to 400mg/kg body weight/day, 0.01 to 300mg/kg body weight/day, 0.1 to 200mg/kg body weight/day, 0.1 to 150mg/kg body weight/day, 0.1 to 100mg/kg body weight/day, 0.5 to 80mg/kg body weight/day, 0.5 to 60mg/kg body weight/day, 0.5 to 50mg/kg body weight/day, 1 to 45mg/kg body weight/day, 1 to 40mg/kg body weight/day, 1 to 35mg/kg body weight/day, 1 to 30 mg/day, 1 to 25 mg/day, or a pharmaceutically acceptable salt thereof may be administered. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases larger doses may be employed without causing any adverse side effects, provided that the larger dose is first divided into several small doses for administration throughout the day. For more information on route of administration and dosage regimen, see, comprehensive pharmaceutical chemistry (Comprehensive Medicinal Chemistry), volume 5, chapter 25.3 (Corwin Hansch; editorial Committee chairman), pegamman Press (Pergamon Press) 1990, which is expressly incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated for short-acting, rapid-release, long-acting, and sustained-release. Thus, the pharmaceutical formulations of the present disclosure may also be formulated for controlled or slow release.

In yet another aspect, a veterinary composition is provided comprising one or more molecules or compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary field and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

The pharmaceutical or veterinary composition may be packaged in various ways depending on the method used to administer the drug. For example, the article for dispensing may comprise a container containing the composition in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cans and the like. The container may also include a tamper evident assembly to prevent easy access to the contents of the package. In addition, a label describing the contents of the container is placed on the container. The tag may also include an appropriate warning. The compositions may also be packaged in unit-dose or multi-dose containers, such as sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

In another aspect, there is also provided a pharmaceutical composition comprising as a first active ingredient one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a second active ingredient.

In some embodiments, the second active ingredient has activity complementary to the compounds provided herein such that it does not adversely affect each other. Such ingredients are suitably present in combination in amounts effective for the intended purpose.

Methods of treating diseases

In another aspect, the present disclosure provides a method for treating cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In some embodiments, the methods relate to the treatment of cancer, such as lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, blood cancer, colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary tract cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central Nervous System (CNS) tumors, primary CNS lymphomas, spinal axis tumors, brain stem glioma, MYH-related polyposis, or pituitary adenoma.

In some embodiments, the cancer is associated with a KRAS G12D mutation. In certain embodiments, the cancer is hematologic cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer.

In another aspect, the present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising:

(a) Determining that the cancer is associated with a KRAS G12D mutation; and

(b) Administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In another aspect, the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In another aspect, the present disclosure provides a method for modulating the activity of a KRAS G12D mutein comprising reacting the KRAS G12D mutein with a compound of the present disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In yet another aspect, the present disclosure provides a method for preparing a labeled KRAS G12D mutein comprising reacting the KRAS G12D mutein with a compound provided herein or a pharmaceutically acceptable salt thereof to produce the labeled KRAS G12D mutein.

Examples

The following examples are included for illustrative purposes. However, it should be understood that these examples are not limiting of the present disclosure and are intended only to demonstrate methods of practicing the present disclosure. Those skilled in the art will recognize that the described chemical reactions can be readily adapted to produce a variety of other compounds of the present disclosure, and alternative methods for producing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, non-exemplary compounds according to the present disclosure may be successfully synthesized by modifications apparent to those skilled in the art, such as by appropriate protection of interfering groups, by use of other suitable reagents and building blocks than those described, and/or by conventional modifications to reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for preparing other compounds of the present disclosure.

Example 1

Step 1 preparation of Compounds 1-2

Compound 1-1 (640 mg,2.59mmol,1.00 eq.) and DIEA (1.67 g,12.9mmol, 2.25mL,5.00 eq.) in POCl at 25 ℃ ₃ (6.70 mL) and then heated to 100deg.C and stirred for 1 hour. TLC (PE/etoac=1/1, rf=0.9) indicated complete consumption of compound 1-1 and formation of a new spot. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 1-2 (750 mg, crude product) was obtained.

Step 2 preparation of Compounds 1-4

Compound 1-2 (300 mg,1.01mmol,1.00 eq.) in DCM (4.00 mL) and DIEA (262 mg,2.03mmol, 353. Mu.L, 2.00 eq.) and compounds 1-3 (215 mg,1.01mmol, 1.00 eq.) were added. The mixture was stirred at 25℃for 0.5 h. LC-MS (product: rt=1.078 min) showed complete consumption of compound 1-2 and the desired mass was detected. The reaction mixture was treated with H ₂ O (30.0 mL) was quenched and extracted with DCM (30.0 mL. Times.3). The combined organic fractions were washed with brine (40.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ PE/etoac=30/1 to 5:1; TLC, PE/etoac=5/1, r _f =0.5) was purified. As confirmed by H NMR and F NMR, compound 1-4 (400 mg, 847. Mu. Mol,83.6% yield) was obtained.

LC-MS：(M+H) ⁺ ＝473.1

¹ H NMR：(400MHz，DMSO-d ₆ )δ8.11(d，J＝7.2Hz，1H)，7.99(d，J＝10.0Hz，1H)，4.41 -4.28(m，2H)，4.22(s，2H)，3.67-3.52(m，2H)，1.79(s，2H)，1.62(d，J＝8.0Hz，2H)，1.46(s， 9H)。

Step 3 preparation of Compounds 1-6

To a solution of compound 1-5 in THF (5.00 mL) at 0 ℃ was added NaH (33.9 mg,848 μmol, 60.0% purity, 1.00 eq), stirred for 0.5 hours, then compound 1-4 (400 mg,848 μmol,1.00 eq) was added to the mixture at 0 ℃. The mixture was stirred at 80℃for 12 hours. LC-MS (product: rt=0.818 min) showed that compounds 1-4 were retained and the desired mass was detected. The reaction mixture was treated with NH ₄ Aqueous Cl (saturated, 30.0 mL) was quenched and extracted with DCM (20.0 mL. Times.3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 50X 10 μm; mobile phase: [ hexane-EtOH)]；B％：1％-30%,15 min). As confirmed by H NMR, F NMR and SFC, compounds 1-6 (180 mg, 302. Mu. Mol, 35.7% yield) were obtained.

LC-MS：(M+H) ⁺ ＝596.3

¹ H NMR：(400MHz，DMSO-d ₆ )δ7.90(d，J＝6.8Hz，1H)，7.85(d，J＝10.0Hz，1H)，5.35 -5.18(m，1H)，4.32-4.28(m，1H)，4.22(s，2H)，4.09-3.93(m，2H)，3.58-3.44(m，3H)，3.11- 3.04(m，2H)，3.00(s，1H)，2.86-2.78(m，1H)，2.13-2.07(m，1H)，2.05-2.01(m，1H)，2.00- 1.94(m，1H)，1.85-1.64(m，7H)，1.45(s，9H)。

SFC: rt=1.214 min, 100% ee

Step 4. Preparation of Compounds 1-8

Compounds 1 to 6 (180 mg, 303. Mu. Mol,1.00 eq.) and compounds 1 to 7 (195 mg, 394. Mu. Mol, 1.30 eq.) in dioxane (3.00 mL) and H at 25 ℃ ₂ Cs was added to a solution in O (1.00 mL) ₂ CO ₃ (296 mg, 908. Mu. Mol,3.00 eq.) and Pd (dppf) Cl ₂ (44.3 mg, 60.6. Mu. Mol,0.20 eq.) and then the reaction mixture was taken up in N ₂ Stirring is carried out for 3 hours at 100℃under an atmosphere. LC-MS (product: rt=1.062 minutes) showed that compounds 1-6 were completely consumed and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-CN 250X 70X 10 μm; mobile phase: [ hexane-EtOH) ]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -35%,15 min). As confirmed by SFC, compounds 1-8 (80.0 mg, 90.6. Mu. Mol,29.9% yield) were obtained.

LC-MS：(M+H) ⁺ ＝882.6

SFC：RT ₁ =0.668 min, 52.8% ee, rt ₂ =1.026 min, 47.2% ee

Step 5 preparation of Compounds 1-9

To a solution of compounds 1-8 (40.0 mg, 45.3. Mu. Mol,1.00 eq.) in DCM (3.00 mL) was added HCl/dioxane (4M, 4.00mL,353 eq.). The mixture was stirred at 0℃for 0.5 h. LC-MS (product: rt=0.862 min) showed that compounds 1-8 were completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Compounds 1 to 9 (30.0 mg, crude product) were obtained.

LC-MS：(M+H) ⁺ ＝738.6

Step 6 preparation of Compound 1

To a solution of compounds 1-9 (30.0 mg, 40.65. Mu. Mol,1.00 eq.) in DMF (1.50 mL) was added CsF (30.9 mg, 203. Mu. Mol, 7.49. Mu. L,5.00 eq.). The mixture was stirred at 25℃for 12 hours. LC-MS (product: rt=0.749 min) showed that compounds 1-9 were completely consumed and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep HPLC (column: waters Xbridge 150 x 25mm x 5 μm; mobile phase: [ water (NH) ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B%:35% -65%,10 min). Compound 1 (4.00 mg, 6.44 μmol,15.8% yield, 93.7% purity) was obtained as confirmed by LC-MS, HPLC, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝582.4

HPLC:93.7% purity

¹ H NMR：(400MHz，DMSO-d ₆ )δ10.16(s，1H)，7.88(d，J＝8.0Hz，1H)，7.60(d，J＝10.8 Hz，1H)，7.55-7.51(m，1H)，7.48-7.39(m，2H)，7.31(d，J＝2.8Hz，1H)，7.01(d，J＝1.6Hz， 1H)，5.40-5.18(m，1H)，4.35-4.18(m，2H)，4.09-4.04(m，1H)，4.01-3.96(m，1H)，3.91- 3.82(m，2H)，3.61(s，1H)，3.59-3.53(m，2H)，3.12-3.07(m，2H)，3.02(s，1H)，2.91-2.77 (m，2H)，2.16-2.10(m，1H)，2.05(s，1H)，2.03-1.95(m，1H)，1.91-1.70(m，7H)。

SFC：RT ₁ =0.469 min, 54.9% ee, rt ₂ =1.385 min, 45.1% ee.

Example 2

Step 1 preparation of Compound 2-2

POCl at 0deg.C ₃ To a solution of compound 2-1 (3.00 g,11.6mmol,1.00 eq.) and DIEA (4.49 g,34.7mmol,6.05mL,3.00 eq.) were added and the mixture was stirred at 110 ℃ for 1 hour. TLC (SiO) ₂ ，PE/EtOAc＝1/1，R _f =0.9) indicates that about 20% of compound 2-1 was retained and a major new spot of lower polarity was detected. The mixture was concentrated to give the product. The crude product was used in the next step without further purification. Compound 2-2 (3.43 g,11.6mmol,100% yield) was obtained.

Step 2 preparation of Compounds 2-4

To a solution of compound 2-2 (1.60 g,5.41mmol,1.00 eq.) and compound 2-3 (1.03 g,4.87mmol, 0.90 eq.) in DCM (20.0 mL) was added DIEA (3.49 g,27.0mmol,4.71mL,5.00 eq.) at-40℃and the mixture was stirred at 25℃for 1 hour. LC-MS (product: rt=0.996 min) showed complete consumption of compound 2-2 and detection of one major peak with the desired mass. HPLC showed detection of about 83% of the desired compound. The reaction mixture was quenched with ice water (50.0 mL), and then diluted with EtOAc (50.0 mL) and extracted with EtOAc (50.0 ml×2). The combined organic layers were washed with brine (50.0 mL), and passed through Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% nh ₃ ·H ₂ O) purification. As confirmed by H NMR, F NMR and special NMR, compound 2-4 (1.30 g,2.76mmol, 51.0% yield) was obtained.

¹ H NMR：(400MHz，DMSO-d ₆ )δ8.12(d，J＝6.80Hz，1H)，7.99(d，J＝10.0Hz，1H)， 4.44-4.28(m，2H)，4.22(br s，2H)，3.66-3.49(m，2H)，1.86-1.73(m，2H)，1.62(br d，J＝ 8.40Hz，2H)，1.46(s，9H)。

Step 3 preparation of Compounds 2-6

To a solution of compound 2-5 (195 mg,1.38mmol,1.00 eq.) in DMF (5.00 mL) was added NaH (66.1 mg,1.65mmol,60.0% purity, 1.20 eq.) at 0deg.C and the mixture was stirred at 0deg.C for 30 min, then compound 2-4 (650 mg,1.38mmol,1.00 eq.) was added and the mixture was stirred at 25deg.C for 1.5 h. LC-MS (product: rt=0.849 min) showed complete consumption of compounds 2-4. Several new peaks are shown on LC-MS and about 50% of the desired compound is detected. The reaction mixture was quenched with ice water (20.0 mL), and then diluted with EtOAc (20.0 mL) and extracted with EtOAc (20.0 ml×2). The combined organic layers were washed with brine (20.0. 20.0 mL), dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Phenomenex Synergi Max-RP 250X 50mm X10. Mu.m; mobile phase: [ water (FA) -ACN)]The method comprises the steps of carrying out a first treatment on the surface of the B%: 20% -50%,20 min). Compound 2-6 (340 mg, 590. Mu. Mol,42.8% yield) was obtained as confirmed by H NMR, F NMR (EW 29126-264-P1B 1) and SFC.

¹ H NMR：(400MHz，DMSO-d ₆ )δ8.51(s，2H)，7.91-7.83(dd，J ₁ ＝6.4Hz，J ₂ ＝19.2Hz， 2H)，4.29-4.22(m，4H)，3.56-3.42(m，4H)，2.94-2.89(m，2H)，1.89-1.66(m，10H)，1.58- 1.51(m，2H)，1.45(s，9H)。

Step 4 preparation of Compounds 2-8

To compound 2-6 (250 mg, 434. Mu. Mol,1.00 eq.) in THF (2.00 mL) and H ₂ To a solution of compound 2-7 (214 mg, 434. Mu. Mol,1.00 eq.) in O (1.00 mL), K ₃ PO ₄ (276 mg,1.30mmol, 3.00 eq.) and Ad2nBuP-Pd-G3 (31.6 mg, 43.4. Mu. Mol,0.10 eq.) and then stirring the mixture at 60℃for 3 hours. LC-MS (product: rt=1.053 min) showed complete consumption of compounds 2-6 and the desired mass was detected. The mixture was filtered and concentrated to give the product. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 70X 10 μm; mobile phase: [ hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -35%,15 min). Compound 2-8 (240 mg, 278. Mu. Mol,64.0% yield) was obtained.

LC-MS：(M+H) ⁺ ＝864.5。

Step 5 preparation of Compounds 2-9

To a solution of compounds 2-8 (220 mg,255 μmol,1.00 eq.) in DCM (1.00 mL) was added HCl/dioxane (4.00 m,255 μl,4.00 eq.) at 0 ℃ and the mixture was stirred at 0 ℃ for 15 min. LC-MS (product: rt=0.875 min) showed that compounds 2-8 were completely consumed and one main peak with the desired mass was detected. The reaction mixture was taken up in ice water (10.0 mL) and saturated NaHCO ₃ The aqueous solution (10.0 mL) was quenched and then diluted with DCM (10.0 mL) and extracted with DCM (10.0 mL. Times.2). The combined organic layers were washed with brine (10.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 2-9 (183 mg, 254. Mu. Mol,99.8% yield) was obtained.

LC-MS：(M+H) ⁺ ＝720.6。

Preparation of Steps 6.2-10

To a solution of compound 2-9 (183 mg, 254. Mu. Mol,1.00 eq.) in DMF (1.00 mL) was added CsF (193 mg,1.27mmol,5.00 eq.) and the mixture was stirred at 25℃for 12 hours. LC-MS (product: rt=0.757 min) showed that about 8% of compounds 2-9 were retained. Several new peaks are shown on LC-MS and about 66% of the desired compound is detected. The mixture was filtered to give the product. The residue was purified by preparative HPLC (column: phenomenex Synergi C18 150 x 25mm x 10 μm; mobile phase: [ water (FA) -ACN ];% B: 5% -35%, 9 min). As confirmed by HPLC, H NMR, F NMR and SFC, 2-10 (38.6 mg, 62.9. Mu. Mol,24.8% yield, 99.4% purity, FA) was obtained.

¹ H NMR：(400MHz，DMSO-d6)δ8.24(s，1H)，7.87(dd，J ₁ ＝1.2Hz，J ₂ ＝8.0Hz，1H)， 7.59(d，J＝10.4Hz，1H)，7.50-7.46(m，2H)，7.43-7.39(m，1H)，7.31(d，J＝2.4Hz，1H)， 7.02(d，J＝2.8Hz，1H)，4.28-4.17(m，2H)，4.04(s，2H)，3.64-3.59(m，4H)，3.49(br d，J＝ 12.4Hz，3H)，3.04-2.97(m，2H)，2.65-2.59(m，2H)，1.94-1.89(m，2H)，1.85-1.71(m，7H)， 1.65-1.60(m，2H)。

Step 7 preparation of Compound 2

The residue was purified by prep HPLC (column: waters Xbridge 150 x 25mm x 5 μm; mobile phase: [ water (NH) ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B%:32% -62%,8 min). Compound 2 (2.50 mg,4.10 μmol,16.7% yield) was obtained as confirmed by LC-MS, HPLC, H NMR and F NMR.

LC-MS：(M+H) ⁺ ＝583.4

HPLC:96.6% purity

¹ H NMR：(400MHz，DMSO-d6)δ10.12(s，1H)，7.90-7.86(m，1H)，7.56(d，J＝15.2Hz， 1H)，7.48-7.34(m，3H)，7.31-7.30(m，1H)，7.01(d，J＝2.8Hz，1H)，4.26-4.15(m，2H)，3.96 (s，2H)，3.61(s，1H)，3.50-3.42(m，3H)，3.38(br s，3H)，2.94-2.90(m，2H)，2.62-2.58(m， 2H)，1.92-1.84(m，2H)，1.81-1.66(m，7H)，1.60-1.53(m，2H)。

Example 3

Step 1 preparation of Compound 3-2

To a solution of compound 3-1 (10.0 g,48.0mmol,1.00 eq.) in EtOH (200 mL) was added Ag ₂ SO ₄ (14.9 g,48.1mmol,8.15mL,1.00 eq.) and I ₂ (13.4 g,52.9mmol,10.6mL,1.10 eq.) then the reaction mixture was stirred at 20deg.C for 2 hours. TLC (SiO) ₂ PE/etoac=10/1, rf=0.7) showed that compound 3-1 was consumed and a new spot formed. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO 2, PE/etoac=1/0 to 10/1). As confirmed by H NMR and F NMR, compound 3-2 (6.20 g,18.5mmol,38.6% yield) was obtained as a yellow solid.

¹ H NMR：(400MHz，DMSO-d6)δ7.56-7.53(m，1H)，5.27(s，2H)。

Step 2.3-3 preparation

Compound 3-2 (7.50 g,22.4mmol,1.00 eq.) TEA (15.9 g,157mmol,21.9mL, 7.00 eq.) andPd(dppf)Cl ₂ ·CH ₂ Cl ₂ (1.83 g,2.25mmol,0.10 eq.) in MeOH (150 mL) and N ₂ Purging 3 times. The suspension was degassed under vacuum and purged several times with CO, then the reaction mixture was stirred at 25 ℃ for 6 hours under CO (15 psi). TLC (SiO) ₂ ，PE/EtOAc＝1/0，R _f =0.4) shows that compound 3-2 was consumed and a new spot was formed. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ PE/etoac=1/0). As confirmed by LC-MS, H NMR and F NMR, compound 3-3 (5.4 g,20.3mmol,90.3% yield, 100% purity) was obtained.

LC-MS：(M+H) ⁺ ＝268.0

¹ H NMR：EW28805-300-P1A(400MHz，DMSO-d6)δ7.48-7.45(m，1H)，6.64(s，2H)， 3.83(s，3H)。

Step 3 preparation of Compounds 3-4

To a solution of compound 3-3 (5.40 g,20.3mmol,100% purity, 1.00 eq.) in MeOH (100 mL) was added NaOH (1.62 g,40.6mmol,2.00 eq.) in H ₂ A solution in O (100 mL) was added and the reaction mixture was stirred at 20deg.C for 2 hours. TLC (SiO 2, PE/etoac=10/1, r _f =0.05) shows that compound 3-3 was consumed and a new spot was formed. The reaction mixture was concentrated to remove MeOH, extracted with PE (100 mL) and the aqueous layer was adjusted to ph=7 with HCl (1M), extracted with EtOAc (100 ml×3) and the combined organic layers were extracted with H ₂ O (300 mL), brine (300 mL), washed over Na ₂ SO ₄ Dried, filtered and the filtrate concentrated to give a residue. The residue was used directly in the next step without purification. As confirmed by H NMR and F NMR, compound 3-4 (4.80 g,19.0mmol,93.8% yield) was obtained.

¹ H NMR：(400MHz，DMSO-d6)δ7.72-7.21(m，1H)。

Step 4 preparation of Compounds 3-5

A mixture of compounds 3-4 (4.80 g,19.0mmol,1.00 eq.) and urea (11.4 g,190mmol,10.2mL, 10.0 eq.) was stirred at 180deg.C for 3 hours. The desired mass was detected on LC-MS (EW 28805-305-P1A, product: rt=0.384 min). The reaction mixture was cooled to 100℃and H was added to the reaction ₂ O (50.0 mL), the mixture was stirred at 100deg.C for 1 hour, then filtered and the filter cake was collected. The filter cake was slurried with PE (50.0 mL) at 25℃for 1 hour. As confirmed by H NMR and F NMR, compound 3-5 (4.50 g, crude product) was obtained.

¹ H NMR：(400MHz，DMSO-d6)δ11.40-11.71(m，2H)，7.64-7.61(m，1H)。

Step 5 preparation of Compounds 3-6

Compound 3-5 (2.00 g,7.22mmol,1.00 eq.) and DIEA (2.80 g,21.6mmol,3.77mL, 3.00 eq.) were combined in POCl ₃ The mixture in (20.0 mL) was stirred at 110℃for 1 hour. TLC (SiO) ₂ ，PE/EtOAc ＝5/1，R _f =0.9) indicates that compound 3-5 was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 3-6 (2.27 g, crude product) was obtained as a black oil.

Step 6 preparation of Compounds 3-8

To a solution of compound 3-6 (2.27 g,7.23mmol,1.00 eq.) in DCM (40.0 mL) was added DIEA (6.54 g,50.6mmol,8.82mL,7.00 eq.) and compound 3-7 (1.07 g, 5.06mmol, 0.70 eq). The mixture was stirred at-40℃for 3 hours. The desired compound was detected by LC-MS (product: rt=1.078 min). The mixture was combined with H in DCM (30.0 mL. Times.3) ₂ O (50.0 ml×2). The organic phase was separated, washed with brine (60.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 70X 10 μm; mobile phase: [ hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -15%,15 min). As confirmed by LC-MS, H NMR, F NMR and special NMR, compound 3-8 (2.00 g,4.03mmol,55.6% yield, 98.6% purity) was obtained.

LC-MS：(M+H) ⁺ ＝491.1

¹ H NMR：(400MHz，DMSO-d6)δ7.87(d，J＝10.0Hz，1H)，4.43-4.16(m，4H)，3.60(d， J＝10.0Hz，2H)，1.78(d，J＝4.2Hz，2H)，1.62(d，J＝7.6Hz 2H)，1.46(s，9H)。

Step 7 preparation of Compounds 3-14

At N ₂ To a solution of compound 3-8 (1.60 g,3.22mmol,98.6% purity, 1.00 eq.) in DMSO (14.0 mL) was added KF (3.74 g,64.4mmol,1.51mL,20.0 eq.). The mixture was stirred at 120℃for 5 hours. LC-MS (product: rt=0.948 min) and HPLC showed complete consumption of compounds 3-8, where the desired mass was detected. The mixture was combined with H in EtOAc (50.0 mL. Times.3) ₂ O (50.0 ml×2). The organic phase was separated, washed with brine (60.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Kromasil Eternity XT, 250 x 80mm x 10 μm; mobile phase: [ water (NH) ₄ HCO ₃ )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the B%:45% -75%, min). As confirmed by LC-MS, H NMR and F NMR, compound 3-14 (480 mg,2.07mmol,64.3% yield, 100% purity) was obtained.

LC-MS: EW30627-117-P1B, product: rt=1.043 min, (m+h) ⁺ ＝475.0

¹ H NMR：EW30627-117-P1A(400MHz，DMSO-d6)δ7.92(d，J＝10.0Hz，1H)，4.37(d， J＝11.2Hz，2H)，4.23(s，2H)，3.62(d，J＝12.0Hz，2H)，1.87-1.69(m，2H)，1.63(d，J＝7.6 Hz，2H)，1.46(s，9H)。

Step 8 preparation of Compounds 3-10

To a solution of compound 3-9 (292 mg,1.84mmol,0.90 eq.) in THF (10.0 mL) was added NaH (81.6 mg,2.04mmol,60% purity, 1.00 eq.) at 0 ℃ and after stirring at 0 ℃ for 0.5 hours, compound 3-14 (480 mg,2.04mmol,98.6% purity, 1.00 eq.) was added to the mixture at 0 ℃. The mixture was stirred at 25℃for 2 hours. LC-MS (product: rt=0.884 min) showed complete consumption of compounds 3-14 and the desired mass was detected. The reaction mixture was treated with saturated NH ₄ Aqueous Cl (50.0 mL) was quenched and extracted with DCM (30.0 mL ×3). The combined organic fractions were washed with brine (50.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-CN 250X 70X 10 μm; mobile phase: [ heptane-EtOH (0.1% NH) ₃ H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -40%,20 min). As confirmed by LC-MS, H NMR, F NMR, SFC and special NMR, compound 3-10 was obtained (800mg,1.31 mmol,63.9% yield, 100% purity).

LC-MS：(M+H) ⁺ ＝614.1

¹ H NMR：(400MHz，CDCl ₃ )δ7.34-7.29(m，1H)，5.36-5.18(m，1H)，4.41-4.20(m， 5H)，4.16-4.09(m，1H)，3.54(s，2H)，3.30-3.12(m，3H)，3.01-2.92(m，1H)，2.32-2.11(m，3H)，2.00-1.86(m，5H)，1.78(d，J＝8.4Hz，2H)，1.51(s，9H)。

Step 9 preparation of Compounds 3-12

At N ₂ Down compound 3-10 (200 mg, 326. Mu. Mol,100% purity, 1.00 eq.) in THF (3.00 mL) and H ₂ To a solution of compound 3-11 (194 mg, 392. Mu. Mol,1.20 eq.) in O (1.00 mL), K was added ₃ PO ₄ (207 mg, 979. Mu. Mol,3.00 eq.) and Ad2nBuP-Pd-G3 (47.5 mg, 65.3. Mu. Mol,0.20 eq.) and then stirring the mixture at 60℃for 3 hours. LC-MS (product: rt=1.095 minutes) showed that compounds 3-10 were retained and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3 μm; mobile phase: [ water (TFA) -ACN)]The method comprises the steps of carrying out a first treatment on the surface of the B%:67% -87%,7 min). As confirmed by SFC, compound 3-12 (100 mg, 111. Mu. Mol,34.0% yield) was obtained.

Step 10 preparation of Compounds 3-13

To a solution of compound 3-12 (100 mg,111 μmol,1.00 eq.) in DCM (3.00 mL) was added HCl/dioxane (4.00 m,3.00mL,108 eq.). The mixture was stirred at 0℃for 0.5 h. LC-MS (product: rt=0.884 min) showed that compounds 3-12 were retained and the desired mass was detected. The mixture was treated with saturated NaHCO ₃ The aqueous solution was adjusted to ph=7 and extracted with DCM (10.0 ml×3). The combined organic fractions were washed with brine (20.0. 20.0 mL), dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was used directly in the next step without purification. Compound 3-13 (80.0 mg, crude product) was obtained as a yellow oil.

Step 11 preparation of Compound 3

To a solution of compound 3-13 (80.0 mg, 105. Mu. Mol, crude product purity, 1.00 eq.) in DMF (1.00 mL) was added CsF (80.3 mg, 529. Mu. Mol, 19.5. Mu.L, 5.00 eq.). The mixture was stirred at 20℃for 12 hours. LC-MS (product: rt=0.680 min) showed complete consumption of compounds 3-13 and the desired mass was detected. The reaction mixture was filtered and the filtrate was collected. The filtrate was purified by preparative HPLC (column: phenomenex C18 x 30mm x 3 μm; mobile phase: [ water (FA) -ACN ];: B%:5% -35%,7 min). Compound 3 (9.75 mg,15.0 μmol, 14.1% yield, 99.4% purity, FA) was obtained as confirmed by LC-MS, HPLC, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝600.3

¹ H NMR：(400MHz，DMSO-d6)δ7.89(d，J＝7.6Hz，1H)，7.55-7.40(m，3H)，7.35(d，J ＝2.4Hz，1H)，7.08(s，1H)，5.37-5.19(m，1H)，4.24(d，J＝12.0Hz，2H)，4.06(d，J＝10.4Hz， 2H)，3.97(d，J＝10.4Hz，2H)，3.60(s，2H)，3.11-3.06(m，3H)，3.01(s，2H)，2.86-2.78(m， 3H)，2.14-1.97(m，3H)，1.85-1.67(m，6H)。

Example 4

Step 1 preparation of Compound 4-3

Compound 4-1 (5.00 g,21.3mmol,1.00 eq.) and compound 4-2 (12.8g,214mmol,11.5 mL,10.0 eq.) were stirred at 180℃for 3 hours. LC-MS (product: rt=0.418 min) showed complete consumption of compound 4-1 and the desired mass was detected. The reaction mixture was cooled to 100℃and H was added to the reaction ₂ O (50.0 mL), then filtered and the filter cake concentrated. The crude product was triturated with PE (50.0 mL) at 25℃for 1 hour. As confirmed by H NMR and F NMR,compound 4-3 (5.10 g,19.6mmol,92.1% yield) was obtained.

¹ H NMR：(400MHz，DMSO-d ₆ )δ11.4(s，2H)，7.70(d，J＝8.4Hz，1H)，7.41(d，J＝5.6 Hz，1H)。

Step 2 preparation of Compound 4-4

To compound 3-3 (2.00 g,7.72mmol,1.00 eq.) in POCl ₃ DIEA (2.99 g,23.2mmol,4.03mL,3.00 eq.) was added to the solution in (20.0 mL). The mixture was stirred at 110℃for 1 hour. TLC (SiO) ₂ PE/etoac=5/1, rf=0.7) indicates that compound 3-3 was retained and a new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 3-4 (2.00 g, crude product) was obtained as a red oil.

Step 3 preparation of Compounds 4-6

To a solution of compound 4-4 (1.80 g,6.08mmol,1.00 eq.) in DCM (20.0 mL) was added DIEA (5.50 g,42.6mmol,7.42mL,7.00 eq.) and compound 4-5 (1.24 g,5.47mmol,0.90 eq.) at-40 ℃. The mixture was stirred at 50℃for 2 hours. LC-MS (product: rt=1.042 min) showed complete consumption of compound 4-4 and the desired mass was detected. The reaction mixture was treated with H ₂ O (30.0 mL) was quenched and extracted with DCM (30.0 mL. Times.3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-CN 250X 70X 10 μm; mobile phase: [ hexane-EtOH)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -30%,15 min). As confirmed by H NMR, F NMR, special NMR and SFC, compound 4-6 (1.35 g,2.78mmol,45.6% yield) was obtained.

¹ H NMR：(400MHz，DMSO-d ₆ )δ8.15-8.06(m，1H)，8.02(d，J＝10.0Hz，1H)，4.30- 4.08(m，3H)，4.07-3.97(m，1H)，3.94-3.73(m，1H)，3.71-3.57(m，1H)，2.46-2.38(m，1H)， 2.24-1.98(m，2H)，1.84-1.54(m，3H)，1.24-1.01(m，9H)。

Step 4 preparation of Compounds 4-8

To a solution of compound 4-7 (328 mg,2.06mmol,1.00 eq.) in THF (10.0 mL) was added NaH (82.3 mg,2.06mmol,60.0% purity, 1.00 eq.) at 0 ℃ and stirred for 0.5 hours, then compound 4-6 (1.00 g,2.06mmol,1.00 eq.) was added to the mixture at 0 ℃. The mixture was stirred at 80℃for 2 hours. TLC (SiO) ₂ ，DCM/MeOH＝10/1，R _f =0.6) indicates that compound 4-6 was retained and a new spot was formed. The reaction mixture was treated with saturated NH ₄ Aqueous Cl (30.0 mL) was quenched and extracted with EtOAc (30.0 mL. Times.3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 70X 10 μm; mobile phase: [ hexane-EtOH)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -30%,15 min). As confirmed by LC-MS, H NMR, F NMR and SFC, compound 4-8 (880 mg,1.42mmol,69.1% yield, 98.4% purity) was obtained.

LC-MS：(M+H) ⁺ ＝610.3

¹ H NMR：(400MHz，DMSO-d ₆ )δ7.95-7.77(m，2H)，5.39-5.12(m，1H)，4.26-4.12(m， 2H)，4.12-4.05(m，1H)，4.05-3.99(m，2H)，3.99-3.89(m，1H)，3.85-3.55(m，2H)，3.08(br d，J＝5.2Hz，2H)，3.00(br s，1H)，2.88-2.73(m 1H)，2.48-2.36(m，1H)，2.22-2.05(m，3H)， 2.05-1.92(m，2H)，1.88-1.59(m，6H)，1.23-1.07(m，9H)。

Step 5 preparation of Compounds 4-8-a and 4-8-b

Compounds 4-8 were purified by preparative HPLC (column DAICEL CHIRALPAK IC (250 mm. Times.30 mm,10 μm); mobile phase: [0.1% NH) ₃ H ₂ O MEOH]The method comprises the steps of carrying out a first treatment on the surface of the B%:30% -30%,10.1 min) and preparative HPLC (column: DAICEL CHIRALPAK IC (250 mm. Times.30 mm,10 μm); mobile phase: [0.1% NH ₃ H ₂ O MEOH]The method comprises the steps of carrying out a first treatment on the surface of the B%:30% -30%,4.4 minutes). As confirmed by LC-MS, SFC, H NMR and F NMR, compound 4-8-a (420 mg, 652. Mu. Mol,38.5% yield, 94.5% purity) was obtained as a yellow solid. Compound 8_peak2 (510 mg,810 μmol,47.8% yield, 96.7% purity) was obtained as a white solid as confirmed by LC-MS, SFC, H NMR and F NMR.

4-8-a：

LC-MS：(M+H) ⁺ ＝610.2

¹ H NMR：(400MHz，DMSO-d ₆ )δ7.97-7.83(m，2H)，5.39-5.14(m，1H)，4.30-4.12(m，2H)，4.12-4.04(m，1H)，4.04-4.00(m，2H)，3.99-3.83(m，1H)，3.82-3.57(m，1H)，3.71- 3.55(m，1H)，3.14-3.05(m，2H)，3.01(br s，1H)，2.87-2.78(m，1H)，2.48-2.40(m，1H)，2.22 -2.05(m，3H)，2.04-1.92(m，2H)，1.89-1.80(m，1H)，1.80-1.54(m，5H)，1.24-1.07(m， 9H)。

4-8-b：

LC-MS：(M+H) ⁺ ＝610.2

¹ H NMR：(400MHz，DMSO-d ₆ )δ7.97-7.83(m，2H)，5.39-5.14(m，1H)，4.30-4.12(m， 2H)，4.12-4.04(m，1H)，4.04-4.00(m，2H)，3.99-3.83(m，1H)，3.82-3.57(m，1H)，3.71- 3.55(m，1H)，3.14-3.05(m，2H)，3.01(br s，1H)，2.87-2.78(m，1H)，2.48-2.40(m，1H)，2.22 -2.05(m，3H)，2.04-1.92(m，2H)，1.89-1.80(m，1H)，1.80-1.54(m，5H)，1.24-1.07(m， 8H)。

Step 6 preparation of Compound 4-10-a

To compound 4-8-a (380 mg, 590. Mu. Mol,94.5% purity, 1.00 eq.) in THF (3.00 mL) and H ₂ To a solution of compound 4-9 (350 mg, 708. Mu. Mol,1.20 eq.) in O (1.00 mL), K was added ₃ PO ₄ (376 mg,1.77mmol,3.00 eq) and Ad2nBuP-Pd-G3 (43.0 mg, 59.0. Mu. Mol,0.10 eq) and then stirring the mixture at 60℃for 3 hours. LC-MS (product: rt= 1.043,1.073 min) showed complete consumption of compound 4-8-a and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: phenomenex luna C, 150X 40mm X15 μm; mobile phase: [ water (FA) -ACN) ]The method comprises the steps of carrying out a first treatment on the surface of the B%:45% -75%,10 min). As confirmed by SFC, compound 4-10-a (320 mg, 357. Mu. Mol,60.5% yield) was obtained.

Step 7 preparation of Compound 4-11-a

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To a solution of compound 4-10-a (160 mg, 179. Mu. Mol,1.00 eq.) in DCM (6.00 mL) was added HCl/dioxane (4.00M, 4.00mL,89.6 eq.) at 0deg.C. The mixture was stirred at 0 ℃ for 4 hours. LC-MS (product: rt=0.859 min) showed that compound 4-10-a was retained and the desired mass was detected. The mixture was treated with Na ₂ CO ₃ The aqueous solution (saturated) was adjusted to ph=7 and extracted with DCM (20.0 ml×3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. Compound 4-11-a (140 mg, crude product) was obtained as a yellow oil.

Step 8 preparation of Compound 4-a

To a solution of compound 4-11-a (140 mg, 186. Mu. Mol, crude product purity, 1.00 eq.) in DMF (1.00 mL) was added CsF (141 mg, 931. Mu. Mol,5.00 eq.). The mixture was stirred at 25℃for 12 hours. LC-MS (product: rt=0.674 min) showed that compound 4-11-a was retained and the desired mass was detected. The reaction mixture was filtered to give a residue. The residue was purified by means of preparative HPLC (column: phenomenex Synergi C: 150X 25mm X10 μm; mobile phase: [ water (FA) -ACN ];% B: 3% -33%,10 min). Compound 4-a (31.8 mg, 52.2. Mu. Mol,28.0% yield, 97.8% purity, FA) was obtained as confirmed by LC-MS, HPLC, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝596.3

HPLC:97.8% purity

¹ H NMR：(400MHz，DMSO-d ₆ )δ8.25(s，1H)，7.87(dd，J ₁ ＝1.2Hz，J ₂ ＝8.0Hz，1H)，7.66-7.60(m，1H)，7.51-7.45(m，2H)，7.44-7.38(m，1H)，7.31(d，J＝2.4Hz，1H)，7.03(d，J ＝2.4Hz，1H)，5.37-5.18(m，1H)，4.51(br d，J＝12.8Hz，1H)，4.31(br d，J＝12.8Hz，1H)， 4.07-4.03(m，1H)，4.01-3.97(m，1H)，3.90-3.80(m，5H)，3.60(s，1H)，3.57(s，1H)，3.40- 3.37(m，1H)，3.12-3.06(m，2H)，3.01(s，1H)，2.87-2.79(m，1H)，2.19-2.07(m，2H)，2.04(br d，J＝2.4Hz，1H)，2.03-1.92(m，3H)，1.92-1.81(m，2H)，1.80-1.69(m，2H)，1.69-1.53 (m，2H)。

Step 9 preparation of Compound 4-10-b

To compound 4-8-b (300 mg, 477. Mu. Mol,96.7% purity, 1.00 eq.) in THF (3.00 mL) and H ₂ To a solution of compound 4-9 (283 mg, 572. Mu. Mol,1.20 eq.) in O (1.00 mL), K was added ₃ PO ₄ (304 mg,1.43mmol,3.00 eq) and Ad2nBuP-Pd-G3 (34.7 mg, 47.7. Mu. Mol,0.10 eq) and then the mixture was stirred at 75℃for 12 hours. LC-MS (product: rt=1.062, 1.077, 1.117 minutes) showed that compound 4-8-b was retained and the desired mass was detected. The reaction mixture was filtered and depressurizedConcentrated down to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-CN 250X 70X 10 μm; mobile phase: [ hexane-EtOH)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -35%,20 min) and preparative HPLC (column: phenomnex C18X 30X mm X3 μm; mobile phase: [ Water (FA) -ACN]The method comprises the steps of carrying out a first treatment on the surface of the B%:42% -72%,7 min). As confirmed by SFC, compound 4-10-b (75.0 mg, 83.7. Mu. Mol,17.5% yield) was obtained.

Step 10 preparation of Compound 4-11-b

To a solution of compound 4-10-b (75.0 mg,83.7 μmol,1.00 eq.) in DCM (2.00 mL) was added HCl/dioxane (4.00 m,2.00mL,95.6 eq.) at 0 ℃. The mixture was stirred at 0℃for 0.5 h. LC-MS (product: rt=0.870 min) showed complete consumption of compound 4-10-b and the desired mass was detected. The mixture was treated with Na ₂ CO ₃ The aqueous solution (saturated) was adjusted to ph=7 and extracted with DCM (20.0 ml×3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. Compound 4-11-b (65.0 mg, crude product) was obtained as a yellow oil.

Step 11 preparation of Compound 4-b

To a solution of compound 4-11-b (65.0 mg, 86.4. Mu. Mol, crude product purity, 1.00 eq.) in DMF (1.00 mL) was added CsF (65.7 mg, 432. Mu. Mol,5.00 eq.). The mixture was stirred at 25℃for 12 hours. LC-MS (product: rt=0.735 min) showed that compound 4-11-b was retained and the desired mass was detected. The reaction mixture was filtered to give a residue. The residue was purified by means of preparative HPLC (column: phenomenex Synergi C: 150X 25mm X10 μm; mobile phase: [ water (FA) -ACN ];: B%:2% -32%,10 min). Compound 4-b (20.3 mg, 33.6. Mu. Mol, 38.8% yield, 98.3% purity, FA) was obtained as confirmed by LC-MS, HPLC, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝596.3

HPLC: purity of 98.3%

¹ H NMR：EW28938-265-P1A(400MHz，DMSO-d ₆ )δ8.25(s，1H)，7.87(dd，J ₁ ＝1.2Hz， J ₂ ＝8.0Hz，1H)，7.68-7.58(m，1H)，7.51-7.45(m，2H)，7.44-7.38(m，1H)，7.31(d，J＝2.4 Hz，1H)，7.02(d，J＝2.4Hz，1H)，5.37-5.19(m，1H)，4.51(br d，J＝14Hz，1H)，4.31(br d，J＝ 12.8Hz，1H)，4.10-4.05(m，1H)，3.98-3.93(m，1H)，3.87-3.76(m，5H)，3.61(s，1H)，3.56 (s，1H)，3.38-3.33(m，1H)，3.12-3.05(m，2H)，3.01(s，1H)，2.87-2.79(m，1H)，2.18-2.07 (m，2H)，2.05(br d，J＝2.4Hz，1H)，2.02-1.90(m，3H)，1.90-1.80(m，2H)，1.80-1.70(m， 2H)，1.65-1.49(m，2H)。

Example 5

Step 1 preparation of Compound 5-3

To a solution of compound 5-1 (250 mg, 845. Mu. Mol,1.00 eq.) in DCM (3.00 mL) was added DIEA (540 mg,4.22mmol, 736. Mu.L, 5.00 eq.) and compound 5-2 (174 mg, 760. Mu. Mol, 0.90 eq.) at-40℃and the mixture was stirred at-40℃for 30 min. LC-MS (product: rt=0.983 min) showed complete consumption of compound 5-1 and detection of one major peak with the desired mass. The reaction mixture was quenched with ice water (20.0 mL) and then diluted with EtOAc (20.0 mL) and extracted with EtOAc (20.0 ml×2), the combined organic layers were washed with brine (20.0 mL), over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250 x 70 x 10 μm; mobile phase: [ Hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -15%,15 min). As confirmed by H NMR and F NMR, compound 5-3 (300 mg, 615. Mu. Mol,72.8% yield) was obtained.

¹ H NMR：(400MHz，DMSO-d6)δ8.10(d，J＝6.8Hz，1H)，8.00(d，J＝10.0Hz，1H)， 4.72-4.62(m，2H)，4.01(d，J＝18.4Hz，2H)，3.89-3.76(m，3H)，3.67(d，J＝12.8Hz，1H)， 3.58-3.55(m，2H)，1.46(s，9H)。

Step 2 preparation of Compounds 5-5

To a solution of compound 5-4 (91.4 mg, 574. Mu. Mol,1.00 eq.) in THF (3.00 mL) was added NaH (23.0 mg, 574. Mu. Mol,60.0% purity, 1.00 eq.) at 0deg.C for 1 hour, then compound 3 (280 mg, 574. Mu. Mol,1.00 eq.) was added, and the mixture was stirred at 80deg.C for 4 hours. LC-MS (product: rt=0.797 min) showed complete consumption of compound 5-3 and detection of one major peak with the desired mass. The reaction mixture was passed through ice water (10.0 mL) and saturated NH ₄ Aqueous Cl (10.0 mL) was quenched and then diluted with EtOAc (20.0 mL) and extracted with EtOAc (20.0 ml×2). The combined organic layers were washed with brine (20.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 70X 10 μm; mobile phase: [ hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -30%,15 min). As confirmed by H NMR and F NMR, compound 5-5 (240 mg, 393. Mu. Mol,68.5% yield) was obtained.

H NMR：(400MHz，DMSO-d6)δ7.94-7.83(m，2H)，5.28(d，J＝52.0Hz，1H)，4.68- 4.52(m，2H)，4.10-3.95(m，4H)，3.92-3.80(m，2H)，3.75-3.54(m，4H)，3.16-2.99(m，3H)， 2.89-2.78(m，1H)，2.17-1.96(m，3H)，1.88-1.71(m，3H)，1.46(s，9H)。

Step 3 preparation of Compounds 5-7

To compound 5-5 (220 mg, 360. Mu. Mol,1.00 eq.) in THF (2.00 mL) and H ₂ To a solution of compound 5-6 (178 mg, 360. Mu. Mol,1.00 eq.) in O (2.00 mL), K ₃ PO ₄ (229 mg,1.08mmol, 3.00 eq.) and Ad2nBuP-Pd-G3 (26.2 mg, 36.0. Mu. Mol,0.10 eq.) then the mixture was taken under N ₂ Stirring is carried out for 3 hours at 60℃under an atmosphere. LC-MS (product: rt=0.973 min) showed complete consumption of compound 5-5 and detection of one major peak with the desired mass. The mixture was filtered and concentrated to give the product. The residue was purified by preparative HPLC (column Welch Ultimate XB-CN 250X 50X 10 μm; mobile phase: [ heptane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:10% -50%,20 min). Compound 5-7 (230 mg, 256. Mu. Mol,71.06% yield) was obtained as a yellow solid.

Step 4 preparation of Compounds 5-8

To a solution of compounds 5-7 (120 mg,134 μmol,1.00 eq.) in DCM (1.00 mL) was added HCl/dioxane (4.00 m,66.8 μl,2.00 eq.) at 0 ℃ and the mixture was stirred at 0 ℃ for 30 min. LC-MS (product: rt=0.815 min) showed that compounds 5-7 were completely consumed and one main peak with the desired mass was detected. The reaction mixture was passed through saturated NaHCO ₃ The aqueous solution (10.0 mL) was quenched and then diluted with DCM (10.0 mL) and extracted with DCM (10.0 mL. Times.2). The combined organic layers were washed with brine (10.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compounds 5-8 (100 mg, 133. Mu. Mol,99.27% yield) were obtained as yellow solids.

Step 5 preparation of Compound 5

To a solution of compounds 5-8 (100 mg, 133. Mu. Mol,1.00 eq.) in DMF (1.00 mL) was added CsF (101 mg, 663. Mu. Mol, 24.5. Mu.L, 5.00 eq.) and the mixture was stirred at 20℃for 12 hours. LC-MS (product: rt=0.618 min) showed that compounds 5-8 were completely consumed and one main peak with the desired mass was detected. The mixture was filtered to give a residue. The residue was purified by preparative HPLC (column: phenomenex C18 x 30mm x 3 μm; mobile phase: [ water (FA) -ACN ];: B%:2% -32%,7 min). Compound 5 (23.2 mg,37.8 μmol, 28.5% yield, 97.3% purity) was obtained as a white solid as confirmed by HPLC, H NMR, F NMR and SFC.

HPLC:97.26% purity

H NMR：(400MHz，DMSO-d6)δ8.18(s，1H)，7.90-7.85(m，1H)，7.63(d，J＝8.0Hz， 1H)，7.49-7.38(m，3H)，7.31(d，J＝4.0Hz，1H)，7.04-7.00(m，1H)，5.28(d，J＝56.0Hz， 1H)，4.65-4.48(m，2H)，4.08-4.04(m，1H)，3.99-3.95(m，1H)，3.88-3.83(m，2H)，3.78- 3.68(m，5H)，3.60(s，1H)，3.13-3.07(m，2H)，3.02(s，1H)，2.94-2.89(m，2H)，2.87-2.79 (m，1H)，2.21-1.97(m，3H)，1.91-1.69(m，3H)。

Example 6

Step 1 preparation of Compound 6-2

To compound 6-1 (1.50 g,5.79mmol,1.00 eq.) and DIEA (2.25 g,17.4mmol, 3.03mL,3.00 eq.) in POCl at 0deg.C ₃ (15.0 mL) and then heated to 110℃and stirred for 1 hour. TLC (SiO) ₂ ，PE/EtOAc＝3/1，R _f =0.7) indicates that compound 6-1 was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 6-2 (1.71 g, crude product) was obtained as a black oil.

Step 2 preparation of Compound 6-4

To a solution of compound 6-2 (500 mg,1.69mmol,1.00 eq.) in DCM (10.0 mL) was added DIEA (1.53 g,11.8mmol,2.06mL,7.00 eq.) and compound 6-3 (267 mg,1.18mmol,0.70 eq.). The mixture was stirred at-40℃for 1 hour. LC-MS (product: rt=1.104 min) showed complete consumption of compound 6-2, the desired mass was detected. The combined reaction mixture was taken up in DCM (30.0 mL. Times.3) with H ₂ O (50.0 mL ×2). The organic phase was separated, washed with brine (60.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The combined residue was purified by column chromatography (SiO ₂ PE/etoac=50/1 to 5/1) and by preparative HPLC (column: welch Ultimate XB-CN 250 x 70 x 10 μm; mobile phase: [ Hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:5% -45%,20 min). Compound 6-4 (298 mg, 613. Mu. Mol,36.3% yield, 100% purity) was obtained as confirmed by LC-MS, H NMR, F NMR and special NMR.

LC-MS：(M+H) ⁺ ＝487.1

H NMR：(400MHz，DMSO-d6)δ8.12(d，J＝6.8Hz，1H)，8.09-7.93(m，1H)，4.55- 4.46(m，2H)，4.20(d，J＝15.2Hz，2H)，3.67-3.57(m，2H)，3.03(s，1H)，1.57-1.84(m，5H)， 1.45(s，9H)。

Step 3 preparation of Compound 6-6

To a solution of compound 6-5 (70.8 mg, 444. Mu. Mol,0.90 eq.) in THF (8.00 mL) was added NaH (19.7 mg, 494. Mu. Mol,60.0% purity, 1.00 eq.) at 0deg.C, stirred for 0.5 hours, and compound 6-4 (240 mg, 494. Mu. Mol,100% purity, 1.00 eq.) was added to the mixture at 0deg.C. The mixture was stirred at 25℃for 2 hours. The desired compound mass was detected on LC-MS (product: rt=0.873 min). The reaction mixture was treated with NH ₄ Aqueous Cl (saturated, 30.0 mL) was quenched and extracted with EtOAc (20.0 mL. Times.3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The combined residue was purified by preparative HPLC (column: welch Ultimate XB-SiOH 250 x 50 x 10 μm; mobile phase: [ hexane-EtOH)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -25%,15 min). Compound 6-6 (250 mg, 380. Mu. Mol,76.9% yield, 92.5% purity) was obtained as confirmed by LC-MS, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝610.0

H NMR：(400MHz，DMSO-d6)δ7.92(d，J＝7.2Hz，1H)，7.81-7.77(m，1H)，5.25(d，J ＝54.0Hz，1H)，4.46-4.38(m，2H)，4.18(d，J＝12.4Hz，2H)，4.09-3.98(m，2H)，3.54-3.41 (m，3H)，3.13-3.00(m，3H)，2.85-2.81(m，1H)，2.11-2.09(m，1H)，2.03-1.83(m，4H)，1.80- 1.67(m，6H)，1.44(s，9H)。

Step 4 preparation of Compounds 6-8

To compound 6-6 (230 mg, 349. Mu. Mol,92.5% purity, 1.00 eq), compound 7 (173 mg, 349. Mu. Mol,99.5% purity, 1.00 eq) and K ₃ PO ₄ (148 mg, 699. Mu. Mol,2.00 eq.) in THF (8.00 mL) and H ₂ To a solution of Ad2nBuP-Pd-G3 (12.7 mg, 17.5. Mu. Mol,0.05 eq.) in O (0.50 mL) was added. The mixture was stirred at 60℃for 6 hours. The desired compound mass was detected on LC-MS (product: rt=0.985 min). The mixture was filtered, and the filtrate was concentrated to give a residue. Will be combinedThe combined residue was purified by preparative HPLC (column: welch Ultimate XB-SiOH 250 x 70 x 10 μm; mobile phase: [ hexane-EtOH)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -20%,15 min). The residue was purified by preparative HPLC (column: phenomenex C18X 30mm X3 μm; mobile phase: [ water (FA) -ACN)]The method comprises the steps of carrying out a first treatment on the surface of the B%:45% -75%,7 min). As confirmed by LC-MS, compound 6-8 (40.0 mg, 40.6. Mu. Mol,11.6% yield, 91.0% purity) was obtained.

LC-MS：(M+H) ⁺ ＝896.6

Step 5 preparation of Compounds 6-9

To a solution of compound 6-8 (40.0 mg,40.6 μmol,91.0% purity, 1.00 eq.) in DCM (2.00 mL) was added HCl/dioxane (4.00 m,910 μl,89.6 eq.). The mixture was stirred at 0 ℃ for 2 hours. LC-MS (product: rt=0.885 min) showed complete consumption of compounds 6-8, where the desired mass was detected. The mixture was treated with NaHCO ₃ (saturation) was adjusted to ph=7 and mixed with H in DCM (10.0 ml×3) ₂ O (20.0 mL. Times.2). The organic phase was separated, washed with brine (15.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was used in the next step without purification. Compound 6-9 (30.5 mg, crude) was obtained as a brown oil.

Step 6 preparation of Compound 6

To a solution of compound 6-9 (30.5 mg, 40.6. Mu. Mol, crude product purity, 1.00 eq.) in DMF (1.00 mL) was added CsF (18.5 mg, 121. Mu. Mol, 4.49. Mu.L, 3.00 eq.). The mixture was stirred at 25℃for 12 hours. LC-MS (product: rt=0.755 min) showed complete consumption of compounds 6-9, where the desired mass was detected. The reaction mixture was filtered and the filtrate was collected and purified by preparative HPLC (column Phenomenex Luna C, 150 x 25mm x 10 μm; mobile phase: [ water (FA) -ACN ]; B%:4% -34%,10 min). As confirmed by LC-MS, HPLC, H NMR, F NMR and SFC, compound 6 (14.0 mg,21.5 μmol,53.0% yield, 98.7% purity, FA) was obtained.

LC-MS：(M+H) ⁺ ＝596.4

HPLC: purity of 98.7%

H NMR：(400MHz，DMSO-d6)δ8.26(s，1H)，7.87(d，J＝8.4Hz，1H)，7.57(d，J＝10.0 Hz 1H)，7.52(d，J＝7.2Hz，1H)，7.47(d，J＝6.8Hz，1H)，7.43-7.39(m，1H)，7.31(d，J＝2.4 Hz，1H)，7.03(d，J＝1.2Hz，1H)，5.25-5.21(m，1H)，4.37-4.32(m，2H)，4.08(d，J＝10.4 Hz，1H)，4.01-3.97(m，1H)，3.62-3.53(m，5H)，3.22(s，3H)，3.10-2.99(m，4H)，2.86-2.80 (m，1H)，2.18-2.11(m，1H)，2.05-2.00(m，2H)，1.91-1.75(m，6H)。

Example 7

Step 1 preparation of Compound 7-3

At N ₂ Pd/C (50.0 mg, 992. Mu. Mol,10.0% purity, 0.60 eq.) was added to a solution of compounds 7-10 (500 mg,1.65mmol,1.00 eq.) in THF (30.0 mL) under an atmosphere, and the mixture was then taken up in H ₂ (2.00 mg, 992. Mu. Mol) was stirred at 30℃for 12 hours. TLC (SiO) ₂ ，PE/EtOAc＝3/1，R _f =0.80) indicates that compounds 7-10 were retained and some new spots were formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. No purification was performed. Compound 7-3 (400 mg, crude product) was obtained as a colorless solid.

Step 2 preparation of Compound 7-2

DIEA (5.24 g,40.5mmol,7.06mL,7.00 eq.) at 0deg.C to POCl ₃ To a solution in (15.0 mL) was added compound 7-1 (1.50 g,5.79mmol,1.00 eq.) and the reaction mixture was stirred at 110℃for 1 hour. TLC (SiO) ₂ ，PE/EtOAc＝3/1，R _f =0.80) indicates that compound 7-1 was retained and a new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. No purification was performed. Compound 7-2 (1.70 g, crude product) was obtained as a red oil.

Step 3 preparation of Compound 7-4

To a solution of compound 7-2 (400 mg,1.35mmol,1.00 eq.) in DCM (5.00 mL) at-40℃were added DIEA (1.22 g,9.46mmol,1.65mL,7.00 eq.) and compound 7-3 (284 mg,1.34mmol, 1.00 eq.) and the mixture was stirred at 25℃for 1 hour. LC-MS (product: rt=1.043 min) showed complete consumption of compound 7-2 and detection of one major peak with the desired mass. The reaction mixture was taken up in DCM (20.0 mL. Times.3) with H ₂ O (20.0 mL). The organic phase was separated, washed with brine (20.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-CN 250X 70X 10 μm; mobile phase: [ hexane-EtOH)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -30%,20 min). As confirmed by H NMR, F NMR and special NMR, compound 7-4 (435 mg, 922. Mu. Mol, 68.2% yield) was obtained.

H NMR：EW30877-74-P1B1(400MHz，DMSO-d6)δ8.11(d，J＝6.8Hz1H)，7.84(d，J＝ 9.6Hz，1H)，4.96(d，J＝17.2Hz，2H)，3.91-3.82(m，2H)，3.36(m，1H)，3.17(d，J＝12.0Hz， 1H)，1.93-1.92(m，2H)，1.70-1.67(m，2H)，1.43(s，9H)

Step 4 preparation of Compounds 7-6

To a solution of compound 7-5 (118 mg, 741. Mu. Mol,1.00 eq.) in THF (5.00 mL) at 0deg.C was added NaH (29.6 mg, 741. Mu. Mol,60.0% purity, 1.00 eq.) and the mixture was stirred for 0.5 hours, then compound 7-4 (350 mg, 741. Mu. Mol,1.00 eq.) was added at 80deg.C and the mixture was stirred for 1.5 hours. LC-MS (product: rt=0.758 min) showed that the desired mass was detected. The reaction mixture was taken up in EtOAc (30.0 mL X3) and NH ₄ Cl (30.0 mL) was partitioned between. The organic phase was separated, washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 70X 10 μm; mobile phase: [ hexane-EtOH) ]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -20%,15 min). Compound 7-6 (250 mg, crude product) was obtained as a yellow solid.

Step 5 preparation of Compounds 7-8

At N ₂ Compounds 7 to 6 (220 mg, 370. Mu. Mol,1.00 eq.) and 7 to 7 (183 mg, 370. Mu. Mol,99.5% purity, 1.00 eq.) and K were added to the mixture under an atmosphere at 25 ℃ ₃ PO ₄ (235 mg,1.11mmol,3.00 eq.) in THF (5.00 mL) and H ₂ To a solution of Ad2nBuP-Pd-G3 (26.9 mg, 37.0. Mu. Mol,0.10 eq.) in O (1.00 mL) was added, and the mixture was stirred at 60℃for 3 hours. LC-MS (product: rt=1.008 min) showed the detection of the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-CN 250X 70X 10 μm; mobile phase: [ hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -30%,20 min). Compounds 7-8 (230 mg, crude) were obtained as yellow solids.

Step 6 preparation of Compounds 7-9

To a solution of compounds 7-8 (230 mg,260 μmol,1.00 eq.) in DCM (2.00 mL) was added HCl/dioxane (4.00 m,1.00mL,15.3 eq.) at 0 ℃ and the mixture was stirred at 0 ℃ for 1 hour. LC-MS (product: rt=0.877 min) showed complete consumption of compound 7-8 and detection of one major peak with the desired mass. The mixture was treated with NaHCO ₃ (saturation) was adjusted to ph=7 and mixed with H in DCM (10.0 ml×2) ₂ O (10.0 ml×2). The organic phase was separated, washed with brine (10.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. No purification was performed. Compounds 7-9 (120 mg, crude) were obtained as yellow solids.

Step 7 preparation of Compound 7

To a solution of compounds 7-9 (120 mg, 162. Mu. Mol,1.00 eq.) in DMF (2.00 mL) was added CsF (24.7 mg, 162. Mu. Mol, 6.00. Mu.L, 1.00 eq.) and the mixture was stirred at 25℃for 12 hours. LC-MS (product: rt=0.714 min) showed the detection of the desired mass. The reaction mixture was filtered to give a residue. The residue was purified by means of preparative HPLC (column: phenomenex C18X 30mm X3 μm; mobile phase: [ water (FA) -ACN ];: B%:5% -35%,7 min). Compound 7 (10.27 mg,15.3 μmol,9.42% yield, 93.6% purity, FA) was obtained as confirmed by LC-MS, HPLC, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝582.3

HPLC:93.6% purity

¹ H NMR：(400MHz，DMSO-d6)δ8.21(s，1H)，7.88-7.86(m，1H)，7.62(d，J＝10.4Hz， 1H)，7.50-7.46(m，2H)，7.43-7.39(m，1H)，7.31(d，J＝2Hz，1H)，7.03-7.02(m，1H)，5.34 -521(m，1H)，4.78-4.73(m，2H)4.05(d，J＝10Hz，1H)，3.96(d，J＝10.4Hz，1H)，3.61(s， 2H)，3.13-3.01(m，5H)，2.85-2.77(m，3H)，2.19-2.09(m，1H)，2.05-1.74(m，9H)。

Example 8

Step 1 preparation of Compound 8-2

Compound 8-1 (1.50 g,5.79mmol,1.00 eq.) and DIEA (3.74 g,29.0mmol,5.04mL, 5.00 eq.) were added to POCl ₃ The mixture in (15.0 mL) was stirred at 110℃for 1 hour. TLC (SiO) ₂ ，PE/EA＝ 3/1，R _f =0.6) indicates that compound 8-1 was retained and a new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 8-2 (1.70 g, crude product) was obtained as a red oil.

Step 2 preparation of Compound 8-4

To a solution of compound 8-2 (400 mg,1.35mmol,1.00 eq.) in DCM (6.00 mL) was added DIEA (1.22 g,9.46mmol,1.65mL,7.00 eq.) and compound 8-3 (188 mg, 946. Mu. Mol, 0.70 eq.) at-40 ℃. The mixture was stirred at-40℃for 0.5 h. TLC (SiO) ₂ ，PE/EA＝3/1，R _f =0.6) indicates that compound 8-2 was completely consumed and a new spot was formed. The combined reaction mixture was taken up with H ₂ O (30.0 mL) was quenched and extracted with DCM (20.0 mL. Times.3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ PE/ea=30/1 to 3/1). As confirmed by LC-MS, H NMR, F NMR and special NMR, compound 8-2 (490 mg,1.03mmol,76.4% yield,96.5% purity).

LC-MS：(M+H) ⁺ ＝459.0

H NMR：(400MHz，DMSO-d6)δ8.08-7.94(m，2H)，5.20(d，J＝8.8Hz，1H)，4.55(d，J ＝18.4Hz，1H)，4.26(s，1H)，3.83(s，1H)，3.46(d，J＝10.0Hz，1H)，3.41(s，1H)，1.97(s，2H)， 1.37(d，J＝13.2Hz，9H)。

Step 3 preparation of Compounds 8-6

To a solution of compound 8-5 (138 mg, 864. Mu. Mol,1.00 eq.) in THF (3.00 mL) was added NaH (34.6 mg, 864. Mu. Mol,60.0% purity, 1.00 eq.) at 0deg.C, stirred for 0.5 hours, then compound 8-4 (410 mg, 864. Mu. Mol,96.5% purity, 1.00 eq.) was added to the mixture at 0deg.C. The mixture was stirred at 80℃for 1 hour. LC-MS (product: rt=0.796 min) showed complete consumption of compound 8-4 and the desired mass was detected. The reaction mixture was treated with NH ₄ Aqueous Cl (saturated, 30.0 mL) was quenched and extracted with DCM (20.0 mL. Times.3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 50X 10 μm; mobile phase: [ hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -30%,15 min). As confirmed by H NMR, F NMR and SFC, compound 8-6 (220 mg, 379. Mu. Mol,43.8% yield) was obtained.

H NMR：(400MHz，DMSO-d6)δ7.98-7.87(m，1H)，7.87-7.66(m，1H)，5.36-5.12(m， 2H)，4.53(br d，J＝18.8Hz，1H)，4.24(br d，J＝7.2Hz，1H)，4.09-3.95(m，2H)，3.77-3.69 (m，1H)，3.32-3.26(m，1H)，3.11-3.04(m，2H)，3.00(s，1H)，2.86-2.77(m，1H)，2.16-2.07 (m，1H)，2.07-1.67(m，8H)，1.36(br d，J＝14.4Hz，9H)。

Step 4 preparation of Compounds 8-8

To compound 8-6 (200 mg, 345. Mu. Mol,1.00 eq.) in THF (4.50 mL) and H ₂ To a solution of compound 8-7 (171 mg, 345. Mu. Mol,99.5% purity, 1.00 eq.) K, was added in O (1.50 mL) ₃ PO ₄ (219 mg, 1.03mmol,3.00 eq.) and Ad2nBuP-Pd-G3 (50.2 mg, 68.9. Mu. Mol,0.20 eq.) and the mixture was stirred at 60℃for 3 hours. LC-MS (product: rt=0.975 min) showed complete consumption of compound 8-6 and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 70X 10 μm; mobile phase: [ hexane-EtOH (0.1% NH) ₃ ·H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -35%,15 min) and preparative HPLC (column: phenomnex C18X 30mm X3 μm; mobile phase: [ Water (FA) -ACN]The method comprises the steps of carrying out a first treatment on the surface of the B%:40% -70%,7 min). Compound 8-8 (70.0 mg, 80.6. Mu. Mol,23.4% yield) was obtained as a yellow solid.

Step 5 preparation of Compounds 8-9

To a solution of compounds 8-8 (70.0 mg, 80.6. Mu. Mol,1.00 eq.) in DCM (2.00 mL) was added HCl/dioxane (4.00M, 2.00 mL) at 0deg.C. The mixture was stirred at 25℃for 0.5 h. LC-MS (product: rt= 0.871 min) showed that compounds 8-8 were retained and the desired mass was detected. The mixture was treated with NaHCO ₃ The aqueous solution (saturated) was adjusted to ph=7 and extracted with DCM (10.0 ml×3). The combined organic fractions were washed with brine (20.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. Compounds 8-9 (60.0 mg, crude) were obtained as yellow solids.

Step 6 preparation of Compound 8

To a solution of compound 8-9 (60.0 mg, 82.9. Mu. Mol,1.00 eq.) in DMF (1.00 mL) was added CsF (62.9 mg, 414. Mu. Mol,5.00 eq.). The mixture was stirred at 25℃for 12 hours. LC-MS (product: rt=0.717 minutes) showed that compounds 8-9 were retained and the desired mass was detected. The reaction mixture was filtered to give a residue. The residue was purified by means of preparative HPLC (column: phenomenex C18X 30mm X3 μm; mobile phase: [ water (FA) -ACN ]; B%:2% -32%,7 min). Compound 8 (11.8 mg,18.5 μmol,22.4% yield, 96.3% purity, FA) was obtained as confirmed by LC-MS, HPLC, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝568.4

HPLC:99.5% purity

H NMR：(400MHz，DMSO-d6)δ 8.25(s，2H)，7.87(d，J＝8.0Hz，1H)，7.73-7.63(m， 1H)，7.49-7.38(m，3H)，7.31(d，J＝2.4Hz，1H)，7.06-6.97(m，1H)，5.37-5.18(m，1H)，5.09 (br d，J＝14.0Hz，1H)，4.29-4.23(m，1H)，4.08-4.01(m，2H)，4.00-3.95(m，1H)，3.85- 3.78(m，1H)，3.71(s，1H)，3.60(s，1H)，3.28-3.21(m，1H)，3.19-3.14(m，1H)，3.13-3.07 (m，2H)，3.01(s，1H)，2.87-2.79(m，1H)，2.18-2.09(m，1H)，2.07-1.94(m，3H)，1.87-1.72 (m，4H)。

Example 9

Step 1 preparation of Compound 9-3

At N ₂ Down compound 9-1 (200 mg, 327. Mu. Mol,1.00 eq.) in THF (3.00 mL) and H ₂ To a solution in O (1.00 mL) was added Compound 9-2 (201 mg, 392. Mu. Mol,1.20 eq.) K ₃ PO ₄ (208 mg, 980. Mu. Mol, 3.00 eq.) and Ad2nBuP-Pd-G3 (47.6 mg, 65.3. Mu. Mol,0.20 eq)) The mixture was then stirred at 60 ℃ for 3 hours. LC-MS (product: rt=1.064 min) showed that compound 9-1 was retained and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Welch Ultimate XB-SiOH 250X 70X 10 μm; mobile phase: [ hexane-EtOH (0.1% NH) ₃ .H ₂ O)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -20%,15 min) and preparative HPLC (column: 3Phenomenex Luna C18 75X 30mm X3 μm; mobile phase: [ Water (TFA) -ACN]The method comprises the steps of carrying out a first treatment on the surface of the B%:65% -85%,8 min). As confirmed by SFC, compound 9-3 (40.0 mg, 43.6. Mu. Mol,13.3% yield) was obtained.

Step 2 preparation of Compound 9-4

To a solution of compound 9-3 (40.0 mg,43.6 μmol,1.00 eq.) in DCM (2.00 mL) was added HCl/dioxane (4.00 m,2.00 mL) at 0 ℃. The mixture was stirred at 15℃for 1 hour. LC-MS (product: rt=0.868 min) showed that compound 9-3 was retained and the desired mass was detected. The mixture was treated with NaHCO ₃ The aqueous solution (saturated) was adjusted to ph=7 and extracted with DCM (10.0 ml×3). The combined organic fractions were washed with brine (30.0 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. Compound 9-4 (40.0 mg, crude product) was obtained.

Step 3 preparation of Compound 9

To a solution of compound 9-4 (40.0 mg, 51.7. Mu. Mol,1.00 eq.) in DMF (1.00 mL) was added CsF (39.3 mg, 258. Mu. Mol,5.00 eq.). The mixture was stirred at 15℃for 12 hours. LC-MS (product: rt=0.749 min) showed that compound 9-4 was completely consumed and the desired mass was detected. The reaction mixture was filtered to give a residue. The residue was purified by means of preparative HPLC (column: phenomenex C18X 30mm X3 μm; mobile phase: [ water (FA) -ACN ];: B%:5% -35%,7 min). Compound 9 (15.4 mg,23.1 μmol,44.7% yield, 99.4% purity, FA) was obtained as confirmed by LC-MS, HPLC, H NMR, F NMR and SFC.

LC-MS：(M+H) ⁺ ＝618.5

HPLC:99.4% purity

H NMR：(400MHz，DMSO-d6)δ8.22(s，1H)，7.99(dd，J1＝6.0Hz，J2＝9.2Hz，1H)， 7.55(br d，J＝10.0Hz，1H)，7.48(t，J＝8.8Hz，1H)，7.41(d，J＝2.4Hz，1H)，7.14(d，J＝1.6 Hz，1H)，5.37-5.17(m，1H)，4.25(br t，J＝10.8Hz，2H)，4.09-4.05(m，1H)，3.99-3.95(m， 2H)，3.61(br s，1H)，3.56(br s，1H)，3.53(br s，1H)，3.49(br s，1H)，3.46(br s，1H)，3.12-3.06 (m，2H)，3.01(s，1H)，2.87-2.79(m，1H)，2.19-2.09(m，1H)，2.08-1.96(m，2H)，1.90-1.62 (m，7H)。

Example 10

Step 1 preparation of Compound 10-3

To a solution of compound 10-1 (15.0 g,72.1mmol,1.00 eq.) in DCM (150 mL) was added compound 10-2 (10.8 g,79.3mmol,8.46mL,1.10 eq.) and TEA (21.9 g,216mmol,30.1mL, 3 eq.) and the mixture was stirred at 20deg.C for 1 hour. LC-MS (product: rt=1.011 min) showed that compound 10-1 was completely consumed and a main peak with the desired mass was detected. The reaction mixture was washed with water (500 mL), then diluted with DCM (500 mL) and extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (500 mL), with Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 10-3 (24.0 g, crude product) was obtained as a white solid.

Step 2: preparation of Compound 10-4

Compound 10-3 (24.0 g,77.9mmol,1.00 eq.) was combined with MeOH (240 mL) and H at 0deg.C ₂ NaOH (9.35 g,234mmol,3.00 eq.) was added to a solution of O (70.0 mL) and the mixture was stirred at 20deg.C for 2 hours. LC-MS (product: rt1=0.193) showed complete consumption of compound 10-3, several new peaks on LC-MS, 57% of the desired compound was detected. The reaction mixture was concentrated to remove MeOH, extracted with EtOAc (250 mL), the aqueous layer was ph=1 adjusted with HCl (1M), extracted with EtOAc (250 mL x 3), and the combined organic layers were extracted with H ₂ O (250 mL) and brine (250 mL) were washed with Na ₂ SO ₄ Drying, filtering, and concentrating the filtrate to obtain a residue. The residue was purified by preparative HPLC (column: welch Ultimate XB-SiOH 250 x 50 x 10 μm; mobile phase: [ hexane-EtOH (0.1% FA))]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -25%,15 min). As confirmed by H NMR and F NMR, compound 10-4 (8.70 g,29.6mmol,38.0% yield) was obtained as a white solid.

H NMR：(400MHz，DMSO-d6)δ12.69(s，1H)，10.11(s，1H)，7.93-7.87(m，1H)， 7.29-7.24(m，1H)，3.44(s，2H)。

Step 3: preparation of Compound 10-5

Compound 10-4 (4.00 g,13.6mmol,1.00 eq.) was added to P ₂ O ₅ A solution of/MsOH (16.2 g,68.0mmol, 10.7mL,5.00 eq.) in N ₂ Stirring is carried out for 36 hours at 100℃under an atmosphere. LC-MS (product: rt1=0.279) showed complete consumption of compound 10-4, and detection of a major peak with the desired mass. The reaction mixture was quenched with ice water (200 mL), filtered, the filter cake was the product, the filtrate was diluted with DCM (200 mL) and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL), and with Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 10-5 (4.00 g, crude product) was obtained as a white solid.

Step 4: preparation of Compound 10-5

POCl was added to a mixture of compound 10-5 (100 mg, 365 umol,1.00 eq.) in toluene (1.00 mL) at 0deg.C ₃ (555 mg,3.63mmol, 337. Mu.L, 10.0 eq.) and DIEA (140 mg,1.09mmol, 189. Mu.L, 3.00 eq.) and the mixture was stirred at 110℃for 1 hour. TLC (SiO) ₂ PE/etoac=10/1) showed that compound 10-5 was completely consumed, forming a new spot. Concentrating the mixture to remove POCl ₃ The mixture was then quenched with water (20.0 mL) and NaHCO ₃ Saturated aqueous (20.0 mL) was washed, diluted with DCM (50.0 mL) and extracted with DCM (50.0 mL x 2). The combined organic layers were washed with brine (50.0 mL), na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 10-6 (120 mg, crude) was obtained as a brown solid.

Step 5: preparation of Compound 10-8

To a solution of compound 10-6 (700 mg,2.24mmol,1.00 eq.) in DMF (7.00 mL) was added compound 10-7 (552 mg,2.46mmol,1.10 eq.) and K2CO ₃ (1.24 g,8.95mmol,4.00 eq.) then the mixture was stirred at 80℃for 1 hour. LC-MS (product: rt1=0.825) showed complete consumption of compound 10-6, and the desired mass was detected. The reaction mixture was quenched with ice water (50.0 mL), then diluted with EtOAc (50.0 mL) and extracted with EtOAc (50.0 mL. Times.2). The combined organic layers were washed with brine (200 mL), na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give a residue. Preparation of residuesHPLC (column Welch Ultimate XB-CN 250.5010 μm; mobile phase: [ hexane-EtOH)]The method comprises the steps of carrying out a first treatment on the surface of the B%:1% -15%,10 min). As confirmed by H NMR and F NMR, compound 10-8 (215 mg, 439.90. Mu. Mol,19.66% yield) was obtained as a white solid.

H NMR：(400MHz，DMSO-d6)δ7.70-7.59(m，1H)，7.20(s，1H)，4.25(s，2H)，3.51- 3.42(m，2H)，3.16-3.05(m，2H)，2.10-1.89(m，4H)，1.44(s，9H)

Step 6: preparation of Compounds 10-10

To a solution of compound 10-8 (215 mg, 440. Mu. Mol,1.00 eq.) in DMF (2.00 mL) was added compound 10-9 (70.0 mg, 440. Mu. Mol,1.00 eq.) and K ₂ CO ₃ (243 mg,1.76mmol,4.00 eq.) and then the mixture was stirred at 120℃for 24 hours. LC-MS (product: rt1=0.834) showed complete consumption of compound 10-8, and the desired mass was detected. The reaction mixture was quenched with ice water (20.0 mL), then diluted with DCM (20.0 mL) and extracted with DCM (20.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: phenomnex C1875 x 30mm x 3 μm; mobile phase: [ water (FA) -ACN)]The method comprises the steps of carrying out a first treatment on the surface of the B%:25% -55%,7 min). As confirmed by H NMR and F NMR, compound 10-10 (70.0 mg, 114. Mu. Mol,26.02% yield) was obtained as a white solid.

H NMR：(400MHz，DMSO-d6)δ7.56(d，J＝12.0Hz，1H)，6.63(s，1H)，5.45-5.14(m， 1H)，4.31-4.00(m，4H)，3.62-3.58(m，1H)，3.19-2.91(m，5H)，2.86-2.80(m，1H)，2.16- 1.91(m，7H)，1.89-1.70(m，4H)，1.43(s，9H)。

Step 7: preparation of Compound 10i12

To compound 10-10 (50.0 mg,818 mu mol,1.00 eq.) in THF (1.00 mL) and H ₂ To a solution of compound 10-11 (46.1 mg, 89.9. Mu. Mol,1.10 eq.) in O (0.30 mL), ad was added ₂ nBuP-Pd-G ₃ (5.95 mg, 8.18. Mu. Mol,0.10 eq.) and K ₃ PO ₄ (52.1 mg, 245. Mu. Mol,3.00 eq.) the mixture was then stirred under microwave conditions at 60℃for 30 minutes. LC-MS (product: rt1=0.733) showed complete consumption of compound 10-10, the desired mass was detected. The reaction mixture was quenched with ice water (50.0 mL), then diluted with DCM (50.0 mL) and extracted with DCM (50.0 mL x 2). The combined organic layers were washed with brine (50.0 mL), na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: phenomnex C18X 30mm X3 μm; mobile phase: [ water (FA) -ACN)]The method comprises the steps of carrying out a first treatment on the surface of the B%:48% -78%,7 min). Compound 10-12 (20.0 mg, 21.81. Mu. Mol,26.67% yield) was obtained as a white solid.

Step 8: preparation of Compounds 10-13

To a solution of compound 10-12 (20.0 mg, 21.8. Mu. Mol,1.00 eq.) in DCM (1.00 mL) was added HCl/dioxane (4.00M, 5.45. Mu.L, 1.00 eq.) at 0deg.C, and the mixture was stirred at 0deg.C for 30 min. LC-MS (product: rt1=0.586) showed complete consumption of compound 10-12, and the desired mass was detected. The reaction mixture was quenched with ice water (10.0 mL) and NaHCO ₃ The saturated aqueous solution (10.0 mL) was quenched, then diluted with DCM (20.0. 20.0 mL) and extracted with DCM (20.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give a residue. The residue was used in the next step without further purification. Compound 10-13 (15.0 mg, 19.4. Mu. Mol,89.0% yield) was obtained as a white solid.

Step 9: preparation of Compound 10

To a solution of compound 10-13 (15.0 mg, 19.4. Mu. Mol,1.00 eq.) in DMF (1.00 mL) was added CsF (14.7 mg, 97.0. Mu. Mol, 3.58. Mu.L, 5.00 eq.) and the mixture was stirred at 20℃for 10 hours. LC-MS (product: rt1=0.430) showed that compound 10-13 was completely consumed and one main peak with the desired mass was detected. The mixture was filtered to give a residue. The residue was purified by means of preparative HPLC (column: phenomenex C18X 30mm X3 μm; mobile phase: [ water (FA) -ACN ];: B%:5% -35%,7 min). Compound 10 (120. Mu.g, 0.195. Mu. Mol,1.00% yield) was obtained.

Example 11

Biochemical assay

Measurement 1:

AGS cells expressing G12D (ATCC CRL-1739) were grown in DMEM medium supplemented with 10% fetal bovine serum, 10mM HEPES and penicillin/streptomycin. Cells were plated at a density of 10,000 cells/well in tissue culture treated 96-well plates and allowed to adhere for 16 to 18 hours. The diluted compound was then added at a final concentration of 0.5% dmso. After 1 hour of compound treatment, the Phospho-ERK1/2 content was detected using the Advanced Phospho-ERK1/2 (THR 202/TYR 204) kit (Cisbio 64 AERPEH). The medium was removed, 50 μl lysis buffer 1 was added and the plates were incubated for 30 min at room temperature. Then 16 μl of cell lysis was transferred to a new low-volume HTRF plate, and 2 μ l Advanced PhosphoERK1/2Eu Cryptate antibody and 2 μ l Advanced PhosphoERK1/2 d2 antibody were added to the cell lysis plate. After 4 hours of incubation at room temperature, the excitation was performed on Envision: 320nm, emission: the assay plates were read at 615nm and 665 nm.

The inhibition ratio was calculated by (sample-Min)/(Max-Min) ×100%

Max: wells treated with 10 μm positive control

Min: media pores

Dose response curve and IC ₅₀ Log (inhibitor) and response-Variable slope (log (inhibitor) vs. response-Variable slope) were used to generate by GraphPad Prism software.

The compounds of the present disclosure exhibit an IC of 1nM to 500nM ₅₀ Values.

Measurement 2: KRAS G12D-SOS1 Activity assay

1 Xassay buffer (modified Tris buffer) was prepared. Test compounds were transferred to assay plates by Echo in 100% dmso. The final fraction of DMSO was 0.25%. A GTPase mixture was prepared in 1 Xassay buffer. Transfer 10 μl of GTPase cocktail to assay plate and for low control transfer 10 μl of 1 Xassay buffer. GEF mixed solution was prepared in 1x assay buffer. Mu.l of the GEF mixture was transferred to the assay plate. GTP solutions were prepared in 1 Xassay buffer. Transfer 5 μl of GTP solution to assay plate. A detection reagent solution was prepared in 1 Xassay buffer. Transfer 10. Mu.l of the detection reagent solution to the assay plate. Plates were read on Spectra Max Paradigm at 580nm excitation and 620 nm emission for 2 hours. Equation (1) was used in Excel to fit the data to obtain the inhibition value. Fitting data to obtain IC using equation (2) in XL-Fit ₅₀ Values.

Equation (1): inhibition% = (Max-signal)/(Max-Min) 100

Equation (2): y=bottom+ (top-bottom)/(1+ (IC 50/X) ×hill slope)

Y is% inhibition, and X is compound concentration.

Compound 1 of the present disclosure exhibited an IC of 35nM ₅₀ Values. Other compounds of the present disclosure exhibit IC's of 1nM to 500nM ₅₀ Values.

Measurement 3: tumor cell antiproliferation assay (CTG assay)

Procedure

1. When the cell confluency reached 80%, cells were collected and counted.

2. The GP2D cell suspension was diluted to 2000 cells/well. Mu.l of the cell suspension was inoculated into each well of a 96-well plate.

3. The cell plates were returned to 37℃with 5% CO ₂ In an incubator.

4. After 24 hours of incubation, 20 μl of diluted compound solution was added to the designated wells of the plate. The compound was laid out on the next slide and the final DMSO concentration was 0.5%.

5. The plates were returned to the incubator and incubated for a further 5 days.

6. After 5 days of incubation, CTG assays were completed according to manufacturer's manual.

7. And (3) data calculation:

inhibition% = ((RFU) _{Compounds of formula (I)} -AVER(RFU _{Negative control} ))/((AVER(RFU _sTsP )-AVER(RFU _{Negative control} ))×100％

Table 1 provides the results for exemplary compounds of the present disclosure.

TABLE 1

Numbering of compounds	GP2D CTG 3D IC ₅₀ (nM)
		1	7.4
2	139.9
		3	3.3
7	105.9
		8	536.1
9	1.0
		10	236.3

The foregoing description is considered as illustrative only of the principles of the disclosure. In addition, since numerous modifications and variations will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown and described above. Accordingly, all suitable modifications and equivalents may be resorted to as falling within the scope of the invention as defined by the appended claims.

Claims

1. A compound having formula (IIb) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

Ring a is:

L ¹ is O;

L ² selected from the group consisting of: bond, alkyl, alkenyl, alkynyl;

R ¹ to be covered by one or more R ^b SubstitutedWherein each R is ^b Independently halogen, alkoxy or-OC (O) NR ^d R ^e ，R ^d And R is ^e Each independently is alkyl;

R ² naphthyl optionally substituted with one or more groups selected from cyano, halogen, hydroxy, alkyl, alkenyl or alkynyl;

R ³ is hydrogen;

R ⁴ is halogen;

R ⁵ hydrogen or halogen;

wherein the alkyl group is C _1-6 An alkyl group; the alkenyl group contains 2 to 6 carbon atoms; the alkynyl group contains 2 to 6 carbon atoms; the alkoxy group is C _1-6 An alkoxy group;

wherein the compound or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is not a compound as shown below:

2. the compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L ² Is C _1-6 An alkyl group.

3. A compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ¹ Is covered by one R ^b Substituted

4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ^b Is halogen.

5. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ^b Is C _1-6 An alkoxy group.

6. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ^b is-OC (O) NR ^d R ^e Wherein R is ^d And R is ^e Each independently is C _1-6 An alkyl group.

7. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula selected from the group consisting of:

8. a pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is formulated for oral administration.

10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is formulated for injection.

11. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 8 to 10, in the manufacture of a medicament for the treatment of cancer.

12. The use of claim 11, wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, hematological cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, sarcoma of soft tissue, cancer of the urinary tract, cancer of the penis, cancer of the prostate, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, neoplasm of the central nervous system, primary neoplasm of the central nervous system, neoplasm of the spinal cord shaft, brain stem glioma, MYH-related polyposis, or pituitary adenoma.

13. The use of claim 11, wherein the cancer is cutaneous or intraocular melanoma, colorectal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, chronic or acute leukemia, renal cell carcinoma or renal pelvis cancer.

14. The use of claim 12, wherein the cancer is associated with a KRas G12D mutation.

15. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 8 to 10, in the manufacture of a medicament for modulating the activity of a KRas G12D mutein.

16. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 8 to 10, in the manufacture of a medicament for inhibiting tumor metastasis.