WO2025161263A1 - Benzomorpholine compound and use thereof - Google Patents

Abstract

Disclosed in the present invention are a benzomorpholine compound and a use thereof. Specifically disclosed are a compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound provided in the present invention has good TRPM3 inhibitory activity and is expected to treat related diseases.

Description

A benzomorpholine compound and its application

This application claims priority to Chinese Patent Application No. 2024101367219 filed on January 31, 2024, and Chinese Patent Application No. 2024108297081 filed on June 25, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications.

Technical Field

The present invention relates to a benzomorpholine compound and application thereof.

Background Art

The TRP superfamily consists of proteins with six transmembrane domains (6TMs) that assemble as homo- or heterotetramers to form cation-permeable ion channels.

TRP channel dysfunction has been directly implicated in the etiology of a variety of inherited and acquired diseases. Indeed, loss-of-function and gain-of-function mutations in TRP channel genes have been identified as direct causes of inherited diseases including brachymemma, hypomagnesemia with secondary hypocalcemia, polycystic kidney disease, mucopolysaccharidosis type IV, and familial focal segmental glomerulosclerosis. Furthermore, TRP channel function/dysfunction has been directly linked to a wide range of pathological conditions, including chronic pain, hypertension, cancer, and neurodegenerative disorders.

TRPM3 (transient receptor potential M-type 3) represents a promising pharmacological target. TRPM3 is expressed in a large subset of small-diameter sensory neurons from the dorsal root and trigeminal ganglion and is involved in heat sensing. The neurosteroid pregnenolone sulfate is a known potent activator of TRPM3. The neurosteroid pregnenolone sulfate causes pain in wild-type mice, but not in TRPM3 knockout mice. It has also been recently shown that CFA-induced inflammation and inflammatory pain are abolished in TRPM3 knockout mice. Therefore, TRPM3 antagonists can be used as analgesics to combat pain, such as inflammatory pain.

There remains a significant medical need for new, alternative and/or better therapeutics for preventing or treating TRPM3-mediated conditions, more particularly for pain (e.g., inflammatory pain). There is an urgent need for therapeutics with good efficacy, low or no side effects, and/or good or improved pharmacokinetic or kinetic properties for certain types of pain.

Summary of the Invention

The present invention provides a class of novel compounds that are antagonists of TRPM3 and can be used as modulators of TRPM3-mediated disorders. The compounds provided by the present invention have good TRPM3 inhibitory activity and are expected to treat related diseases.

The present invention provides a compound I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

in,

X is N or CH;

Y is O or -CH ₂ -;

^L1 is -L ^a -L ^b -L ^c -L ^d -;

L ^a , L ^b , L ^c and L ^d are each independently a connecting bond, O, S or ^{And La} , ^Lb , ^Lc and ^Ld are not simultaneously connected bonds ^{; O} , ^S and The number of is 1 or 2;

R ⁶ , R ^6a and R ^6b are each independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl substituted with one or more R ^6-1 ;

R ^6-1 are each independently hydroxy, halogen, amino, -NHC ₁ -C ₆ alkyl or -N(C ₁ -C ₆ alkyl) ₂ ;

U is 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , 5-10 membered heteroaryl substituted by one or more R ^9-2 , or 3-8 membered cycloalkyl substituted by one or more R ^9-a ;

R ^9-1 , R ^9-2 and R ^9-a are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, Oxo, -O-(3-8 membered cycloalkyl) or C ₁ -C ₆ alkyl substituted by one or more R ^9-4 ;

R ^9-3 are each independently H, C ₁ -C ₆ alkyl or 3-8 membered cycloalkyl;

R ^9-4 are each independently hydroxy, halogen or C ₁ -C ₆ alkoxy;

R ¹ , R ² and R ³ are each independently H, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkyl substituted by one or more halogens;

R ⁴ , R ^4a , R ^5a and R ⁵ are each independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl or C ₁ -C ₆ alkyl substituted by one or more halogens;

Alternatively, R ⁴ and R ^4a together with their adjacent carbon atoms form a 3-8 membered cycloalkyl group;

W is L ² R ⁷ ;

L ² is a linking bond, -CH ₂ -, -NH- or -N(C ₁ -C ₆ alkyl)-;

R ⁷ is 3-8 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , C ₁ -C ₆ alkyl substituted by one or more R ^7-3 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 ;

R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, hydroxy, oxo, amino, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, -O-(3-8 membered cycloalkyl), C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ;

R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxy, amino, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -NHC ₁ -C ₆ Alkyl, -N(C ₁ -C ₆ alkyl) ₂ ,

R ^7-3 are each independently halogen, hydroxy, amino, C ₁ -C ₆ alkoxy, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ ,

R ^7-2-1 are each independently H, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, or C ₁ -C ₆ alkyl substituted by one or more C ₆ -C ₁₀ aryl groups;

The heteroatoms in the 3-12 membered heterocycloalkyl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3;

The heteroatoms in the 5-10 membered heteroaryl group are selected from one or more of N, O and S; and the number of heteroatoms is 1, 2 or 3.

In one plan,

^L1 is Wherein end a is connected to U;

U is 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , or 5-10 membered heteroaryl substituted by one or more R ^9-2 ;

R ^9-1 and R ^9-2 are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, Oxo, -O-(3-8 membered cycloalkyl) or C ₁ -C ₆ alkyl substituted by one or more R ^9-4 ;

R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, hydroxy, oxo, amino, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, -O-(3-8 membered cycloalkyl), C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ;

R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxy, amino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ ,

R ^7-2-1 are each independently H, C ₁ -C ₆ alkyl or 3-8 membered cycloalkyl.

In a certain embodiment, each C ₁ -C ₆ alkyl group can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In a certain embodiment, each C ₂ -C ₆ alkenyl group can independently be vinyl, propenyl, allyl, butenyl or pentenyl, preferably vinyl.

In a certain embodiment, each C ₂ -C ₆ alkynyl group independently can be ethynyl, propynyl, propargyl, butynyl or pentynyl.

In a certain embodiment, each C ₁ -C ₆ alkoxy group can independently be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

In one embodiment, each halogen can independently be fluorine, chlorine, bromine or iodine.

In a certain embodiment, the heteroatom in each 3-12 membered heterocycloalkyl group can independently be N; the number of heteroatoms can independently be 1 or 2.

In a certain embodiment, each 3-12 membered heterocycloalkyl group can independently be a 4-10 membered heterocycloalkyl group.

In a certain embodiment, each 3-12 membered heterocyclyl group can independently be a monocyclic or bicyclic ring, and the bicyclic ring can be a bridged ring or a spiro ring.

In certain aspects, each "plurality" can independently be 2 or 3.

In a certain embodiment, each C ₆ -C ₁₀ aryl group is independently phenyl or naphthyl, preferably phenyl.

In a certain embodiment, each 5-10 membered heteroaryl group can independently be a 5-6 membered heteroaryl group.

In one embodiment, the heteroatom in each 5-10 membered heteroaryl group can independently be N, S or O; and the number of heteroatoms can independently be 1 or 2.

In one embodiment, each 5-10 membered heteroaryl group is independently monocyclic or bicyclic.

In one embodiment, each 3-8 membered cycloalkyl group can independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.

In one embodiment, the pharmaceutically acceptable salt may be hydrochloride, formate or trifluoroacetate.

In one embodiment, X is N.

In one embodiment, Y is O.

In one scheme, ^L1 is Preferably The a end is connected to U.

In one ^embodiment , O ^{, S and} The number of is 1.

In one embodiment, R ⁶ , R ^6a and R ^6b are each independently H or C ₁ -C ₆ alkyl, preferably H.

In one embodiment, U is C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ aryl substituted with one or more R ^9-1 , or 5-10 membered heteroaryl substituted with one or more R ^9-2 .

In one embodiment, U is C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, C _{6 -C} 10 substituted with one or more R ^9-1 C ₁₀ aryl or 5-10 membered heteroaryl substituted by one or more R ^9-2 .

In one embodiment, U is a 3-8 membered cycloalkyl group.

In one embodiment, R ^9-1 and R ^9-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, or a C ₁ -C ₆ alkyl group substituted by one or more R ^9-4 .

In one embodiment, R ^9-1 , R ^9-2 and R ^9-a are each independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, or a C ₁ -C ₆ alkyl group substituted by one or more R ^9-4 .

In one embodiment, R ^9-a is independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, or a C ₁ -C ₆ alkyl group substituted by one or more R ^9-4 .

In one embodiment, R ^9-3 are each independently H or C ₁ -C ₆ alkyl, preferably H.

In one embodiment, R ^9-4 is halogen.

In one embodiment, R ¹ , R ² and R ³ are each independently H or halogen; preferably, R ¹ and R ³ are H, and R ² is H or halogen.

In one embodiment, R ^4a is H.

In one embodiment, R ⁵ and R ^5a are H.

In one embodiment, ^R4 is H or _C1 - _C6 alkyl, preferably H.

In one embodiment, L ² is a bond, -CH ₂ - or -NH-, preferably -NH-.

In one embodiment, L ² is a bond, -NH- or -N(CH ₃ )-.

In one embodiment, ^L2 is -N( _CH3 )-.

In one embodiment, R ⁷ is 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 .

In one embodiment, R ⁷ is C ₁ -C ₆ alkyl substituted with one or more R ^7-3 .

In one embodiment, R ^7-3 is hydroxy or

In one embodiment, R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, amino, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 .

In one embodiment, R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, amino, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ - _C6 alkyl, C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 .

In one embodiment, R ^7-1 , R ^7-2 and R ^7-4 are each independently

In one embodiment, R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxyl, C ₂ -C ₆ alkenyl,

In one embodiment, R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl,

In one embodiment, R ^7-1-1 and R ^7-1-2 are each independently C ₁ -C ₆ alkoxy.

In one embodiment, R ^7-2-1 is each independently H or C ₁ -C ₆ alkyl.

In one embodiment, R ^7-2-1 is each independently H, C ₁ -C ₆ alkyl, or C _{1 -C 6} alkyl substituted with one or more C ₆ -C ₁₀ aryl groups.

In one embodiment, R ^7-2-1 is each independently a 3-8 membered cycloalkyl group or a C _{1 -C 6} alkyl group substituted with one or more C 6 -C ₁₀ aryl groups.

In a certain embodiment, when L ² is a connecting bond, R ⁷ is a 3-12 membered heterocycloalkyl or a 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 ; the 3-12 membered heterocycloalkyl is preferably a spiro ring;

Preferably, the heteroatom of the 3-12 membered heterocycloalkyl group may be N, and the number of heteroatoms may be 1 or 2;

More preferably, the N atom in the 3-12 membered heterocycloalkyl group is connected to ^L2 .

In one embodiment, R ⁷ is a 3-12 membered heterocycloalkyl group or a 3-12 membered heterocycloalkyl group substituted with one or more R ^7-1 groups;

Preferably, ^R7 is a 5-6 membered heterocycloalkyl group or a 5-6 membered heterocycloalkyl group substituted by one or more halogens; the heteroatom of the 5-6 membered heterocycloalkyl group is N, and the number of heteroatoms may be 1 or 2;

More preferably, R ⁷ is piperidinyl, tetrahydropyrrolyl, tetrahydropyrrolyl substituted by one or more halogens, or piperidinyl substituted by one or more halogens;

More preferably, R ⁷ is piperidinyl substituted by 1 or 2 F groups or tetrahydropyrrolyl substituted by 1 or 2 F groups.

In one scheme, ^L1 is The a end is connected to U.

In one scheme, U is

In one scheme, U is

In a certain scheme, U is

In one scheme, W is

In one scheme, W is

In one scheme, W is

In one plan,

X is N or CH;

Y is O or -CH ₂ -;

^L1 is Wherein end a is connected to U;

R ⁶ , R ^6a and R ^6b are each independently H or C ₁ -C ₆ alkyl;

U is C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , or 5-10 membered heteroaryl substituted by one or more R ^9-2 ;

R ^9-1 and R ^9-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, C ₁ -C ₆ alkyl substituted by one or more halogens;

R ^9-3 are each independently H or C ₁ -C ₆ alkyl

R ¹ , R ² and R ³ are each independently H, halogen or C ₁ -C ₆ alkyl;

R ⁴ and R ^4a are each independently H or C ₁ -C ₆ alkyl;

Alternatively, R ⁴ and R ^4a together with their adjacent carbon atoms form a 3-8 membered cycloalkyl group;

^R5 and ^R5a are H;

W is L ² R ⁷ ;

L ² is a linking bond, -CH ₂ - or -NH-;

R ⁷ is 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 ;

R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, amino, -NHC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ;

R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxyl, C ₂ -C ₆ alkenyl,

R ^7-2-1 are each independently H or C ₁ -C ₆ alkyl;

The heteroatoms in the 3-12 membered heterocycloalkyl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3;

The heteroatoms in the 5-10 membered heteroaryl group are selected from one or more of N, O and S; and the number of heteroatoms is 1, 2 or 3.

In one plan,

X is N or CH;

Y is O or -CH ₂ -;

^L1 is Wherein end a is connected to U;

R ⁶ , R ^6a and R ^6b are each independently H or C ₁ -C ₆ alkyl;

U is C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , or 5-10 membered heteroaryl substituted by one or more R ^9-2 ;

R ^9-1 and R ^9-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, C ₁ -C ₆ alkyl substituted by one or more halogens;

R ^9-3 are each independently H or C ₁ -C ₆ alkyl

R ¹ , R ² and R ³ are each independently H, halogen or C ₁ -C ₆ alkyl;

R ⁴ and R ^4a are each independently H or C ₁ -C ₆ alkyl;

Alternatively, R ⁴ and R ^4a together with their adjacent carbon atoms form a 3-8 membered cycloalkyl group;

^R5 and ^R5a are H;

W is L ² R ⁷ ;

L ² is a linking bond, -CH ₂ - or -NH-;

R ⁷ is 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , C ₁ -C ₆ alkyl substituted by one or more R ^7-3 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 ;

R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, amino, -NHC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ;

R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, R ^7-3 are each independently hydroxyl or R ^7-2-1 are each independently H, C ₁ -C ₆ alkyl, or C _{1 -C 6} alkyl substituted with one or more C ₆ -C ₁₀ aryl groups;

The heteroatoms in the 3-12 membered heterocycloalkyl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3;

The heteroatoms in the 5-10 membered heteroaryl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3. indivual.

In one embodiment, the compound I of the present invention is compound I-1, I-2 or I-3,

wherein R ¹ , R ² , R ³ , R ⁴ , R ^4a , R ⁵ , R ^5a , L ¹ , U and W have the same meanings as described above.

In a certain embodiment, the compound I or its stereoisomer is selected from any one of the following compounds:

In a certain embodiment, the pharmaceutically acceptable salt of Compound I is selected from any one of the following compounds:

The present invention also provides a compound II,

wherein R ¹ , R ² , R ³ , R ⁴ , R ^4a , R ⁵ , R ^5a , L ¹ and U have the same meanings as described above.

On the other hand, the present invention also provides a pharmaceutical composition comprising the above-mentioned Compound I, its stereoisomers or pharmaceutically acceptable salts, and at least one pharmaceutical excipient.

On the other hand, the present invention also provides a use of the above-mentioned compound I, its stereoisomers or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating pain; the pain is preferably inflammatory pain.

On the other hand, the present invention also provides a use of Compound I as described above, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition as described above in the preparation of a medicament for preventing and/or treating a TRPM3-mediated disease; the TRPM3-mediated disease is preferably pain, more preferably inflammatory pain.

In another aspect, the present invention further provides a use of Compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the preparation of a TRPM3 antagonist. The TRPM3 antagonist can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, for example, as a standard or control sample for comparison, or prepared according to conventional methods in the art to provide a kit for rapid detection of the effect of antagonizing TRPM3.

the term

Unless otherwise indicated, the definitions of groups and terms in the present specification and claims, including definitions provided as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the present specification.

Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C ₁ -C ₆ alkyl or C _1-6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5, or 6 carbon atoms.

As used herein, numerical ranges such as 0 to 10, 1-6, 1-3, etc., defined in substituents indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, or 6.

The term "plurality" refers to 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, preferably 2, 3 or 4.

The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., _C1 - _C6 or _C1 - _C4 ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₂ to C ₆ ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp ² double bonds. Alkenyl groups include, but are not limited to, vinyl, wait.

The term "alkynyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₂ to C ₆ ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp ³ triple bonds. Alkynyl groups include, but are not limited to, ethynyl, wait.

The term "alkoxy" refers to the group R ^X -O-, where R ^X is defined as the term "alkyl." Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term "halogen" refers to F, Cl, Br, I.

The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₃ to C ₁₀ or C ₃ to C ₆ ), which is a single ring. Cycloalkyl groups include, but are not limited to: wait.

The term "oxo" refers to =0, where an oxygen atom replaces two hydrogen atoms on the same carbon atom, i.e., a carbonyl group replaces a methylene group, e.g. After oxygenation

The term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group having a specified number of ring atoms (e.g., 3-12, 4-10, or 4-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is monocyclic or polycyclic, and the polycyclic rings may be bridged, fused, or spirocyclic. The polycyclic rings may also be bicyclic or tricyclic. The heterocycloalkyl group is attached to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl groups include, but are not limited to: wait.

The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10 or 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic, with two atoms and one bond shared between the rings, and each ring is aromatic. A heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms. Heteroaryl groups include, but are not limited to: wait.

The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

The term "prevent" refers to reducing the risk of developing a disease.

The term "patient" refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive progress of the present invention is that the compounds provided by the present invention have good TRPM3 inhibitory activity and are expected to treat related diseases.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods without specific conditions were carried out according to conventional methods and conditions, or selected according to the product instructions.

Example 1 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303001

Step 1 Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303001-2

6-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303001-1 (10 g, 46.72 mmol, 1.00 eq) was dissolved in dioxane (200 mL). Pd(dppf) _Cl₂ (1.71 g, 2.34 mmol, 0.05 eq), BPD (23.73 g, 93.43 mmol, 2 eq), and KOAc (11.46 g, 116.79 mmol, 2.50 eq) were added to the reaction mixture. The reaction mixture was stirred at 100°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303001-2 (12 g, 45.96 mmol, 98.37% yield) as a yellow oil.

LC-MS [M+H] ⁺ = 262.0.

Step 2 Preparation of 3,4-dihydro-2H-benzo[b][1,4]oxazepine-6-ol JD-5303001-3

6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303001-2 (11 g, 42.13 mmol, 1 eq) was dissolved in a mixture of tetrahydrofuran (110 mL) and water (110 mL). AcOH (12.65 g, 210.63 mmol, 12.06 mL, 5.0 eq) and H ₂ O ₂ (47.79 g, 421.50 mmol, 40.50 mL, 30% purity, 10.01 eq) were added to the reaction mixture. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by the addition of _Na₂SO₃ (aq., 600 mL) at 0°C, followed by extraction with EtOAc (900 mL, 300 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, _and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , petroleum ether/ethyl acetate = 50/1-1) to afford 3,4-dihydro-2H-benzo[b][1,4]oxazepine-6-ol JD-5303001-3 (4.17 g, 27.59 mmol, 65.49% yield) as a brown oil.

LC-MS [M] = 150.1.

Step 3 Preparation of (4-methyl-1,3-thiazolyl-5-yl)methanol JD-5303001b

LAH (2.00 M, 29.2 mL, 2.00 eq) was dissolved in THF (50.0 mL) and stirred for 30 minutes. Ethyl 4-methyl-1,3-thiazolin-5-carboxylate JD-5303001a was then added, and the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was quenched by the addition of _H₂O (2.00 mL) at -10°C, then diluted with 15% NaOH (2.00 mL) and _H₂O (6.00 mL), stirred at 25°C for 15 minutes, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , petroleum ether/ethyl acetate = 1/1) to afford (4-methyl-1,3-thiazolin-5-yl)methanol JD-5303001b (2.50 g, 19.3 mmol, 66.2% yield) as a yellow solid.

LC-MS [M+H] ⁺ = 130.3.

Step 4 Preparation of 5-(chloromethyl)-4-methyl-1,3-thiazolyl JD-5303001c

(4-Methyl-1,3-thiazolin-5-yl)methanol JD-5303001b (400 mg, 3.10 mmol, 1.00 eq) and _SOCl₂ were dissolved in THF (25.0 mL), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with _H₂O (30.0 mL) and extracted with EtOAC (30.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to afford 5-(chloromethyl)-4-methyl-1,3-thiazolin-5-yl)methanol JD-5303001c (500 mg, crude) as a colorless oil.

Step 5 Preparation of JD-5303001-4 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin

3,4-Dihydro-2H-benzo[b][1,4]oxazepin-6-ol JD _- 5303001-3 (0.20 g, 1.32 mmol, 1.00 eq) was dissolved in DMF (2 mL). _K₂CO₃ (365 mg, 2.65 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (292 mg, 1.98 mmol, 1.50 eq) were added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was washed with _H₂O (10 mL) and ethyl acetate (10 mL, 5 mL x 2). The organic phase was collected and concentrated under reduced pressure to yield a residue. The residue was purified by preparative chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1:1) to give JD-5303001-4 (0.12 g, 457 μmol, yield 34.5%) of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-5-ol) as a colorless oil.

LC-MS [M+H] ⁺ = 263.1.

Step 6 Preparation of 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester JD-5303001-5

JD-5303001-4 (20.3 mg, 91.4 μmol, 1.20 eq) of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin) and DIEA (39.4 mg, 304 μmol, 53.1 μL, 4.00 eq) were dissolved in THF (1.00 mL) and purged with _N₂ three times. The mixture was cooled to 0°C. BTC (0.09 g, 303 μmol, 0.40 eq) was added to the mixture, and the mixture was stirred at 25°C for 1 hour. To the mixture was then added 2-methylpropane-2-yl 4-amino-3,3-difluorotetrahydropyrrole-1-carboxylate JD-5303001d (20.0 mg, 76.2 μmol, 1.00 eq). The mixture was stirred at 25°C for 2 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.53) showed complete consumption of the starting material, with the formation of a new spot. The reaction mixture was quenched by the addition of 5 mL of _H₂O at 0°C, then extracted with 15 mL of ethyl acetate (5 mL x 3) and concentrated under reduced pressure to obtain a residue. Purification by preparative high performance liquid chromatography gave 2-methylprop-2-yl 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303001-5 (25.0 mg) as a white solid.

Step 7 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303001

2-Methylpropane-2-yl-3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303001-5 (40.0 mg, 78.3 μmol, 1.00 eq) and TMSCl (17.0 mg, 156 μmol, 19.8 μL, 2 eq) were added to TFE (1.00 mL) and stirred at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford compound JD-5303001 (23.0 mg, 51.4 μmol, 65.6% yield, HCl salt).

LC-MS [M+H] ⁺ = 411.0.

¹ H NMR: (400MHz, DMSO-d6) δ = 2.40 (s, 3H), 3.40-3.51 (m, 1H), 3.74 (br s,5H),4.05-4.22(m,2H),4.71-4.87(m,1H),5.18(s,2H),6.66(dd,J＝8.88,2.88Hz,1H),6.79(d,J＝8.88Hz,1H),7.35(d, J＝2.88Hz,1H),7.61(d,J＝8.38Hz,1H),9.10(s,1H),10.02-10.46(m,2H).

Example 2 Preparation of N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303002

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303002a to prepare N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303002 as a yellow gum (0.073 g, 181 μmol, yield 88.5%, purity 96.4%).

LC-MS [M+H] ⁺ = 389.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.52-1.73 (m, 2H) 1.86 (br d, J = 10.88Hz, 2H) 2.40 (s, 3H) 2.80 (br dd,J＝19.39,9.51Hz,2H)3.07-3.25(m,2H)3.68-3.80(m,2H)3.89-4.01(m,1H)4.12(br s,2H)5.18(s,2H)6.61(dd,J＝8.88,2.88Hz,1H)6.76(d,J＝8.88Hz,1H)7.17(br d,J＝7.38Hz,1H)7.40(d,J＝2.88Hz,1H)9.14-9.30(m,2H)9.42(br s,1H).

Example 3 Preparation of N-[(3S)-hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303003

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303003a to prepare N-[(3S)-hexahydropyridine -3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303003 was obtained as a yellow gum (48.9 mg, 124 μmol, yield 71.6%, purity 99.0%).

LC-MS [M+H] ⁺ = 389.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.50-1.70 (m, 2H) 1.81-1.95 (m, 2H) 2.39 (s, 3H) 2.77 (br t, J = 9.94Hz, 2H) 3.18 (br d, J = 12.01Hz, 1H) 3.30 (br d,J＝10.13Hz,1H)3.69(br d,J＝2.88Hz,2H)3.85-3.96(m,1H)4.13(t,J＝4.57Hz,2H)5.17(s,2H)6.63(dd,J＝8.88,2.88Hz,1H) 6.78(d,J＝8.88Hz,1H)6.96(d,J＝7.38Hz,1H)7.36(d,J＝2.88Hz,1H)8.54-8.73(m,2H)8.98(s,1H).

Example 4 Preparation of N-[(3R)-hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303004

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303004a to prepare N-[(3R)-hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303004 as a yellow gum (39.11 mg, 99.67 μmol, yield 57.29%, purity 99%).

LC-MS [M+H] ⁺ = 389.0.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.50-1.70 (m, 2H) 1.82-1.95 (m, 2H) 2.39 (s, 3H) 2.72-2.84 (m, 2H) 3.18 (br d, J＝12.38Hz, 1H) 3.30 (br d,J＝9.76Hz,1H)3.65-3.75(m,2H)3.82-3.95(m,1H)4.13(t,J＝4.57Hz,2H)5.17(s,2H)6.63(dd,J＝8.88,2. 88Hz, 1H) 6.78 (d, J = 8.88Hz, 1H) 6.97 (d, J = 7.38Hz, 1H) 7.36 (d, J = 2.88Hz, 1H) 8.52-8.76 (m, 2H) 8.98 (s, 1H).

Example 5 Preparation of N-(1-methylpiperidin-4-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303005

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303005a to prepare N-(1-methylpiperidin-4-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303005 as a yellow gummy compound (71.5 mg, 138 μmol, yield 36.3%, TFA salt).

LC-MS [M+H] ⁺ = 403.1.

¹ H NMR: (400MHz, DMSO-d6)δppm 1.59-1.78(m,2H)1.92-2.06(m,2H)2.39(s,3H)2.72-2.79(m,3H)2.99-3.11(m,2H)3.44(br d,J＝11.76Hz,2H)3.62-3.80(m,3H)4.04-4.16(m,2H)5.16(s,2H)6.61(dd,J＝8.88,2.88Hz,1H)6.74-6.80(m,1H)7.04(br d,J＝7.38Hz,1H)7.34-7.39(m,1H)8.99(s,1H)9.27-9.57(m,1H).

Example 6 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(tetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303006

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303006a to prepare 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(tetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303006 (120 mg, 252 μmol, yield 66.3%) as a white solid.

LC-MS [M+H] ⁺ = 375.0.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 1.91-2.19 (m, 2H), 2.41 (s, 3H), 2.99-3.33 (m, 4H), 3.57-3.91 (m,2H),4.00-4.23(m,2H),4.24-4.37(m,1H),5.19(s,2H),6.50-6.82(m,2H),7.19-7.53(m,2H),9.11(s,1H),9.26-9.57(m,2H).

Example 7 Preparation of N-(5,5-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303007

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303007a to prepare N-(5,5-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303007 (0.045 g, yield 69.9%, purity 97.92%) as a brown gum.

LC-MS [M+H] ⁺ = 425.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 2.17-2.49 (m, 5H) 2.99 (br s, 1H) 3.30 (br d, J = 9.76Hz, 1H) 3.46 (br d,J＝12.76Hz,1H)3.58-3.68(m,1H)3.70-3.79(m,2H)4.08-4.23(m,3H)5.19(s,2H)6.6 3(dd,J＝8.94,2.94Hz,1H)6.78(d,J＝8.88Hz,1H)7.30-7.46(m,2H)9.21(s,1H)9.83(br s,1H)10.68(br s,1H).

Example 8 Preparation of N-(3-aminocyclohexyl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303008

Referring to the method of Example 1, compound JD-5303001d was replaced with JD-5303008a to prepare N-(3-aminocyclohexyl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303008 (75 mg, yield 62.4%, purity 98.8%) as a white solid.

LC-MS ([M+H] ⁺ ) = 403.2.

¹ H NMR (400 MHz, DMSO-d ₆ )δ＝8.92(s,1H),7.35(d,J＝2.9Hz,1H),6.80–6.74(m,1H),6.61(dd,J＝8.8,2 .9Hz,1H),6.39(d,J＝6.8Hz,1H),5.93–5.46(m,2H),5.18(s,2H),4.20–4.09( m,2H),4.06–3.97(m,1H),3.77–3.66(m,2H),3.31–3.22(m,1H),2.41(s,3H) ,1.98–1.78(m,1H),1.76–1.60(m,4H),1.59–1.48(m,2H),1.46–1.37(m,1H).

Example 9 Preparation of N-(hexahydropyridin-4-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303009

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303009a to prepare N-(hexahydropyridin-4-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303009 (80 mg, 205.48 μmol, yield 83.66%, purity 99.78%) as a white solid.

LC-MS [M+H] ⁺ = 389.1.

¹ H NMR: (400MHz, DMSO-d ₆ )δ＝9.04(s,1H),8.80-8.92(m,1H),8.67-8.78(m,1H),7.37(d,J＝2.88Hz,1H),7.05-7.11(m,1H),6 .76(d,J＝8.88Hz,1H),6.60(dd,J＝8.82,2.94Hz,1H),5.15-5.18(m,2H),4.09-4.13(m,2H),3.27(br d,J＝12.26Hz,2H),3.15-3.23(m,1H),2.87-3.05(m,4H),2.39(s,3H),1.94(br d,J＝12.26Hz,2H),1.63-1.76(m,2H).

Example 10 N-(5-amino-2-methylcyclohexyl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H- Preparation of Benzo[b][1,4]oxazepine-4-carboxamide JD-5303010

Step 1 Preparation of [(3-amino-4-methylcyclohexyl)amino]methane-2-methylpropane-2-yl ester JD-5303010b

4-Methylcyclohexane-1,3-diamine JD-5303010a (500 mg, 3.90 mmol, 1.0 eq) was dissolved in dichloromethane (5.0 mL). Triethylamine (592 mg, 5.85 mmol, 1.5 eq) and (Boc)2O (851 mg, 3.90 mmol, 1.0 eq) were added, and the reaction mixture was allowed to react at room temperature for 15 hours. The mixture was quenched by the addition of water (10 mL) at room temperature and then extracted with dichloromethane (30 mL, 10.0 mL x 3). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 10/1) to obtain 2-methylpropan-2-yl [(3-amino-4-methylcyclohexyl)amino]methanoate JD-5303010b (150 mg, 16.8% yield) as a yellow oil.

LC-MS [M+H] ⁺ = 229.2.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.00–6.43(m,1H),2.99–2.52(m,2H),2.31–1.78(m,2H),1.73–1.56(m,2H),1.53–1.44(m,1H),1.40–1.34(m,10H),1.12–0.74(m,6H).

Step 2 Preparation of N-(5-amino-2-methylcyclohexyl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303010

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303010b to prepare N-(5-amino-2-methylcyclohexyl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303010 (11.9 mg, yield 53.7%, purity 98.82%) as a white solid.

LC-MS [M+H] ⁺ = 417.2.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.97(s,1H),7.89(s,2H),7.37–7.22(m,1H),6.97–6.82(m,1H),6.79–6.73( m,1H),6.64–6.57(m,1H),5.16(s,2H),4.19–4.03(m,2H),3.81–3.71(m,1H),3.6 7–3.57(m,1H),3.13–2.99(m,1H),2.38(s,3H),2.15–1.95(m,1H),1.95–1.80(m, 1H),1.79–1.66(m,1H),1.66–1.27(m,4H),1.19–0.99(m,1H),0.95–0.82(m,3H).

Example 11 Preparation of N-(azepan-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide JD-5303011

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303011a to prepare N-(azepan-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide JD-5303011 (58 mg, yield 48.3%, purity 98.9%) as a white solid.

LC-MS ([M+H] ⁺ ) = 403.2.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝8.98(s,1H),7.38(d,J＝2.9Hz,1H),7.06(d,J＝7.6Hz,1H),6.78(d,J＝8.8Hz,1H),6.63(dd,J＝8.9,2.9Hz,1H),5.17(s,2H),4.13(t,J＝4 .4Hz,2H),4.09–3.98(m,1H),3.76–3.68(m,2H),3.45–3.20(m,5H),2.39(s,3H),2.04–1.91(m,1H),1.88–1.63(m,4H),1.62–1.44(m,1H).

Example 12 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(4-azabicyclo[2.2.2]oct-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303012

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303012a to prepare 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(4-azabicyclo[2.2.2]oct-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303012 (13.8 mg, yield 8.7%, yield 97.71%) as a yellow solid.

LC-MS ([M+H] ⁺ )=415.2.

¹ H NMR (300MHz, CDCl ₃ ): δ8.70(s,1H),7.42(d,J＝3.0Hz,1H),6.82(d,J＝9.0Hz,1H),6.70–6.59( m,2H),5.12(s,2H),4.30(s,1H),4.21(t,J＝4.8Hz,2H),4.00–3.91(m,2H), 3.86–3.71(m,2H),3.55–3.43(m,1H),3.28–3.03(m,3H),2.47(s,3H),2.38 (d,J＝4.8Hz,1H),2.25–2.16(m,1H),2.04–1.96(m,2H),1.82–1.73(m,1H).

Example 13 Preparation of N-(4-fluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303013

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303013a to prepare N-(4-fluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303013 (4.6 mg, 11.3 μmol, yield 28.6%, purity 99.6%) as a white solid.

LC-MS [M+H] ⁺ = 407.0.

¹ H NMR: (400MHz, DMSO-d6) δ = 8.99 (s, 1H), 8.66-8.93 (m, 2H), 7.36 (d, J = 2.88Hz, 1H),7.14-7.19(m,1H),6.78-6.83(m,1H),6.65(dd,J＝8.94,2.94Hz,1H),5.17 (s,2H),4.87-5.11(m,1H),4.06-4.27(m,3H),3.78(ddd,J＝13.35,5.35,2.69 Hz,2H),3.17-3.29(m,2H),2.90-3.12(m,2H),2.39(s,3H),1.90-2.28(m,2H).

Example 14 Preparation of N-(2H-pyrazol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303014

Step 1 Preparation of 6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303014-2

Imidazole (45.0 mg, 661 μmol, 2.00 eq) was added to a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazepine-6-ol JD-5303014-1 (50.0 mg, 330 μmol, 1.00 eq) and TBSCl (74.7 mg, 496 μmol, 61.0 μL, 1.50 eq) in DCM (1.00 mL) and stirred at 25 °C for 3 hours. The reaction mixture was quenched with _H2O (10.0 mL) and extracted with DCM (10.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to give 6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303014-2 (100 mg, crude) as a brown oil.

LC-MS [M+H] ⁺ = 266.1.

Step 2 Preparation of 6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303014-3

To a solution of 6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303014-2 (50.0 mg, 188 μmol, 1.00 eq) and 2-methylpyrazol-3-amine JD-5303014a (21.9 mg, 226 μmol, 1.20 eq) in THF (1.00 mL) was added CDI (36.6 mg, 226 μmol, 1.20 eq) and DIEA (29.2 mg, 226 μmol, 39.3 μL, 1.20 eq), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched with _H2O (10.0 mL) and extracted with EtOAc (10.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to give 6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303014-3 (110 mg, crude) as a brown oil.

LC-MS [M+H] ⁺ = 389.4.

Step 3 Preparation of 6-hydroxy-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303014-4

TBAF (50.4 mmol, 1.00 eq) was added to a solution of 6-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303014-3 (50.0 mg, 128 μmol, 1.00 eq) in THF (1.00 mL). mg, 193 μmol, 1.50 eq) and stirred at 25°C for 2 hours. The reaction mixture was quenched with H ₂ O (10.0 mL) and extracted with EtOAc (10.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to give 6-hydroxy-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303014-4 (30.0 mg, crude) as a brown oil.

LC-MS [M+H] ⁺ = 275.0.

Step 4 Preparation of N-(2H-pyrazol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303014

6-Hydroxy-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide JD-5303014-4 (30.0 mg, 109 μmol, 1.00 eq) and (4-methyl-1,3-thiazolin-5-yl)methanol JD-5303001a (28.2 mg, 218 μmol, 2.00 eq) were added to a THF (1.00 mL) solution, and PPh ₃ (57.3 mg, 218 μmol, 2.0 eq) and DIAD (44.2 mg, 218 μmol, 42.4 μL, 2.00 eq) were added, and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched with H ₂ O (10.0 mL) and extracted with EtOAc (10.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to afford N-(2H-pyrazol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide JD-5303014 (1.45 mg, 3.76 μmol, yield 3.44%) as a brown gum.

LC-MS [M+H] ⁺ = 386.1.

¹ H NMR (300MHz, DMSO-d6): δ9.06(s,1H),8.98(s,1H),7.41(d,J＝2.7Hz,1H),7.33(d,J＝1.8Hz,1H),6.82(d,J＝8.7Hz,1H),6.68(dd ,J＝9.0,3.0Hz,1H),6.11(d,J＝2.1Hz,1H),5.18(s,2H),4.22(t,J＝4.5Hz,2H),3.85(t,J＝4.5Hz,2H),3.65(s,3H),2.38(s,3H).

Example 15 Preparation of N-(5-chlorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303015

Step 1. Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303015a to prepare 2-methylprop-2-yl 6-[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate JD-5303015-1 (150 mg, 92.2%) as a yellow solid.

LCMS: 487.2 ([M+H] ⁺ ).

¹ H NMR (400MHz, DMSO-d6): δ8.97(s,1H),7.00(d,J＝2.9Hz,1H),6.80(d,J＝8.8Hz,1H),6.67(dd,J＝8.9,2.9Hz,1H),5. 17(s,2H),4.19–4.06(m,4H),3.92–3.77(m,2H),3.74–3.59(m,2H),3.30–3.17(m,2H),2.39(s,3H),1.37(s,11H).

Step 2. 2-Methylpropane-2-yl-6-[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate JD-5303015-1 (150 mg, 0.31 mmol, 1.0 eq) was dissolved in DCM (2 mL). Dioxane/HCl (1.5 mL, 6.2 mmol, 20.0 eq) was added to the mixture, and the reaction mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was quenched with saturated sodium carbonate solution (3 mL) and then extracted with dichloromethane (10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 35%-45%, 6 min) to obtain JD-5303015 (7 mg, yield 5.0%, purity 96.6%) as a white solid.

LC-MS ([M+H] ⁺ ) = 423.1.

¹ H NMR (300MHz, MeOD) δ＝8.88(s,1H),8.33(brs,0.74H),7.24(d,J＝2.8Hz,1H),6.80(d,J＝8.9Hz,1H),6.67(dd,J＝9.0,2.8Hz,1H),5.19(s,2H),4.65( s,1H),4.42–4.28(m,1H),4.23–4.11(m,2H),3.86–3.69(m,2H),3.43–3.3 2(m,2H),2.91–2.77(m,1H),2.69(s,1H),2.44(s,3H),2.34–2.09(m,2H).

Example 16 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-4-(1,6-diazaspiro[3.5]non-1-ylcarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-1-ol trifluoroformate JD-5303016

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303016a to prepare 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-4-(1,6-diazaspiro[3.5]non-1-ylcarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine trifluorocarbonate JD-5303016 (7.3 mg, yield 7.9%, purity 97.0%) as a white solid.

LC-MS ([M+H] ⁺ ) = 415.3.

¹ H NMR (400MHz, MeOD) δ＝8.96(s,1H),6.85–6.78(m,2H),6.72(dd,J＝2.8Hz,8.8Hz,1H),5.19(s,2H),4.33–4.26(m,1H),4.25–4.14(m,2H),3.85 –3.70(m,2H),3.69–3.60(m,1H),3.55–3.42(m,2H),3.08–2.96(m,1H) ,2.63–2.52(m,1H),2.43(s,3H),2.08–1.94(m,3H),1.88–1.75(m,3H).

Example 17 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-[3-(prop-2-enyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303017

Step 1 Preparation of 2-methylprop-2-yl 3-amino-3-(prop-2-enyl)piperidin-1-carboxylate JD-5303017c

2-Methylprop-2-yl-3-oxo-1-pyridine-1-carboxylate JD-5303017a (400 mg, 2.0 mmol, 1.0 eq) was dissolved in _NH₃ in MeOH (4.0 mL). The reaction mixture was allowed to react at room temperature for 0.5 hours. 4,4,5,5-Tetramethyl-2-(prop-2-enyl)-1,3,2-dioxaborolane JD-5303017b (439 mg, 2.6 mmol, 1.3 eq) was then added to the reaction system and allowed to react at room temperature for 11.5 hours. The mixture was adjusted to pH 10 by adding 15% sodium hydroxide solution (5 mL) at room temperature, and then extracted with dichloromethane (20 mL, 10.0 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 50/1 to 30/1) to give 2-methylpropan-2-yl 3-amino-3-(prop-2-enyl)piperidine-1-carboxylate JD-5303017c (310 mg, yield 64.2%, purity 92%) as a yellow oil.

LC-MS ([M-56+H] ⁺ ) = 185.1.

¹ H NMR (300MHz, DMSO-d ₆ )δ=5.97–5.79(m,1H),5.11–4.98(m,2H),3.39–2.91(m,4H),2.06–1.98(m,2H),1.59–1.42(m,2H),1.38(s,9H),1.37–1.21(m,4H).

Step 2 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-[3-(prop-2-enyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303017

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303017c to prepare 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-[3-(prop-2-enyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303017 (25.1 mg, yield 61.9%, purity 98.2%) as a white solid.

LC-MS ([M+H] ⁺ ) = 429.3.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝8.97(s,1H),8.62–7.96(m,1H),7.31(d,J＝3.0Hz,1H),6.77(d,J＝8.7Hz,1H),6.63(dd, J＝9.0,3.0Hz,1H),6.29(s,1H),5.86–5.68(m,1H),5.18(s,2H),5.14–5.01(m,2H),4.22–4. 03(m,2H),3.92–3.81(m,1H),3.77–3.57(m,2H),3.14–3.00(m,1H),2.81–2.70(m,2H),2.6 7–2.56(m,1H),2.44–2.35(m,4H),2.21–2.07(m,1H),1.80–1.53(m,2H),1.50–1.36(m,1H).

Example 18 Preparation of N-[3-(2-chloroethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303018

Step 1 Preparation of 2-methylpropane-2-yl 1-[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]-1,6-diazaspiro[3.5]nonane-6-carboxylate JD-5303018-1

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303018a to prepare 1-[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]-1,6-diazaspiro[3.5]nonane-6-carboxylic acid-2-methylprop-2-yl ester JD-5303018-1 (150 mg, yield 87.1%, purity 92%) as a yellow oil.

LC-MS ([M+H] ⁺ ) = 515.2.

¹ H NMR (400MHz, DMSO-d ₆ )δ＝8.97(s,1H),6.84(d,J＝2.9Hz,1H),6.74(d,J＝8.8Hz,1H),6.59(dd,J＝8.9,2.9Hz,1H),5.20(s,2H),4.23–3.3 4(m,10H),2.39(s,3H),2.33–2.19(m,1H),2.02–1.85(m,3H),1.69–1.57(m,1H),1.44–1.40(m,1H),1.39(s,9H).

Step 2 Preparation of N-[3-(2-chloroethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303018

2-Methylpropane-2-yl-1-[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]-1,6-diazaspiro[3.5]nonane-6-carboxylate JD-5303018-1 (150 mg, 0.29 mmol, 1.0 eq) was dissolved in DCM (2 mL). Dioxane/HCl (1.46 mL, 5.93 mmol, 20.0 eq) was added to the mixture, and the reaction mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was quenched with saturated sodium carbonate solution (3 mL) and then extracted with DCM (10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (dichloromethane/methanol = 10/1) to give N-[3-(2-chloroethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide JD-5303018 (9 mg, yield 6.8%, purity 97.3%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 451.0.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝9.16(s,2H),8.99(s,1H),7.27(d,J＝2.9Hz,1H),7.02(t,J＝5.6Hz,1H),6.78(d,J＝8.9Hz,1H),6.63(dd,J＝8.9,2.9Hz,1H),5.60(s,1H ),5.18(s,2H),4.16–4.05(m,2H),3.75–3.62(m,2H),3.51(s,2H),3.25–3.14(m,2H),3.09–2.98(m,2H),2.40(s,3H),2.29–2.10(m,4H).

Example 19 Preparation of ethyl (3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridin-3-yl)acetate JD-5303019

Step 1 Preparation of ethyl [(3E)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-ylidene]acetate JD-5303019c

Diethyl (2-ethoxy-2-oxoylideneethyl)phosphonate JD-5303019b (2.7 g, 12.05 mmol, 1.2 eq) was dissolved in tetrahydrofuran (20 mL). NaH (482 mg, 12.05 mmol, 1.2 eq) was added at 0°C and stirred for 0.5 hours. Then, 2-methylprop-2-yl-3-oxoylidenehexahydropyridine-1-carboxylate JD-5303019a (2.0 g, 10.04 mmol, 1.0 eq) was added to the mixture and stirred at room temperature for 2 hours. The mixture was quenched by the addition of saturated aqueous ammonium chloride (20 mL) at 0°C. The mixture was then extracted with ethyl acetate (40 mL, 20 mL x 2). The collected organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 200/1 to 50/1) to give ethyl [(3E)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-ylidene]acetate JD-5303019 (2.4 g, yield 88.7%) as a yellow oil.

LC-MS ([M+Na]) = 292.1.

¹ H NMR (400MHz, CDCl ₃ ): δ＝5.74(s,1H),4.16(q,J＝7.2Hz,2H),3.93(s,2H),3.51–3.44(m,2H), 2.96–2.90(m,2H),1.73–1.66(m,2H),1.45(s,9H),1.28(t,J＝7.2Hz,3H).

Step 2 Preparation of ethyl (3-amino-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)acetate JD-5303019d

Ethyl [(3E)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-ylidene]acetate JD-5303019c (500 mg, 1.85 mmol, 1.0 eq) was dissolved in ethanol (2.4 mL), and aqueous ammonia (1.2 mL) was added at room temperature. The mixture was stirred at 80°C in an autoclave for 15 hours. The mixture was concentrated under reduced pressure to afford ethyl (3-amino-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-ylidene)acetate JD-5303019d (500 mg, crude) as a green oil.

LC-MS ([M+H] ⁺ ) = 287.3.

Step 3 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-[3-(prop-2-enyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303019d to prepare 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-[3-(prop-2-enyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303019 (8.9 mg, yield 30.7%, purity 95.6%) as a white solid.

LC-MS ([M+H] ⁺ )=475.3.

¹ H NMR (300MHz, DMSO-d ₆ ): δ＝8.97(s,1H),8.07(brs,1H),7.31(d,J＝2.7Hz,1H),6.78(d,J＝9.0Hz,1H),6.64( dd,J＝9.0,3.0Hz,1H),6.38(s,1H),5.18(s,2H),4.22–4.06(m,2H),4.02(q,J＝7.2Hz, 2H),3.89–3.78(m,1H),3.78–3.68(m,1H),3.68–3.59(m,1H),3.05(d,J＝12.3Hz,1H),2.92–2.82(m,2H),2.7 7–2.66(m,2H),2.39(s,3H),2.29–2.16(m,1H),1.81–1.65(m,1H),1.65–1.48(m,2H),1.12(t,J＝7.2Hz,3H).

Example 20 Preparation of N-(azetidin-3-yl)-6-{[(4-methyl-1,3-thiazeol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303020

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303020a to prepare N-(azetidin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303020 (55.28 mg, 135.90 μmol, yield 78.23%, purity 97.57%, HCl) as a yellow gum.

LC-MS [M+H] ⁺ = 361.1.

¹ H NMR: (400MHz, DMSO-d ₆ )δ=2.42(s,3H),3.67-3.80(m,2H),3.97-4.16(m,7H),5.21(s,2H),6.64(dd, J＝8.88,2.88Hz,1H),6.77(d,J＝8.88Hz,1H),7.42(d,J＝2.75Hz,1H),7.92(br d,J＝5.88Hz,1H),9.25(br s,1H),9.30(s,1H),9.38(br s,1H).

Example 21 Preparation of N-[(1R,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303021

Referring to the synthetic method of Example 1, compound JD-5303001d was replaced with JD-5303021a to prepare N-[(1R,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303021 (60 mg, yield 74.8%, purity 99.72%) as a white solid.

LC-MS [M+H] ⁺ = 403.2.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.98(s,1H),8.00(s,2H),7.36(d,J＝2.8Hz,1H),6.97(d,J＝7.6Hz,1H),6.76(d, J＝8.8Hz,1H),6.60(dd,J＝8.8,2.8Hz,1H),5.16(s,2H),4.15–4.06(m,2H),3.75–3. 64(m,2H),3.61–3.53(m,1H),3.11–2.99(m,1H),2.39(s,3H),2.13(d,J＝11.6Hz,1H ),1.89(d,J＝12.0Hz,1H),1.82–1.72(m,2H),1.41–1.26(m,2H),1.25–1.11(m,2H).

Example 22 Preparation of N-[(1S,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303022

Referring to the synthetic method of Example 1, compound JD-5303001d was replaced with JD-5303022a to prepare N-[(1S,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303022 (60 mg, yield 74.8%, purity 98.32%) as a white solid.

LC-MS [M+H] ⁺ = 403.2.

¹ H NMR (300MHz, DMSO-d6): δ8.98(s,1H),8.07(s,2H),7.36(d,J＝2.91Hz,1H),6.97( d,J＝7.86Hz,1H),6.79–6.72(m,1H),6.60(dd,J＝8.85,2.91Hz,1H),5.16(s,2H),4 .16–4.06(m,2H),3.75–3.62(m,2H),3.62–3.53(m,1H),3.14–2.98(m,1H),2.39(s ,3H),2.21–2.07(m,1H),1.96–1.85(m,1H),1.83–1.68(m,2H),1.44–1.23(m,4H).

Example 23 Preparation of N-(1H-imidazol-5-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303023

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303023a to prepare N-(1H-imidazol-5-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303023 (3.00 mg, 8.05 μmol, yield 2.11%, purity 99.7%) as a white solid.

LC-MS [M+H] ⁺ = 372.1.

¹ H NMR: (400MHz, DMSO-d ₆ )δ=11.70-11.90(m,1H),9.26-9.31(m,1H),8.97(s,1H),7.35-7.48(m,2H),7.04(s,1H),6.78(d, J＝8.75Hz,1H),6.60-6.67(m,1H),5.18(s,2H),4.11-4.19(m,2H),3.78-3.86(m,2H),2.39(s,3H).

Example 24 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(1,3-thiazolin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303024

Referring to the synthesis method of Example 1, JD-5303001d was replaced with JD-5303024a to prepare 6-{[(4-methyl-1,3-thiazolyl-5-yl)methyl]oxy}-N-(1,3-thiazolyl-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303024 (1.19 mg, 3.06 μmol, yield 4.01%, purity 98.62%) as a yellow gum.

LC-MS [M+H] ⁺ = 388.9.

¹ H NMR: (400MHz, DMSO-d6) δppm 2.38(s,3H)3.79-3.91(m,2H)4.11-4.21(m,2H)5.18(s,2H)6.66(dd,J＝8.88,2.88Hz,1H)6.80 (d, J = 8.88 Hz, 1H) 7.35 (d, J = 2.88 Hz, 1H) 7.42 (d, J = 2.25 Hz, 1H) 8.95-8.97 (m, 1H) 10.11 (s, 1H).

Example 25 Preparation of N-(isoxazol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303025

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303025a to prepare N-(isoxazol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303025 (3.62 mg, 9.72 μmol, yield 12.7%, purity 97.56%) as an off-white solid.

LC-MS [M+H] ⁺ = 373.1.

¹ H NMR: (400MHz, DMSO-d6) δppm 2.38 (s, 3H) 3.83 (br d,J＝4.38Hz,2H)4.15-4.21(m,2H)5.18(s,2H)6.68(dd,J＝8.88,2.88Hz,1H)6.81(dd,J＝ 5.13,3.63Hz,2H)7.35(d,J＝2.75Hz,1H)8.75(d,J＝1.25Hz,1H)8.98(s,1H)10.28(s,1H).

Example 26 Preparation of N-(1-ethylhexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroacetate JD-5303026

N-(Hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303002 (50.0 mg, 128 μmol, 1.00 eq) was added to a DMF (2 mL) solution, followed by K ₂ CO ₃ (35.5 mg, 257 μmol, 2.00 eq), DIEA (33.2 mg, 257 μmol, 44.8 μL, 2.00 eq), and iodoethane JD-5303026a (18.0 mg, 115 μmol, 9.26 μL, 0.90 eq), and the mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched by adding H ₂ O (2.00 mL), and then extracted with EtOAc (4.00 mL, 2.00 mL*2). The organic layer was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch xextreme C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 13%-33% B over 10 minutes) to give N-(1-ethylhexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroacetate JD-5303026 (20.0 mg, 48.0 μmol, 37.3% yield, 99.41%) as a yellow gum.

LC-MS [M+H] ⁺ = 417.2.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 1.22 (t, J = 7.25Hz, 3H), 1.46-1.83 (m, 2H), 1.92 (br d,J＝11.51Hz,2H),2.39(s,3H),2.59-2.80(m,2H),3.11-3.22(m,2H),3.4 1-3.57(m,2H),3.64-3.76(m,2H),3.93(dt,J＝7.66,3.86Hz,1H),4.13(br t,J＝4.25Hz,2H),5.17(s,2H),6.63(dd,J＝8.88,3.00Hz,1H),6.78(d,J＝8.88Hz,1H),7.12(br d,J＝7.75Hz,1H),7.35(d,J＝2.88Hz,1H),8.99(s,1H),9.60(br s,1H).

Example 27 Preparation of N-(1-ethyl-4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303027

K ₂ CO ₃ (33.9 mg, 245 μmol, 2.00 eq) and DIEA (31.7 mg, 245 μmol, 42.7 μL, 2.00 eq) were added to N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine in DMF (1.00 mL). A solution of cyclohexane-4-carboxamide hydrochloride JD-5303028 (50.0 mg, 122 μmol, 1.00 eq) and iodoethane JD-5303026a (38.2 mg, 245 μmol, 19.6 μL, 2.00 eq) was stirred at 25°C for 12 hours. The reaction mixture was quenched by addition of H ₂ O (2.00 mL) and extracted with EtOAc (4.00 mL, 2.00 mL*2). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to obtain a residue. Purification by preparative HPLC gave N-(1-ethyl-4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepane-4-carboxamide JD-5303027 (27.8 mg, 64.0 μmol, yield 52.1%, purity 99.41%) as a colorless gum.

LC-MS [M+H] ⁺ = 436.2.

¹ H NMR: (400MHz, DMSO-d6) δppm 1.18 (t, J＝7.19Hz, 3H) 3.06-3.17 (m, 2H) 3.32 (br d, J＝5.88Hz, 1H) 3.67 (ddd, J＝10.01, 6.69, 3.31Hz, 2H) 3.79 (br dd,J＝5.38,3.00Hz,1H)3.81-3.84(m,1H)3.94(br d,J＝10.88Hz,1H)4.10-4.20(m,2H)4.71-4.89(m,1H)5.03(s,2H)6.68(dd,J＝8.94,2.94Hz,1H)6.81(d, J＝8.88Hz,1H)7.19-7.27(m,2H)7.33(d,J＝2.88Hz,1H)7.37-7.46(m,2H)7.52(td,J＝7.66,1.44Hz,1H).

Example 28 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(3-propylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303056

Step 1 Preparation of 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-propylpiperidin-1-carboxylic acid 2-methylpropane-2-yl ester JD-5303056-1

The intermediate JD-5303017-1 of Example 17 (30 mg, 0.057 mmol, 1.0 eq) was dissolved in MeOH (1.0 mL), and Pd/C (5 mg) (10%) was added. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under a hydrogen atmosphere (15 psi) at room temperature for 15 hours. The mixture was filtered and the filtrate was concentrated to give 2-methylprop-2-yl-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-propylpiperidin-1-carboxylate JD-5303056-1 (26 mg, crude) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 531.2.

Step 2 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(3-propylhexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303056

2-Methylpropane-2-yl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-propylpiperidin-1-carboxylate JD-5303056-1 (26 mg, 0.049 mmol, 1.0 eq) was dissolved in DCM (2 mL). Dioxane/HCl (0.25 mL, 0.98 mmol, 20.0 eq) (4 N) was added to the mixture, and the reaction mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was quenched with sodium hydroxide solution (15%) (3 mL), and then extracted with DCM (20 mL, 10 mL*2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25%-35%, 6 min) to give 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-N-(3-propylhexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303056 (10.1 mg, two-step yield 39.6%, purity 98.2%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 431.2.

¹ H NMR (400MHz, CDCl ₃ )δ＝8.69(s,1H),8.32(brs,0.40H),7.32(s,1H),6.88–6.77(m,1H),6.70–6.58(m,1H) ,5.61(s,1H),5.13(s,2H),4.26(s,1H),4.10(s,1H),4.02–3.88(m,2H),3.74–3.58(m ,1H),3.42–3.26(m,1H),2.86–2.61(m,2H),2.46(s,3H),2.25–2.09(m,1H),1.98–1.8 0(m,2H),1.78–1.59(m,2H),1.49–1.34(m,1H),1.34–1.12(m,2H),1.00–0.85(m,3H).

Example 29 Preparation of N-[3-(2-hydroxyethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303057

Step 1 3-(2-hydroxyethyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[1-[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}] ... Preparation of [b][1,4]oxazepine-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid 2-methylpropane-2-yl ester JD-5303057-1

Intermediate JD-5303019-1 (60 mg, 0.107 mmol, 1.0 eq) from Example 19 was dissolved in tetrahydrofuran (2.0 mL). _LiAlH₄ (1.0 M in THF) (0.16 mL, 0.161 mmol, 1.5 eq) was added at 0°C. The reaction mixture was reacted at 0°C for 0.5 h. The mixture was quenched by the addition of 15% aqueous sodium hydroxide solution (0.1 mL) at 0°C and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by prep-TLC (dichloromethane/methanol = 20/1) to give 2-methylpropan-2-yl 3-(2-hydroxyethyl)-3-{[(6-{[(4-methyl-1,3-thiazeolan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303057-1 (30 mg, 52.3% yield) as a yellow solid.

LCMS: 533.2 ([M+H] ⁺ ).

Step 2 Preparation of N-[3-(2-hydroxyethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303057

2-Methylpropane-2-yl 3-(2-hydroxyethyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303057-1 (30 mg, 0.056 mmol, 1.0 eq) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (128 mg, 1.12 mmol, 20.0 eq) was added, and the reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was then adjusted to pH 11 with aqueous potassium carbonate solution and extracted with dichloromethane (10 mL, 5.0 mL x 2). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*19mm*5mm; mobile phase: [water (FA)-acetonitrile]; B%: 25%-40%, 6 min) to give N-[3-(2-hydroxyethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303057 (7.0 mg, yield 28.5%, purity 97.9%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 433.2.

¹ H NMR (300MHz, MeOD): δ8.88 (s, 1H), 7.27 (d, J = 3.0Hz, 1H), 6.82 (d, J = 9.0Hz, 1H), 6.69 (dd, J = 9. 0,3.0Hz,1H),5.20(s,2H),4.26–4.12(m,3H),3.92–3.82(m,1H),3.71(t,J＝6.6Hz,3H),3.29– 3.25(m,1H),3.06–2.94(m,2H),2.44(s,3H),2.30–2.13(m,2H),2.05–1.60(m,4H).

Example 30 Preparation of 2-(3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridin-3-yl)acetamide 2,2,2-trifluoroacetate JD-5303058

Step 1 Preparation of 3-(formamidomethyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-1-carboxylic acid 2-methylpropane-2-yl ester JD-5303058-1

Intermediate JD-5303019-1 (40 mg, 0.073 mmol, 1.0 eq) from Example 19 was dissolved in dichloromethane (2.0 mL). DIEA (28 mg, 0.219 mmol, 3.0 eq), HATU (33 mg, 0.088 mmol, 1.2 eq), DMAP (0.85 mg, 0.007 mmol, 0.1 eq), and ammonium chloride (6 mg, 0.11 mmol, 1.5 eq) were added, and the reaction mixture was allowed to react at room temperature for 3 hours. The mixture was quenched by the addition of water (10 mL) at room temperature and then extracted with dichloromethane (20 mL, 10.0 mL x 2). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (dichloromethane/methanol = 15/1) to give 2-methylpropan-2-yl 3-(formamidomethyl)-3-{[(6-{[(4-methyl-1,3-thiazeolan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303058-1 (30 mg, 75.3% yield) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 546.2.

Step 2 Preparation of 2-(3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridin-3-yl)acetamide 2,2,2-trifluoroacetate JD-5303058

3-(Formamidomethyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylic acid 2-methylpropane-2-yl ester JD-5303058-1 (50 mg, 0.092 mmol, 1.0 eq) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (210 mg, 1.84 mmol, 20.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18150*19mm*5mm; mobile phase: [water (TFA)-acetonitrile]; B%: 25%-45%, 6 min) to give 2-(3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridin-3-yl)acetamide 2,2,2-trifluoroacetate JD-5303058 (16.2 mg, 39.5% yield, 99.04% purity) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 446.1.

¹ H NMR (300MHz, MeOD): δ8.94(s,1H),7.33(d,J＝2.7Hz,1H),6.82(d,J＝9.0Hz,1H),6 .70(dd,J＝9.0,3.0Hz,1H),5.22(s,2H),4.31–4.17(m,3H),3.88–3.77(m,2H),3. 38–3.32(m,1H),3.09(d,J＝12.9Hz,1H),3.07–2.96(m,1H),2.85(d,J＝14.4Hz,1H ),2.53(d,J＝14.4Hz,1H),2.45(s,3H),2.33(d,J＝13.2Hz,1H),2.06–1.69(m,3H).

Example 31 Preparation of N-[3-(dimethylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303059

Intermediate JD-5303060-1 (19 mg, 0.044 mmol, 1.0 eq) from Example 32 was dissolved in THF (1 mL). BH₃ _- THF (0.22 mL, 0.22 mmol, 5.0 eq) was added to the mixture, and the reaction mixture was allowed to react at room temperature for 15 hours. HCl (1 mL) (1N) and MeOH (2 mL) were added to the reaction system, followed by stirring at room temperature for 20 minutes. The mixture was quenched with saturated sodium carbonate solution (5 mL) and then extracted with ethyl acetate (18 mL, 6 mL x 3). The collected organic phase was washed with brine (6 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25%-35%, 6 min) to give N-[3-(dimethylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303059 (2.3 mg, yield 11.9%, purity 91.2%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 431.2.

¹ H NMR (300MHz, MeOD) δ = 8.88 (s, 1H), 7.16–7.11 (m, 1H), 6.82 (d, J = 9.0Hz, 1H), 6.6 8(dd,J＝3.0,9.0Hz,1H),5.47–5.30(m,1H),5.20(s,2H),4.27–4.14(m,2H),4.14 –4.07(m,1H),3.90–3.62(m,2H),3.31–3.30(m,6H),2.93–2.75(m,1H),2.44(s, 3H),2.40–2.34(m,2H),2.18–1.96(m,2H),1.76–1.69(m,2H),1.60–1.49(m,2H).

Example 32 Preparation of N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303060

Step 1 Preparation of N-[3-(formylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303060-1

The product of Example 8, JD-5303008 (70 mg, 0.17 mmol, 1.0 eq), was dissolved in DCM (2 mL). HCOOH (40 mg, 0.87 mmol, 5.0 eq), HATU (331 mg, 0.87 mmol, 5.0 eq), and DIEA (225 mg, 1.74 mmol, 10.0 eq) were added to the mixture. The reaction mixture was allowed to react at room temperature for 15 hours. The mixture was quenched with saturated potassium carbonate solution (5 mL) and then extracted with dichloromethane (20 mL, 10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (dichloromethane/methanol = 8/1) to give N-[3-(formylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazeolan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide JD-5303060-1 (50 mg, yield 66.7%, purity 94%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 431.3.

¹ H NMR (400MHz, DMSO-d ₆ )δ＝8.97(s,1H),8.16(d,J＝7.6Hz,1H),7.95(s,1H),7.32(d,J＝2.8Hz,1H),6.76(d,J＝8.8Hz,1H),6.70(d,J＝7.2Hz,1H),6.59 (dd,J＝2.8,8.8Hz,1H),5.16(s,2H),4.14–4.06(m,3H),3.89–3.80(m,1H),3.70–3.64(m,2H),2.38(s,3H),1.71–1.36(m,8H).

Step 2 Preparation of N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303060

N-[3-(Formylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303060-1 (50 mg, 0.116 mmol, 1.0 eq) was dissolved in THF (1 mL). _BH₃- THF (0.58 mL, 0.58 mmol, 5.0 eq) was added to the mixture, and the reaction mixture was allowed to react at room temperature for 15 hours. HCl (2 mL) (1N) and MeOH (4 mL) were added to the reaction system, followed by stirring at room temperature for 20 minutes. The mixture was quenched with saturated sodium carbonate solution (10 mL) and extracted with ethyl acetate (30 mL, 10 mL x 3). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25%-35%, 6 min) to give N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303060 (3.1 mg, yield 5.9%, purity 99.8%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 417.2.

¹ H NMR(400MHz,MeOD)δ=8.89(s,1H),8.53(brs,0.73H),7.20(s,1H),6.86–6.76(m,1H),6.69(s,1H) ,5.19(s,2H),4.18(s,2H),4.03(s,1H),3.77(s,2H),2.69(s,3H),2.44(s,3H),2.16–1.54(m,8H).

Example 33 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303028

Step 1 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303028-2

6-Hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303028-1 (1.00 g, 6.06 mmol, 1.00 eq), K₂CO₃ ( _1.67 g, 12.1 mmol, 2.00 eq), and 2-(bromomethyl)-1-fluorobenzene JD-5303028a (1.14 _g , 6.06 mmol, 730 μL, 1.00 eq) were added to a DMF (10.0 mL) solution. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with _H₂O (10.0 mL) and extracted twice with EtOAc (20.0 mL). The organic phase was separated, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1) to give 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303028-2 (250 mg, 914 μmol, yield 15.1%) as a white solid.

LC-MS [M+H] ⁺ = 274.1.

Step 2 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303028-3

6-{[(2-Fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303028-2 (250 mg, 914 μmol, 1.00 eq) was dissolved in THF solution (2.50 mL). BH ₃ -Me ₂ S (10 M, 457 μL, 5.00 eq) was added to the mixture at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by the addition of MeOH (5.00 mL) at 0°C and then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1) to give 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303028-3 (60.0 mg, 231 μmol, yield 25.2%) as a brown oil.

LC-MS [M+H] ⁺ = 260.0.

Step 3 Preparation of 2-methylpropane-2-yl 3,3-difluoro-4-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303028-4

6-{[(2-Fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303028-3 (50.0 mg, 192 μmol, 1.00 eq) and 2-methylprop-2-yl-4-amino-3,3-difluorotetrahydropyrrole-1-carboxylate JD-5303028b (257 mg, 1.16 mmol, 6.00 eq) were dissolved in DMF (1.00 mL), and CDI (69.7 mg, 430 μmol, 2.00 eq) was added. The mixture was stirred at 65°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch xextreme C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 46%-76% B over 10 minutes) to give 3,3-difluoro-4-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester JD-5303028-4 (85.0 mg, 167 μmol, yield 86.8%) as a gray solid.

LC-MS [M+Na] = 530.1.

Step 4 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303028

2-Methylpropane-2-yl 3,3-difluoro-4-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303028-4 (30.0 mg, 59.1 μmol, 1.00 eq) and TMSCl (12.8 mg, 118 μmol, 15.0 μL, 2.00 eq) were added to TFE (1.00 mL) and stirred at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303028 (19.3 mg, 43.5 μmol, HCl yield 73.6%, purity 95.83%) as a white solid.

LC-MS [M+Na] = 408.0.

¹ H NMR: (400MHz, DMSO-d6) δ = 3.42-3.47 (m, 1H), 3.65-3.87 (m, 5H), 4.07-4.26 (m, 2H), 4.74-4.90 (m, 1H), 5.03 (s, 2H), 6.67 (dd, J = 8.88, 2. 88Hz,1H),6.80(d,J＝8.88Hz,1H),7.20-7.29(m,2H),7.35(d,J＝2.88Hz,1H),7.38-7.46(m,1H),7.49-7.61(m,2H),9.87-10.31(m,1H).

Example 34 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303029

Step 1 Preparation of (2-methyl-1,3-oxazacyclopentyl-5-yl)methanol JD-5303029b

Methyl 2-methyl-1,3-oxazacyclopentane-5-carboxylate JD-5303029a (1.00 g, 7.09 mmol, 1.00 eq) was added to a THF (10.0 mL) solution, and LAH (2.50 M, 4.25 mL, 1.50 eq) was added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by the addition of H ₂ O (0.40 mL) at -10°C, then diluted with 15% NaOH (0.40 mL) and H ₂ O (1.20 mL), stirred at 25°C for 15 minutes, and filtered and concentrated under reduced pressure to afford (2-methyl-1,3-oxazacyclopentane-5-yl)methanol JD-5303029b (1.00 g, crude) as a yellow oil.

Step 2 Preparation of 5-(chloromethyl)-2-methyl-1,3-oxazacyclopentane JD-5303029c

To (2-methyl-1,3-oxazacyclopentan-5-yl)methanol JD-5303029b (1.00 g, 8.84 mmol, 1.00 eq) in THF (10.0 mL) was added _SOCl₂ (2.10 g, 17.6 mmol, 1.28 mL, 2.00 eq) _and stirred at 0°C for 1 h. The reaction mixture was quenched with _Na₂CO₃ to adjust the pH to 8. The reaction solution was then slowly quenched in warm water and extracted twice with ethyl acetate. Concentration under reduced pressure afforded 5-(chloromethyl)-2-methyl-1,3-oxazacyclopentan-5-yl)methanol JD-5303029c (1.00 g, crude) as a yellow oil.

Step 3 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303029

Referring to the synthesis method of Example 33, compound JD-5303029c was replaced with JD-5303028b to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303029 (51.2 mg, 124 μmol, yield 79.6%) as a gray gum.

LC-MS [M+H] ⁺ = 411.0.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 2.70 (s, 3H), 3.47 (br s,1H),3.57-3.90(m,5H),4.03-4.24(m,2H),4.70-4.90(m,1H),5.20(s,2H),6.65 (dd,J＝8.88,2.88Hz,1H),6.79(d,J＝8.88Hz,1H),7.36(d,J＝2.75Hz,1H),7.64(br d,J＝8.38Hz,1H),7.82(s,1H),10.18-10.55(m,2H).

Example 35 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-hydroxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303030

Example 35: N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-hydroxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303030 (4.80 mg, 11.3 μmol, yield 8.45%, purity 96.2%) was prepared as a white solid according to the method of Example 37.

LC-MS [M+H] ⁺ = 407.0.

¹ H NMR: (400MHz, CHLOROFORM-d) δ = 3.64 (br s,2H),3.71-3.79(m,2H),3.80-3.87(m,1H),3.94-4.06(m,1H),4.19-4.29(m,2H),4.86(d,J＝12.01Hz,1H),5.00-5. 09(m,1H),5.14(d,J＝12.13Hz,1H),6.46-6.55(m,2H),6.63(dd,J＝8.88,2.75Hz,1H),6.79(d,J＝8.88Hz,1H),7.43(br d,J＝5.50 Hz, 1H), 7.80 (dd, J = 6.94, 1.69Hz, 1H), 12.13-12.55 (m, 1H).

Example 36 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303031

Step 1 Preparation of 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303031b

[2-(Trifluoromethyl)pyridin-3-yl]methanol JD-5303031a (1.00 g, 5.65 mmol, 1.00 eq) was added to a THF (10.0 mL) solution, followed by _SOCl₂ (1.34 g, 11.2 mmol, 820 μL, 2.50 eq ₎ . The mixture was stirred at 25°C for 12 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.58) showed complete consumption of the starting material, with the formation of a new spot. TLC confirmed the clean reaction. The reaction mixture was quenched with _Na₂CO₃ and the pH was adjusted to 8. The reaction solution was then slowly quenched in warm water and extracted twice with ethyl acetate. Concentration under reduced pressure afforded 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303031b (1.18 g, crude) as a brown oil.

Step 2 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303031

Referring to the synthetic method of Example 33, compound JD-5303031b was replaced with JD-5303028a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303031 (4.80 mg, 11.3 μmol, yield 8.45%, purity 96.2%) as a white solid.

LC-MS [M+H] ⁺ = 459.1.

1H NMR: (400MHz, DMSO-d6) δppm 3.41-3.47(m,1H)3.61-3.92(m,5H)4.06-4 .24(m,2H)4.73-4.89(m,1H)5.19(s,2H)6.67(dd,J＝8.94,2.94Hz,1H)6.82(d ,J＝8.88Hz,1H)7.38(d,J＝2.88Hz,1H)7.58(d,J＝8.38Hz,1H)7.78(dd,J＝7.8 8,4.63Hz,1H)8.21(d,J＝7.75Hz,1H)8.72(d,J＝4.00Hz,1H)10.04(br s,2H).

Example 37 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303032

Step 1 Preparation of 3-(chloromethyl)-2-methoxypyridine JD-5303032b

(2-Methoxypyridin-3-yl)methanol JD-5303032a (1.00 g, 7.19 mmol, 1.00 eq) was dissolved in THF (10.0 mL) and _SOCl₂ (1.71 g, 14.3 mmol, 1.04 mL, 2.00 eq) was added. The mixture was stirred at 0° _C for 1 hr. Thin-layer chromatography (plate 1: petroleum ether:ethyl acetate = 2:1, Rf = 0.69) showed complete consumption of the starting material, with the formation of a new spot. The reaction mixture was quenched with _Na₂CO₃ and the pH adjusted to 8. The reaction solution was then slowly quenched in warm water and extracted twice with ethyl acetate. Concentration under reduced pressure provided 3-(chloromethyl)-2-methoxypyridine JD-5303032b (600 mg, crude) as a yellow oil.

Step 2 Preparation of 2-methylpropane-2-yl 3,3-difluoro-4-{[(6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303032-1

Example 32: Using the method of Example 33, 3-(chloromethyl)-2-methoxypyridine JD-5303032b was substituted for JD-5303028a to prepare 3,3-difluoro-4-{[(6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylpropan-2-yl ester JD-5303032-1 (70.0 mg, 134 μmol, yield 45.7%, purity 99.09%) as a white solid.

LC-MS [M+H] ⁺ = 521.2.

Step 3 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303032

Compound 3,3-difluoro-4-{[(6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester JD-5303032-1 (70.0 mg, 134 μmol, 1.00 eq) and TMSCl (29.2 mg, 268 μmol, 34.1 μL, 2.00 eq) were added to TFE (2.00 mL) and stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography (column: Welch xextreme C18 150*25 mm*5 um; mobile phase: [water (TFA)- ACN]; gradient: 14%-44% B over 14 minutes) to afford N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303032 (24.0 mg, 56.5 μmol, 42.0% yield, 99.1% purity) as a white solid.

LC-MS [M+H] ⁺ = 421.1.

¹ H NMR (400 MHz, DMSO-d ₆ )δ=3.62-3.71(m,2H),3.71-3.77(m,2H),3.78-3.85(m,2H),3.91(s,3H),4.09- 4.21(m,2H),4.77-4.87(m,1H),4.94(s,2H),6.65(dd,J＝8.94,2.94Hz,1H),6.8 0(d,J＝8.88Hz,1H),7.01(dd,J＝7.19,5.07Hz,1H),7.33(d,J＝2.88Hz,1H),7.46 (d, J=8.38Hz, 1H), 7.76 (dd, J=7.25, 1.75Hz, 1H), 8.14 (dd, J=4.94, 1.81Hz, 1H).

Example 38 Preparation of N-(hexahydropyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303033

Referring to the synthetic method of Example 33, compound JD-5303028a was replaced with JD-5303033a to prepare N-(hexahydropyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303033 (4.87 mg, 11.4 μmol, yield 61.4%, purity 98.14%) as an off-white solid.

LC-MS [M+H] ⁺ = 436.3.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 1.50-1.73 (m, 2H), 1.81-1.91 (m, 2H), 2.77 (br d, J = 1.63Hz, 2H), 3.14 (br d, J = 12.13Hz, 1H), 3.26 (br d,J＝11.51Hz,1H),3.68-3.76(m,2H),3.86-3.96(m,1H),4.10-4.17(m,2H),5.13(s,2H),6.61(dd,J＝8.88,2.88Hz,1H),6.7 9(d,J＝8.88Hz,1H),7.03(d,J＝7.38Hz,1H),7.40(d,J＝2.75Hz,1H),7.55-7.61(m,1H),7.69-7.81(m,3H),8.71-8.94(m,2H).

Example 39 Preparation of N-(hexahydropyridin-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303034

Step 1 Preparation of 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303034b

[2-(Trifluoromethyl)pyridin-3-yl]methanol JD-5303034a (90.0 mg, 508 μmol, 1.00 eq) was added to THF (2.00 mL). _SOCl₂ (120 mg, 1.02 mmol, 73.8 μL, 2.00 eq) was added at 0°C, and the mixture was stirred at 25°C for 2 h. Thin-layer chromatography (plate 1: petroleum ether:ethyl acetate = 1:1, Rf = 0.58) showed complete consumption of the starting material, with the formation of a new spot. The reaction mixture was quenched with Na₂CO₃ and adjusted to pH 8. The reaction solution was then slowly quenched in warm water and extracted twice with ethyl acetate. The organic phase was collected and concentrated under reduced pressure to yield 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303034b (50.0 mg, crude) as a yellow oil.

Step 2 Preparation of N-(hexahydropyridin-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303034

Referring to the synthetic method of Example 33, compound JD-5303028a was replaced with JD-5303034b to prepare N-(hexahydropyridin-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303034 (7.36 mg, 11.46 μmol, yield 61.47%) as a white solid.

LC-MS [M+H] ⁺ = 437.3.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 1.50-1.61 (m, 1H), 1.63-1.74 (m, 1H), 1.86 (br d, J = 11.01Hz, 2H), 2.78 (q, J = 9.30Hz, 2H), 3.12 (br d,J＝12.13Hz,1H),3.24(br d,J＝9.88Hz,1H),3.70-3.78(m,2H),3.87-3.97(m,1H),4.13(t,J＝4.31Hz,2H),5.18(s,2H),6.62(dd,J＝8.88,3.00Hz,1H),6.79(d,J＝8.88H z,1H),7.09(d,J＝7.50Hz,1H),7.43(d,J＝2.88Hz,1H),7.78(dd,J＝7.88,4.75Hz,1H),8.20(d,J＝7.75Hz,1H),8.72(d,J＝4.38Hz,1H),8.93(br d,J＝9.26Hz,1H),9.14(br d, J = 7.00 Hz, 1H).

Example 40 Preparation of 6-{[(2,6-difluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303035

Referring to the synthesis method of Example 33, compound JD-5303028a was replaced with JD-5303035a to prepare 6-{[(2,6-difluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303035 (50.0 mg, 123 μmol, yield 62.4%, purity 99.81%) as a white solid.

LC-MS [M+H] ⁺ = 404.1.

¹ H NMR: (400 MHz, DMSO-d ₆ )

δ＝1.52-1.72(m,2H),1.81-1.92(m,2H),2.79(br t,J＝9.76Hz,2H),3.11(br d,J＝12.0 1Hz,1H),3.25(br d,J＝10.51Hz,1H),3.73(dt,J＝9.22,4.46Hz,2H),3.87-3.98(m,1H) ,4.13(t,J＝4.32Hz,2H),4.99(s,2H),6.62(dd,J＝8.88,2.88Hz,1H),6.78(d,J＝8.88Hz ,1H),7.09-7.22(m,3H),7.39(d,J＝2.88Hz,1H),7.46-7.57(m,1H),8.89-9.27(m,2H).

Example 41 Preparation of 6-{[(2,3-difluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303036

Step 1 Preparation of 3-(chloromethyl)-1,2-difluorobenzene JD-5303036b

(2,3-Difluorophenyl)methanol JD-5303036a (1.50 g, 10.4 mmol, 1.17 mL, 1.00 eq) was added to a THF (15 mL) solution. _SOCl₂ (2.48 g, 20.8 mmol, 1.51 mL, 2.00 eq) was then added at 25°C. The mixture was stirred at 25°C for 2 hours. Thin-layer chromatography (dichloromethane:methanol = 8:1, Rf = 0.66) indicated complete consumption of the starting material, with the formation of a new spot. The reaction mixture was concentrated under reduced pressure to afford 3-(chloromethyl)-1,2-difluorobenzene JD-5303036b (1.30 g, crude) as a brown solid.

Step 2 Preparation of 6-{[(2,3-difluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303036

Referring to the synthesis method of Example 33, compound JD-5303028a was replaced with JD-5303036b to prepare 6-{[(2,3-difluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303036 (20.6 mg, 49.1 μmol, yield 61.8%, purity 96%) as a pink solid.

LC-MS [M+H] ⁺ = 404.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.52-1.71 (m, 2H) 1.86 (br d, J = 6.75Hz, 2H) 2.77 (br t, J = 10.88Hz, 2H) 3.15 (br d,J＝12.51Hz,1H)3.25-3.29(m,1H)3.71(br d,J＝2.75Hz,2H)3.85-3.97(m,1H)4.13(t,J＝4.50Hz,2H)5.07(s,2H)6.63(dd,J＝8.88,3.00Hz,1H)6.78(d,J＝8.88Hz,1H)7.04(br d,J＝7.38Hz,1H)7.18-7.28(m,1H)7.30-7.38(m,1H)7.39-7.49(m,2H)8.69-8.95(m,2H).

Example 42 6-{[(2-fluoro-4-methylphenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine Preparation of 4-hexanecarboxamide trifluoroacetate JD-5303037

Referring to the synthetic method of Example 33, compound JD-5303028a was replaced with JD-5303037a to prepare 6-{[(2-fluoro-4-methylphenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303037 (0.9 mg, 2.15 μmol, yield 5.38%, purity 95.55%) as a white solid.

LC-MS [M+H] ⁺ = 400.1.

¹ H NMR: (400MHz, DMSO-d ₆ )δ＝8.34-8.70(m,2H),7.26-7.47(m,2H),6.89-7.13(m,3H),6.77(d,J＝8.88Hz,1H),6.61(dd,J＝8.88,2.88Hz,1H),4.86-5.07(m,2 H),4.07-4.19(m,2H),3.83-3.95(m,1H),3.65-3.72(m,2H),2.65-2.84(m,4H),2.32(s,3H),1.79-1.93(m,2H),1.46-1.67(m,2H).

Example 43 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303038

Referring to the synthesis method of Example 33, compound JD-5303028b was replaced with JD-5303002a to prepare 6-{[(2-fluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303038 (26.0 mg, 61.6 μmol, yield 99.7%, HCl) as a yellow gum.

LC-MS [M+H] ⁺ = 386.2.

¹ H NMR: (400MHz, DMSO-d6) δppm 1.47-1.73 (m, 2H) 1.86 (br d,J＝10.13Hz,2H)2.71-2.87(m,2H)3.07-3.30(m,2H)3.67-3.78(m,2H)3.83-3.99(m,1H)4.07-4.17(m,2H)5.02(s,2H)6.62(dd ,J＝8.88,2.88Hz,1H)6.77(d,J＝8.88Hz,1H)7.08(d,J＝7.50Hz,1H)7.20-7.29(m,2H)7.37-7.45(m,2H)7.49-7.56(m,1H)8.92(br d,J＝9.25Hz,1H)9.13(br d,J＝7.50Hz,1H).

Example 44 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(4-methyl-1,3-thiazolin-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303039

Step 1 Preparation of 1-(4-methyl-1,3-thiazolyl-5-yl)ethan-1-ol JD-5303039b

4-Methyl-1,3-thiazolyl-5-carbaldehyde JD-5303039a (2.50 g, 19.6 mmol, 1.00 eq) was dissolved in THF (25 mL) and MeMgBr (3 M, 7.86 mL, 1.20 eq) was added. The mixture was stirred at 0°C under a _nitrogen atmosphere at 0-25°C for 16 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.42) indicated complete consumption of the starting material, with the formation of a new spot. TLC confirmed the reaction was complete. The reaction mixture was quenched by adding saturated NH ₄ Cl (20 mL) solution at 0° C., then diluted with H ₂ O (40 mL) and extracted with ethyl acetate (60 mL, 30 mL*2). The collected organic layer was concentrated under reduced pressure to give 1-(4-methyl-1,3-thiazolyl-5-yl)ethan-1-ol JD-5303039b (2.65 g, crude product) as a yellow oil.

Step 2 Preparation of 5-(1-bromoethyl)-4-methyl-1,3-thiazolyl JD-5303039c

1-(4-Methyl-1,3-thiazolin-5-yl)ethan-1-ol JD-5303039b (1.00 g, 6.98 mmol, 1.00 eq) in THF (10 mL) was added with PBr ₃ (945 mg, 3.49 mmol, 0.50 eq) and stirred at 0°C for 2 hours. The mixture was concentrated under reduced pressure to afford 5-(1-bromoethyl)-4-methyl-1,3-thiazolin-5-yl)ethan-1-ol JD-5303039c (1.40 g, crude) as an off-white solid. The reaction mixture was used in the next step without further purification.

Step 3 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(4-methyl-1,3-thiazolin-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303039

Referring to Example 33, compound JD-5303028a was replaced with JD-5303039c to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(4-methyl-1,3-thiazolin-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroformate JD-5303039 (0.12 g, 376 μmol, yield 5.65%, purity 91.0%) as a white solid.

LC-MS [M+H] ⁺ = 425.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.55(d,J＝6.25Hz,3H)2.36(d,J＝2.00Hz,3H)3.29-3.47(m,2H)3.68-3.77(m,4H)4.10-4.14(m,2H)4.69-4.90(m,1 H)5.64(q,J＝6.25Hz,1H)6.57(dd,J＝8.88,2.25Hz,1H)6.74(d,J＝8.88Hz,1H)7.28(dd,J＝4.57,2.94Hz,1H)7.39(br t,J＝8.13Hz,1H)8.89(s,1H)9.39-9.73(m,2H).

Example 45 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(2-fluorophenyl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303040

Step 1 Preparation of 1-(2-fluorophenyl)ethan-1-ol JD-5303040b

2-Fluorobenzene-1-carbaldehyde JD-5303040a (2.50 g, 20.1 mmol, 2.11 mL, 1.00 eq) was dissolved in THF (25 mL, at 0°C under _N2 atmosphere), and MeMgBr (3 M, 8.06 mL, 1.20 eq) was added. The mixture was stirred at 0-25°C for 16 hours. The reaction mixture was quenched by the addition of _NH4Cl (aq, 30 mL) at 0°C, then diluted with _H2O (50 mL), and extracted with ethyl acetate (60 mL, 30 mL*2). The organic layer was collected, washed with NaCl (aq, 20 ml), and concentrated under reduced pressure to give 1-(2-fluorophenyl)ethan-1-ol JD-5303040b (2.30 g, crude product) as a yellow oil.

Step 2 Preparation of 1-(1-chloroethyl)-2-fluorobenzene JD-5303040c

1-(2-Fluorophenyl)ethan-1-ol JD-5303040b (1.20 g, 8.56 mmol, 1.00 eq) was dissolved in _THF (12 mL), and SOCl₂ (3.06 g, 25.6 mmol, 1.87 mL, 3.00 eq) was added. The reaction mixture was stirred at 25° _C for 16 hours. The reaction mixture was quenched with _Na₂CO₃ and the pH was adjusted to 8. The reaction solution was then slowly quenched in warm water and extracted twice with ethyl acetate. Concentration under reduced pressure provided 1-(1-chloroethyl)-2-fluorobenzene JD-5303040c (1.28 g, crude) as a yellow oil.

Step 3 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(2-fluorophenyl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303040

Referring to the synthetic method of Example 33, compound JD-5303028a was replaced with JD-5303040c to prepare N-(4,4-difluorotetrahydro -1H-pyrrol-3-yl)-6-{[1-(2-fluorophenyl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303040 (7.33 mg, 16.70 μmol, yield 29.03%, purity 96%) was obtained as a yellow oil.

LC-MS [M+H] ⁺ = 422.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.55(d,J＝6.25Hz,3H)2.36(d,J＝2.00Hz,3H)3.29-3.47(m,2H)3.68-3.77(m,4H)4.10-4.14(m,2H)4.69-4.90(m,1 H)5.64(q,J＝6.25Hz,1H)6.57(dd,J＝8.88,2.25Hz,1H)6.74(d,J＝8.88Hz,1H)7.28(dd,J＝4.57,2.94Hz,1H)7.39(br t,J＝8.13Hz,1H)8.89(s,1H)9.39-9.73(m,2H).

Example 46 Preparation of N-(3-aminocyclohexyl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303041

Referring to the synthesis method of Example 33, compound JD-5303028b was replaced with JD-5303041a to prepare N-(3-aminocyclohexyl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303041 (10.8 mg, 25.0 μmol, yield 78.1%, purity 98.48%) as a yellow solid.

LC-MS [M+H] ⁺ = 400.1.

¹ H NMR: (400MHz, DMSO-d6) δppm 1.41-1.77(m,8H)1.86-2.00(m,1H)3.64-3.75(m,2H)3.98(br s,1H)4.05-4.17(m,2H)5.02(s,2H)6.60(dd,J＝8.88,3.00Hz,1H)6.72-6.80(m ,2H)7.18-7.28(m,2H)7.31-7.46(m,2H)7.53(td,J＝7.63,1.50Hz,1H)7.94(br s,3H).

Example 47 Preparation of 6-(benzyloxy)-N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303042

Referring to the synthetic method of Example 33, compound JD-5303028a was replaced with JD-5303042a to prepare 6-(benzyloxy)-N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303042 (7.50 mg, 19.2 μmol, yield 23.5%, purity 97.13%) as a white solid.

LC-MS [M+H] ⁺ = 390.0.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 2.78 (br dd,J＝11.57,8.44Hz,1H),2.89-3.00(m,1H),3.15-3.26(m,2H),3.60-3.69(m,1H),3.73-3.82(m,1H),4.05-4.19( m,2H),4.34(dt,J＝16.45,8.04Hz,1H),4.98(s,2H),6.61(dd,J＝8.94,2.81Hz,1H),6.77(d,J＝8.88Hz,1H),7.09(br d,J＝8.50Hz,1H),7.29-7.47(m,6H).

Example 48 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-({[2-(trifluoromethyl)pyridin-4-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303043

Step 1 Preparation of [2-(trifluoromethyl)pyridin-4-yl]methanol JD-5303043b

BH ₃ -THF (1M, 10.4 mL, 2.00 eq) was added dropwise to 2-(trifluoromethyl)pyridine-4-carboxylic acid JD-5303043a (1.00 g, The mixture was added to a solution of [2-(trifluoromethyl)pyridin- _4- yl]methanol JD-5303043b (5.23 mmol, 1.00 eq) in THF (10 mL) and stirred at 75°C for 2 hours. The reaction mixture was quenched with MeOH (50 mL) at 0°C under N₂. The mixture was stirred at 25°C for 0.5 hours and concentrated under reduced pressure to afford [2-(trifluoromethyl)pyridin-4-yl]methanol JD-5303043b (1.00 g, crude) as a brown oil.

LC-MS [M+H] ⁺ = 178.0.

Step 2 Preparation of 4-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303043c

[2-(Trifluoromethyl)pyridin-4-yl]methanol JD-5303043b (1.00 g, 5.65 mmol, 1.00 eq) was added to a THF (10 mL) solution, followed by _SOCl₂ (1.68 g, 14.1 mmol, 1.03 mL, 2.50 eq). The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with aq _{Na₂CO₃ and} the pH was adjusted to 8. The reaction solution was then slowly quenched in warm water and extracted twice with ethyl acetate. The solution was concentrated under reduced pressure to afford 4-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303043c (0.6 g, crude) as a brown solid.

Step 3 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-({[2-(trifluoromethyl)pyridin-4-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303043

Referring to the synthesis method of Example 33, JD-5303028a was replaced with JD-5303043c to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-({[2-(trifluoromethyl)pyridin-4-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303043 (0.024 g, 51.7 μmol, yield 96.4%, purity 99.0%) as a white solid.

LC-MS [M+H] ⁺ = 459.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 3.41 (br s, 2H) 3.67 (br s,4H)4.08-4.25(m,2H)4.75-4.91(m,1H)5.20(s,2H)6.69(dd,J＝8.94,2.94Hz,1H)6.83(d,J＝8.88H z,1H)7.33-7.52(m,2H)7.74(d,J＝4.88Hz,1H)7.91(s,1H)8.77(d,J＝5.00Hz,1H)9.24-10.08(m,2H).

Example 49 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-oxazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide hydrochloride JD-5303044

Step 1 Preparation of (2-methyl-1,3-oxazacyclopentyl-5-yl)methanol JD-5303044b

Methyl 2-methyl-1,3-oxazacyclopentane-5-carboxylate JD-5303044a (1.00 g, 7.09 mmol, 1.00 eq) was added to a THF (10.0 mL) solution, and LAH (2.50 M, 4.25 mL, 1.50 eq) was added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by the addition of H ₂ O (0.40 mL) at -10°C, then diluted with 15% NaOH (0.40 mL) and H ₂ O (1.20 mL), stirred at 25°C for 15 minutes, and filtered and concentrated under reduced pressure to afford (2-methyl-1,3-oxazacyclopentane-5-yl)methanol JD-5303044b (1.00 g, crude) as a yellow oil.

Step 2 Preparation of 5-(chloromethyl)-2-methyl-1,3-oxazacyclopentane JD-5303044c

To (2-methyl-1,3-oxazacyclopentan-5-yl)methanol JD-5303044b (1.00 g, 8.84 mmol, 1.00 eq) in THF (10.0 mL) was added _SOCl₂ (2.10 g, 17.6 mmol, 1.28 mL, 2.00 eq) _and stirred at 0°C for 1 h. The reaction mixture was quenched with _Na₂CO₃ to adjust the pH to 8. The reaction solution was then slowly quenched in warm water and extracted twice with ethyl acetate. Concentration under reduced pressure afforded 5-(chloromethyl)-2-methyl-1,3-oxazacyclopentan-5-yl)methanol JD-5303044c (1.00 g, crude) as a yellow oil.

Step 3 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-oxazacyclopentan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazacyclopentan-4-carboxamide hydrochloride JD-5303044

Referring to the synthesis method of Example 33, JD-5303028a was replaced with JD-5303044c to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-oxazacyclopentan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazacyclohexane-4-carboxamide hydrochloride JD-5303044 (22.0 mg, 55.7 μmol, yield 91.95%) as a yellow solid.

LC-MS [M+H] ⁺ = 395.0.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 2.41 (s, 3H), 3.46 (br s, 1H), 3.62-3.84 (m, 5H), 4.08-4.20 (m, 2H), 4.81 (br d,J＝9.26Hz,1H),4.97(s,2H),6.65(dd,J＝8.88,2.88Hz,1H),6.79(d,J＝8.88Hz,1H ),7.13(s,1H),7.34(d,J＝2.88Hz,1H),7.59(d,J＝8.38Hz,1H),9.95-10.38(m,2H).

Example 50 Preparation of 3-[(4-{[(4,4-difluorotetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-6-yl)oxy]benzene-1-carboxamide hydrochloride JD-5303045

Referring to the synthesis method of Example 52, compound JD-5303047a was replaced with JD-5303045a to prepare methyl 3-[(4-{[(4,4-difluoro-1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-6-yl)oxy]benzoate JD-5303045-1 (270 mg, 700 μmol, 88.0%) as a yellow gum.

LC-MS [385+Na] ⁺ =408.

Step 1 Preparation of 3-[(4-{[(4,4-difluoro-1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-6-yl)oxy]benzoic acid JD-5303045-2

Methyl 3-[(4-{[(4,4-difluoro-1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-6-yl)oxy]benzoate JD-5303045-1 (120 mg, 224 μmol, 1.00 eq) was dissolved in methanol (1.00 mL) and water (1.00 mL). To the mixture was added NaOH (17.9 mg, 449 μmol, 2.00 eq), and the reaction mixture was stirred at 25 ° C for 16 hours. The reaction solution was quenched by adding _H2O (2.00 mL), and then extracted with MTBE (4.00 mL, 2.00 mL*2). The aqueous phase was diluted with hydrochloric acid to adjust the pH to 4, and then extracted with ethyl acetate (4.00 mL, 2.00 mL*2). The mixture was concentrated under reduced pressure to give 3-[(4-{[(4,4-difluoro-1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-6-yl)oxy]benzoic acid JD-5303045-2 (100 mg, 192 μmol, yield 85.5%) as a white solid.

LC-MS[519-99] ⁺ =420

Step 2 Preparation of 4-[({6-[(3-formamidophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl}carbonyl)amino]-3,3-difluorotetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester JD-5303045-3

3-[(4-{[(4,4-Difluoro-1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-6-yl)oxy]benzoic acid JD-5303045-2 (50.0 mg, 96.2 μmol, 1.00 eq) was dissolved in dioxane (2.00 mL). NH ₄ HCO ₃ (9.13 mg, 115 μmol, 1.26 eq), Boc ₂ O (27.3 mg, 125 μmol, 28.7 μL, 1.30 eq) and Py (4.72 mg, 59.6 μmol, 4.82 μL, 0.62 eq) were added to the reaction mixture. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched by addition of _H₂O (2.00 mL) and extracted with EtOAc (4.00 mL, 2.00 mL x 2). The combined organic layers were concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: CD04-Welch ultimate C18 150*25*7 μm; mobile phase: [water (TFA)-ACN]; gradient: 36%-66% B over 10 minutes) to afford 2-methylpropane-2-yl 4-[({6-[(3-formamidophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-yl}carbonyl)amino]-3,3-difluorotetrahydropyrrole-1-carboxylate JD-5303045-3 (20.0 mg, 38.5 μmol, 40.08% yield) as a white solid.

LC-MS[518-99] ⁺ =419

Step 3 Preparation of 3-[(4-{[(4,4-difluorotetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-6-yl)oxy]benzene-1-carboxamide hydrochloride JD-5303045

4-[({6-[(3-Formamidophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl}carbonyl)amino]-3,3-difluorotetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester JD-5303045-3 (20.0 mg, 38.5 μmol, 1.00 eq) was dissolved in TFE (2.00 mL), and TMSCl (8.38 mg, 77.1 μmol, 9.79 μL, 2.00 eq) was added to the reaction mixture, and the reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-[(4-{[(4,4-difluorotetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-6-yl)oxy]benzene-1-carboxamide hydrochloride JD-5303045 (4.68 mg, 14.3 μmol, yield 37.1%, purity 100.00%) as a white solid.

LC-MS [418+H] ⁺ =419.

¹ H NMR: (400MHz, DMSO-d ₆ )δ＝3.60-3.93(m,6H),4.14-4.29(m,2H),4.67-4.81(m,1H),6.70(dd,J＝8.76,2.75Hz,1H),6.92(d,J＝8.76Hz,1H),7.1 1(dd,J＝8.07,2.31Hz,1H),7.35-7.44(m,3H),7.45-7.54(m,2H),7.58(d,J＝7.75Hz,1H),7.98(s,1H)9.39-9.75(m,2H).

Example 51 N-(Hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[3-ol]- Preparation of [b][1,4]oxazacyclohexane-4-carboxamide JD-5303046

Step 1 Preparation of 2-methylpropane-2-yl 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303046-2

6-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303046-1 (0.9 g, 5.0 mmol, 1.0 eq) was dissolved in dioxane (10.0 mL), and Boc ₂ O (4.4 g, 20.0 mmol, 4.0 eq), TEA (2.5 g, 25.0 mmol, 5.0 eq), and DMAP (61.0 mg, 0.5 mmol, 0.1 eq) were added. The reaction mixture was reacted at 100° C. for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 50/1 to 30/1) to give 2-methylpropane-2-yl 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303046-2 (1.2 g, yield 85.7%, purity 94%) as a white solid.

LC-MS ([M+H ₂ O] ⁺ ) = 298.1.

¹ H NMR (300MHz, CDCl ₃ ) δ = 8.79 (s, 1H), 7.88 (dd, J = 9.0, 2.7Hz, 1H), 6.94 (d, J = 9.0Hz, 1H), 4.33 (t, J = 4.5Hz, 2H), 3.91 (t, J = 4.8Hz, 2H), 1.58 (s, 9H).

Step 2 Preparation of 2-methylpropane-2-yl 6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303046-3

2-Methylpropane-2-yl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303046-2 (1.2 g, 4.3 mmol, 1.0 eq) was dissolved in EtOAc (10.0 mL), and Pd/C (120 mg) (10%) was added. The reaction mixture was reacted at 50°C under a hydrogen atmosphere for 12 hours. The mixture was filtered, and the filtrate was concentrated to afford 2-methylpropane-2-yl-6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303046-3 (1.1 g, crude) as a white solid.

LC-MS ([M+H] ⁺ ) = 251.1.

¹ H NMR (400 MHz, DMSO-d ₆ )

δ=7.12(s,1H),6.52(d,J=8.8,1H),6.21(dd,J=8.4Hz,2.4Hz,1H),4.60(s,2H),4.05(t,J=4.4Hz,2H),3.70(t,J=4.8Hz,2H),1.48(s,9H).

Step 3 Preparation of 2-methylpropane-2-yl 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxylate JD-5303046-4

2-Methylpropane-2-yl-6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303046-3 (0.9 g, 3.6 mmol, 1.0 eq) was dissolved in THF (10.0 mL). 5-(Chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (0.58 g, 4.0 mmol, 1.1 eq) and TEA (0.73 g, 7.2 mmol, 2.0 eq) were added. The reaction mixture was reacted at 60°C for 3 hours. The mixture was quenched by addition of water (20 mL) at room temperature and then extracted with ethyl acetate (40 mL, 20.0 mL x 2). The collected organic phase was washed with water (45 mL, 15.0 mL x 3) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5/1 to 2/1) to give 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylic acid-2-methylpropane-2-yl ester JD-5303046-4 (0.75 g, two-step yield 59.2%, purity 92%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 362.5.

¹ H NMR (400MHz, CDCl ₃ )δ＝8.61(s,1H),7.36(s,1H),6.73(d,J＝8.4Hz,1H),6.34(dd,J＝8.8,2.8Hz,1H),4 .40(s,2H),4.17(t,J＝4.4Hz,2H),3.83(t,J＝4.8Hz,2H),2.46(s,3H),1.53(s,9H).

Step 4 Preparation of 6-[5-(4-methyl-1,3-thiazolin-5-yl)-3-oxo-1-phenyl-4-aza-2-oxazolin-4-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazolin-4-carboxylic acid-2-methylprop-2-yl ester JD-5303046-5

2-Methylpropane-2-yl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxylate JD-5303046-4 (150 mg, 0.42 mmol, 1.0 eq) was dissolved in THF (3.0 mL). NaH (60%) (33 mg, 0.83 mmol, 2.0 eq) was added at 0°C. The reaction mixture was reacted at 0°C for 0.5 hours before CbzCl (127 mg, 0.75 mmol, 1.8 eq) was added. The mixture was then allowed to warm to room temperature and stirred for 11.5 hours. The mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) at room temperature and extracted with ethyl acetate (30 mL, 10.0 mL x 3). The collected organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 5/1 to 3/1) to obtain 6-[5-(4-methyl-1,3-thiazolyl-5-yl)-3-oxoylide-1-phenyl-4-aza-2-oxapent-4-yl]-3,4-dihydro-2H- 2-Methylpropanebenzo[b][1,4]oxazepine-4-carboxylate JD-5303046-5 (180 mg, yield 87.5%, purity 92%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 496.5.

¹ H NMR (300MHz, CDCl ₃ )δ＝8.60(s,1H),7.82–7.62(m,1H),7.29(s,5H),6.77(d,J＝8.7Hz,1H),6.58(s,1H),5.16( s,2H),4.92(s,2H),4.24(t,J＝4.2Hz,2H),3.84(t,J＝4.5Hz,2H),2.17(s,3H),1.49(s,9H).

Step 5 Preparation of benzyl [(3,4-dihydro-2H-benzo[b][1,4]oxazepan-6-yl)[(4-methyl-1,3-thiazolin-5-yl)methyl]amino]methane JD-5303046-6

2-Methylpropane-2-yl-6-[5-(4-methyl-1,3-thiazolin-5-yl)-3-oxo-1-phenyl-4-aza-2-oxazolin-4-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxylate JD-5303046-5 (180 mg, 0.36 mmol, 1.0 eq) was dissolved in DCM (3 mL). Dioxane/HCl (0.91 ml, 3.63 mmol, 10.0 eq) (4 N) was added to the mixture, and the reaction mixture was reacted at room temperature for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was quenched with sodium hydroxide solution (15%) (3 mL), then extracted with DCM (20 mL, 10 mL * 2). The collected organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give benzyl [(3,4-dihydro-2H-benzo[b][1,4]oxazepan-6-yl)[(4-methyl-1,3-thiazolin-5-yl)methyl]amino]methane JD-5303046-6 (125 mg, crude) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 396.6.

Step 6 Preparation of benzyl [(4-{[(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-6-yl)[(4-methyl-1,3-thiazolin-5-yl)methyl]amino]methane JD-5303046-7

Benzyl [(3,4-dihydro-2H-benzo[b][1,4]oxazepin-6-yl)[(4-methyl-1,3-thiazolin-5-yl)methyl]amino]methane JD-5303046-6 (125 mg, 0.32 mmol, 1.0 eq) and TEA (96 mg, 0.95 mmol, 3.0 eq) were dissolved in DCM (1.0 mL), (COCl ₂ ) ₃ (47 mg, 0.16 mmol, 0.5 eq) was added, and the reaction mixture was reacted at room temperature for 0.5 hours. Then 2-methylprop-2-yl 3-aminohexahydropyridine-1-carboxylate JD-5303002a (76 mg, 0.38 mmol, 1.2 eq) was dissolved in DCM (0.5 mL) and added. The mixture was added and stirred at room temperature for 12 hours. The reaction system was quenched with water (5 mL) and extracted with DCM (20 mL, 10 mL * 2). The collected organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain benzyl [(4-{[(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-6-yl)[(4-methyl-1,3-thiazolin-5-yl)methyl]amino]methane JD-5303046-7 (300 mg, crude) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 622.4.

Step 7 Preparation of N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303046

Benzyl [(4-{[(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-6-yl)[(4-methyl-1,3-thiazolin-5-yl)methyl]amino]methane JD-5303046-7 (300 mg, 0.48 mmol, 1.0 eq) was dissolved in DCM (3 mL). TMSI (483 mg, 2.42 mmol, 5.0 eq) was added to the mixture, and the reaction mixture was reacted at room temperature for 12 hours. The mixture was quenched with water (3 mL), and then impurities were extracted with DCM (20 mL, 10 mL*2). The aqueous phase was adjusted to pH 9 with sodium hydroxide (3 mL, 15%) and extracted with DCM (20 mL, 10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150 x 25 mm x 5 mm; mobile phase: water (0.1% FA)-acetonitrile; B%: 15%-25% over 6 min) to afford N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303046 (29.9 mg, 18.3% yield over three steps, 97.9% purity) as a yellow solid.

LC-MS([M-1.34FA+H] ⁺ )=388.3.

¹ H NMR (300 MHz, DMSO-d ₆ )δ＝8.81(s,1H),8.31(brs,1H),6.87(d,J＝2.4Hz,1H),6.75(d,J＝7.5Hz,1H) ,6.61(d,J＝8.7Hz,1H),6.27(dd,J＝8.7,2.4Hz,1H),5.82(s,1H),4.29(s,2H ),4.05(t,J＝4.2Hz,2H),3.86–3.73(m,1H),3.69–3.60(m,2H),3.20–2.93(m ,2H),2.76–2.57(m,2H),2.38(s,3H),1.88–1.70(m,2H),1.65–1.39(m,2H).

Example 52 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303047

Step 1 Preparation of 2-methylpropane-2-yl 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303047-1 Preparation

6-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303001-1 (13.0 g, 60.7 mmol, 1.00 eq) was dissolved in THF (130 mL). Boc ₂ O (26.5 g, 121 mmol, 27.9 mL, 2.00 eq), DMAP (1.48 g, 12.1 mmol, 0.20 eq), and TEA (18.4 g, 182 mmol, 25.4 mL, 3.00 eq) were added and stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 0/1) to give 2-methylpropan-2-yl 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303047-1 (15.0 g, 47.7 mmol, 78.6% yield) as a white solid.

LC-MS [313-55]+ = 258.

Step 2 Preparation of 2-methylpropane-2-yl 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303047-2

To a solution of 2-methylpropan-2-yl 6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303047-1 (250 mg, 994 μmol, 1.00 eq) and 3-iodo-1-methoxybenzene JD-5303047a (465 mg, 1.99 mmol, 236 μL, 2.00 eq) in dioxane (2.50 mL) were added Cs ₂ CO ₃ (972 mg, 2.98 mmol, 3.00 eq) and t-BuXPhos Pd G3 (79.0 mg, 99.4 μmol, 0.10 eq). The mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched by addition of H ₂ O (10.0 mL) and then extracted with EtOAc (20.0 mL). The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1) to give 2-methylpropan-2-yl 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303047-2 (60.0 mg, 167 μmol, yield 16.8%) as a yellow oil.

LC-MS [357-55] ⁺ =302.

Step 3 Preparation of 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303047-3

6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylic acid-2-methylpropane-2-yl ester JD-5303047-2 (60.0 mg, 167 μmol, 1.00 eq) was added to TFE (1.00 mL) solution, and TMSCl (36.4 mg, 335 μmol, 42.6 The mixture was stirred at 25°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to give 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303047-3 (40.0 mg, crude) as a colorless oil.

LC-MS [257+H] ⁺ = 258

Step 4 Preparation of 2-methylpropane-2-yl 3,3-difluoro-4-[({6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl}carbonyl)amino]tetrahydropyrrole-1-carboxylate JD-5303047-4

To a solution of 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303047-3 (40.0 mg, 155 μmol, 1.00 eq) and 2-methylpropan-2-yl-4-amino-3,3-difluorotetrahydropyrrole-1-carboxylate JD-5303001d (69.1 mg, 310 μmol, 2.00 eq) in DMF (1.00 mL) was added CDI (50.4 mg, 310 μmol, 2.00 eq). The mixture was stirred at 65°C for 12 hours. LC-MS showed complete consumption of the starting material, with the detection of a major peak of the desired mass. The reaction mixture was quenched by adding 10.0 mL of _H₂O , then extracted with 20.0 mL of EtOAc. The organic phase was concentrated under reduced pressure to yield the crude product. High performance liquid chromatography (column: CD01-Phenomenex luna C18 150*25*10um; mobile phase: [water (FA)-ACN]; gradient: 54%-84% B over 11 minutes) was used to obtain 2-methylprop-2-yl 3,3-difluoro-4-[({6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-yl}carbonyl)amino]tetrahydropyrrole-1-carboxylate JD-5303047-4 (20.0 mg, 39.5 μmol, yield 25.4%) as a white solid.

LC-MS [505+Na] ⁺ =528.

Step 5 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303047

2-Methylpropane-2-yl-3,3-difluoro-4-[({6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl}carbonyl)amino]tetrahydropyrrole-1-carboxylate JD-5303047-4 (20.0 mg, 39.5 μmol, 1.00 eq) was dissolved in TFE (1.00 mL), and TMSCl (8.60 mg, 79.1 μmol, 10.0 μL, 2.00 eq) was added. The mixture was stirred at 25°C for 2 hours. High performance liquid chromatography (column: CD01-Phenomenex luna C18 150*25*10um; mobile phase: [water (TFA)-ACN]; gradient: 21%-51% B over 10 minutes) was used to obtain N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303047 (14.1 mg, 34.9 μmol, yield 88.2%, purity 99.89%) as a white solid.

LC-MS [405+H] ⁺ =406.

1H NMR: (400MHz, DMSO-d ₆ )δ=3.29-3.36(m,2H),3.65-3.71(m,2H),3.72(s,3H),3.77-3.86(m,2H),4.12-4.30(m,2H),4.65-4.85(m,1H), 6.44-6.54(m,2H)6.60-6.73(m,2H),6.90(d,J＝8.76Hz,1H),7.23(t,J＝8.13Hz,1H),7.37-7.47(m,2H),9.33(br s,2H).

Example 53 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-fluorophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303048

Referring to the synthetic method of Example 52, compound JD-5303047a was replaced with JD-5303048a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-fluorophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303048 (3.84 mg, 9.24 μmol, yield 47.7%) as an off-white solid.

LCMS [393+H] ⁺ =394.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = ppm 3.36-3.43(m,1H)3.59-3.91(m,5H)4.14-4.29(m,2H)4.66-4.84(m,1H)6.72(dd,J＝8.82,2.8 1Hz,1H)6.76-6.83(m,2H)6.86-6.96(m,2H)7.31-7.41(m,1H)7.48(d,J＝2.88Hz,1H)7.60(br d,J＝8.25Hz,1H)9.87(br s,2H).

Example 54 Preparation of N-(hexahydropyridin-3-yl)-6-{[1-(4-methyl-1,3-thiazolin-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303055

Referring to the synthesis method of Example 33, JD-5303028a was replaced with JD-5303039c and JD-5303028b was replaced with JD-5303002a to obtain N-(hexahydropyridin-3-yl)-6-{[1-(4-methyl-1,3-thiazolin-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303055 (25.2 mg, 56.4 μmol, yield 94.5%, purity 98%, hydrochloride) as a white solid.

LC-MS [M+H] ⁺ = 403.1.

¹ H NMR (400MHz, METHANOL-d ₄ )δ1.59-1.65(m,1H),1.66(d,J＝6.38Hz,3H),1.76-1.91(m,1H),1.99-2.12(m,2H),2.41- 2.47(m,3H),2.79-3.01(m,2H),3.34-3.38(m,1H),3.49(dt,J＝12.04,3.80Hz,1H),3.67-3 .81(m,2H),3.99(tt,J＝10.69,3.94Hz,1H),4.11-4.22(m,2H),5.65(q,J＝6.30Hz,1H),6.6 0(ddd,J＝8.94,2.81,0.88Hz,1H),6.76(d,J＝9.01Hz,1H),7.17-7.23(m,1H),8.96(s,1H).

Example 55 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303049

Step 1 Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303049-2

To a solution of 6-bromo-2-methyl-3,4-dihydro-2HJD-5303049-1 (2.50 g, 10.3 mmol, 1.00 eq) in dioxane (25.0 mL) were added BPD (5.25 g, 20.6 mmol, 2.00 eq), KOAc (2.53 g, 25.8 mmol, 2.50 eq) and PdCl ₂ (dppf) (377 mg, 516 μmol, 0.05 eq), and the mixture was stirred at 100° C. under N ₂ atmosphere for 2 h. The reaction mixture was quenched by adding _H2O (20.0 mL), and then extracted with EtOAc (40.0 mL, 20.0 mL*2). The combined organic layers were washed with NaCl (aq., 2.00 mL) and concentrated under reduced pressure to give 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303049-2 (3.00 g, crude) as a black solid.

LC-MS [M] = 289.8.

Step 2 Preparation of 6-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303049-3

2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine -3-Ketone JD-5303049-2 (1.50 g, 5.19 mmol, 1.00 eq) was dissolved in THF (15.0 mL) and _{H2O (7.50 mL), and the temperature was maintained at 0°C. H2O2 (} 2.71 g, 23.9 mmol, 5.53 mL, 30% purity, 4.61 eq) and AcOH (623 mg, 10.3 mmol, 593 μL, 2.00 eq) were added, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by the addition of _Na2CO3 (aq., 16.0 mL) at 0° _C , and then extracted with EtOAc (32.0 mL, 16.0 mL*2). The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 2/1) to give 6-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303049-3 (650 mg, 3.63 mmol, yield 69.9%) as a white solid.

LC-MS [M+H] ⁺ = 180.0.

Step 3 Preparation of 2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303049-4

6-Hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303049-3 (500 mg, 2.79 mmol, 1.00 eq) was mixed with K ₂ CO ₃ (771 mg, 5.58 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (411 mg, 2.79 mmol, 1.00 eq) in DMF (5.00 mL) and stirred at 50°C for 2 hours. The reaction mixture was quenched by addition of H ₂ O (6.00 mL) and extracted with acetic acid (12.0 mL, 6.00 mL*2). The combined organic layers were washed with NaCl (aq., 2.00 mL) and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 50/1 to 2/1) to give 2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303049-4 (400 mg, 1.38 mmol, 49.3% yield) as a white solid.

LC-MS [M+H] ⁺ = 291.0.

Step 4 Preparation of 2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303049-5

BH ₃ -Me ₂ S (10 M, 258 μL, 2.50 eq) was added to a solution of 2-methyl-6-{[(4-methyl-1,3-thiazeolan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303049-4 (300 mg, 1.03 mmol, 1.00 eq) in THF (3.00 mL) at 0° C., and the mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by adding 5.00 mL of MeOH at 0° C., and then concentrated under reduced pressure to give 2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303049-5 (300 mg, crude) as a yellow solid.

LC-MS [M+H] ⁺ = 277.0.

Step 5 3,3-difluoro-4-{[(2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2-[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2-[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2-[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy] ... Preparation of [b][1,4]oxazacyclohexan-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid 2-methylprop-2-yl ester JD-5303049-5

To a solution of 2-methylpropan-2-yl 4-amino-3,3-difluorotetrahydropyrrole-1-carboxylate JD-5303001d (160 mg, 723 μmol, 2.00 eq) in DMF (4.00 mL) was added CDI (130 mg, 806 μmol, 2.23 eq), and the mixture was stirred at 65°C for 1 hour. Then, 2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303049-5 (100 mg, 361 μmol, 1.00 eq) was added at 25°C, and the mixture was stirred at 65°C for 2 hours. The reactants were concentrated and purified by HPLC (column: Welch xextreme C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 40%-70% B over 10 minutes). The combined product was purified by HPLC to give 3,3-difluoro-4-{[(2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester JD-5303049-5 (120 mg, 228 μmol, yield 63.2%) as a white solid.

LC-MS [M+H] ⁺ = 525.1.

Step 6 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303049

3,3-Difluoro-4-{[(2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylpropan-2-yl ester JD-5303049-5 (100 mg, 190 μmol, 1.00 eq) was added to a TFE (2.00 mL) solution, and TMSCl (41.4 mg, 381 μmol, 48.3 μL, 2.00 eq) was added, and the mixture was stirred at 25 ° C for 1 hr. The reaction mixture was concentrated under reduced pressure to give N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-2-methyl-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303049 (35.1 mg, 82.7 μmol, yield 43.3%, purity 98.89%) as a white gum.

LC-MS [M+H] ⁺ = 425.0.

¹ H NMR: (400 MHz, DMSO-d ₆ )δ＝1.26(t,J＝6.13Hz,3H),2.39(s,3H),2.81(td,J＝11.69,8.38Hz,1H),2.8 9-3.03(m,1H),3.12-3.26(m,3H),3.87-4.03(m,1H),4.07-4.24(m,1H),4.2 8-4.46(m,1H),5.16(s,2H),6.63(dd,J＝8.88,2.88Hz,1H),6.78(dd,J＝8.82 ,2.69Hz,1H),7.09-7.20(m,1H),7.30(dd,J＝6.38,2.88Hz,1H),8.98(s,1H).

Example 56 N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3 ... Preparation of Hydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-4-carboxamide Hydrochloride JD-5303050

Step 1 Preparation of 1-[(4-bromo-2-nitrophenyl)oxy]cyclopropane-1-carboxylic acid JD-5303050-2

To a solution of 1-hydroxycyclopropane-1-carboxylic acid JD-5303050a (16.1 g, 73.4 mmol, 9.05 mL, 1.50 eq) in DMF (100 mL) was added NaH (4.90 g, 122 mmol, 60% purity, 2.50 eq) at 0°C under N2 atmosphere, and the mixture was stirred at 0°C for 1 hour. 4-Bromo-1-fluoro-2-nitrobenzene JD-5303050-1 (5.00 g, 48.9 mmol, 1.00 eq) was then added, and stirring was continued at 25°C for 15 hours. The reaction mixture was quenched by the addition of _H₂O (300 mL) at 0°C and extracted with ethyl acetate (150 mL*3). The aqueous phase was adjusted to pH 6 by the addition of 2M HCl, followed by extraction with EtAOc (300 mL, 150 mL*2). The collected organic layer was washed with brine (10 mL*3), dried over anhydrous _MgSO₄ , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , petroleum ether/ethyl acetate = 50/1 to 2/1) to afford 1-[(4-bromo-2-nitrophenyl)oxy]cyclopropane-1-carboxylic acid JD-5303050-2 (11.0 g, 36.4 mmol, yield 74.3%) as a yellow solid.

LC-MS [M] = 301.9.

Step 2 Preparation of 6-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-3

1-[(4-Bromo-2-nitrophenyl)oxy]cyclopropane-1-carboxylic acid JD-5303050-2 (4.00 g, 13.2 mmol, 1.00 eq) was added to a solution of ethanol (28.0 mL) and water (4.00 mL), followed by the addition of NH ₄ Cl (2.83 g, 52.9 mmol, 4.00 eq) and Fe (2.96 g, 52.9 mmol, 4.00 eq), and the mixture was stirred at 90° C. for 16 h. The filtrate was filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 2/1) to give 6-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1′-cyclopropane]-3-one JD-5303050-3 (2.20 g, 8.66 mmol, yield 65.3%) as a white solid.

LC-MS [M+2] = 256.1.

Step 3 Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-4

6-Bromo-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-3 (2.20 g, 8.66 mmol, 1.00 eq) was dissolved in dioxane (25.0 mL), and BPD (4.40 g, 17.3 mmol, 2.00 eq), KOAc (2.12 g, 21.6 mmol, 2.50 eq) and _PdCl2 (dppf) (316 mg, 432 μmol, 0.05 eq) were added. The mixture was stirred at 100°C under N2 atmosphere for 2 hours. The reaction mixture was quenched by adding _H2O (25.0 mL), extracted with EtOAc (50.0 mL, 25.0 mL*2), and concentrated under reduced pressure to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-4 (3.00 g, crude) as a black solid.

LC-MS [M+H] ⁺ = 302.1.

Step 4 Preparation of 6-hydroxy-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-5

6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-4 (2.60 g, 8.63 mmol, 1.00 eq) was dissolved in THF (26.0 mL) and _H2O (13.0 mL), and the temperature was controlled at about 0°C. _H2O2 (5.18 _g , 45.6 mmol, 4.39 mL, 30% purity, 5.29 eq) and AcOH (5.18 g, 86.3 mmol, 4.94 mL, 10.0 eq) were added, and the mixture was stirred at 25°C for 2 hours. The reaction _mixture was quenched by adding _Na₂SO₃ (aq., 50.0 mL), extracted with ethyl acetate (100 mL, 50.0 mL x 2), and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , petroleum ether/ethyl acetate = 50/1 to 2/1) to afford 6-hydroxy-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-5 (1.20 g, 6.28 mmol, 72.7% yield) as a white solid.

LC-MS [M+H] ⁺ = 192.1.

Step 5 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane]-3-one JD-5303050-6

6-Hydroxy-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-3-one JD-5303050-5 (1.00 g, 5.23 mmol, 1.00 eq) was added to a DMF (10.0 mL) solution, followed by K ₂ CO ₃ (1.45 g, 10.4 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (772 mg, 5.23 mmol, 1.00 eq). The mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched by addition of H ₂ O (20.0 mL) and extracted with EtOAc (40.0 mL, 20.0 mL*2). The combined organic layers were washed with NaCl (aq., 3.00 mL) and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 50/1 to 2/1) to give 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane]-3-one JD-5303050-6 (600 mg, 1.98 mmol, 37.9% yield) as an off-white solid.

LC-MS [M+H] ⁺ = 303.2.

Step 6 Preparation of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane]JD-5303050-7

6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane]-3-one JD-5303050-6 (100 mg, 330 μmol, 1.00 eq) was added to THF (2.00 mL), and BH ₃ -Me ₂ S (10 M, 82.6 μL, 2.50 eq) was added at 0° C. The mixture was stirred at 25° C. for 6 h. The reaction mixture was quenched by the addition of 5.00 mL of methanol at 0° C. and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: CD04-Welch ultratimate C18 150*25*7um; mobile phase: [water (TFA)-ACN]; gradient: 25%-45% B over 10 minutes) to give 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane] JD-5303050-7 (30.0 mg, 104 μmol, yield 31.4%) as a brown oil.

LC-MS [M+H] ⁺ = 289.0.

Step 7 Preparation of 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane]-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester JD-5303050-8

2-Methylpropane-2-yl 4-amino-3,3-difluorotetrahydropyrrole-1-carboxylate JD-5303001d (46.2 mg, 208 μmol, 2.00 eq) and CDI (37.6 mg, 232 μmol, 2.23 eq) were added to a DMF (1.00 mL) solution and stirred at 65°C for 1 h. Then, 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane] JD-5303050-7 (30.0 mg, 104 μmol, 1.00 eq) was added and the mixture was allowed to react at 65°C for 16 h. The reaction mixture was quenched by adding H ₂ O (2.00 mL), and then extracted with EtOAc 4.00 mL (2.00 mL*2). The organic layer was collected and concentrated under reduced pressure to obtain a residue. The product was purified by HPLC (column: CD04-Welch ultratimate C18 150*25*7um; mobile phase: [water (TFA)-ACN]; gradient: 38%-68% B over 10 minutes) to give 2-methylprop-2-yl 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane]-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303050-8 (30.0 mg, 55.9 μmol, 53.7% yield) as a white solid.

LC-MS [M+H] ⁺ = 537.1.

Step 8 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-4-carboxamide JD-5303050

TMSCl (12.1 mg, 111 μmol, 14.1 μL, 2.00 eq) was added to a solution of 2-methylpropan-2-yl 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepin-2,1'-cyclopropane]-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303050-8 (30.0 mg, 55.9 μmol, 1.00 eq) in TFE (3.00 mL) and stirred at 25 ° C for 2 h. The reaction mixture was concentrated under reduced pressure to give N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-4-carboxamide hydrochloride JD-5303050 (18.0 mg, 18.33 μmol, 32.7% yield, 100% purity) as a yellow gum.

LC-MS [M+H] ⁺ = 437.0.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 0.68-0.84 (m, 2H), 0.90 (s, 2H) 2.40 (s, 3H), 3.47 (br s, 1H), 3.68 (br s, 3H), 3.85 (br s,2H),4.79(dt,J＝11.48,8.58Hz,1H),5.20(s,2H),6.68(d,J＝2.88Hz,1H),6.72-6.79( m,1H),7.36(d,J＝2.88Hz,1H),7.60(d,J＝8.38Hz,1H),9.10(s,1H),10.08-10.41(m,2H)

Example 57 7-Fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzene Preparation of 4-oxazacyclohexane-4-carboxamide hydrochloride JD-5303051

Step 1 Preparation of [(5-fluoro-4-methoxy-2-nitrophenyl)oxy]acetic acid methyl ester JD-5303051-2

To methyl glycolate JD-5303051a (4.29 g, 47.5 mmol, 3.67 mL, 0.90 eq) in THF (100 mL) was added NaH (1.90 g, 47.5 mmol, 60% purity, 0.90 eq). The mixture was stirred at 0°C for 0.5 hours. 2,4-Difluoro-1-methoxy-5-nitrobenzene JD-5303051-1 (10.0 g, 52.8 mmol, 1.00 eq) was added to the mixture, and the mixture was allowed to stand at 25°C for 2 hours. The reaction mixture was quenched by the addition of 10.0 mL of _NH₄Cl at 0°C, diluted with 30.0 mL of _H₂O , and extracted with 30 mL of ethyl acetate. The organic phase was separated, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to give methyl [(5-fluoro-4-methoxy-2-nitrophenyl)oxy]acetate JD-5303051-2 (1.80 g, 6.94 mmol, yield 13.1%) as a yellow oil.

LC-MS [M+Na] = 282.0.

Step 2 Preparation of 7-fluoro-6-methoxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepine-3-one JD-5303051-3

Iron powder (3.88 g, 69.4 mmol, 10.0 eq) was added to methyl [(5-fluoro-4-methoxy-2-nitrophenyl)oxy]acetate JD-5303051-2 (1.80 g, 6.94 mmol, 1.00 eq), followed by the addition of EtOH (20.0 mL) and AcOH (20.0 mL), and the mixture was stirred at 50°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford 7-fluoro-6-methoxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepan-3-one JD-5303051-3 (1.40 g, crude) as a brown solid.

LC-MS [M+H] ⁺ = 198.1.

Step 3 Preparation of 7-fluoro-6-hydroxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepine-3-one JD-5303051-4

BBr ₃ (8.89 g, 35.5 mmol, 3.42 mL, 5.00 eq) in a solution of 7-fluoro-6-methoxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-3-one JD-5303051-3 (1.40 g, 7.10 mmol, 1.00 eq) was added to DCM (15.0 mL) and stirred at -78°C for 3 hours. The reaction mixture was quenched by adding 10 mL of MeOH at -78°C, diluted with 10.0 mL of _H2O , extracted with 20.0 mL (10.0 mL*2) of DCM, and concentrated under reduced pressure to give 7-fluoro-6-hydroxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepine-3-one JD-5303051-4 (500 mg, crude) as a brown solid.

LC-MS [MH] ₋ = 182.8.

Step 4 Preparation of 7-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-3-one JD-5303051-5

To a solution of 7-fluoro-6-hydroxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-3-one JD-5303051-4 (500 mg, 2.73 mmol, 1.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (362 mg, 2.46 mmol, 0.90 eq) in DMF (5.00 mL) was added K ₂ CO ₃ (754 mg, 5.46 mmol, 2.00 eq), and the mixture was stirred at 25° C. for 4 hours. The reaction mixture was quenched with _H2O (10.0 mL) and extracted with EtOAc (20.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to give 7-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-3-one JD-5303051-5 (800 mg, crude) as a brown solid.

LC-MS [M+H] ⁺ = 295.0.

Step 5 Preparation of JD-5303051-6 7-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin

7-Fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-3-one JD-5303051-5 (200 mg, 679 μmol, 1.00 eq) was added to a THF (2.00 mL) solution, and BMS (10 M, 339 μL, 5.00 eq) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by adding 5.00 mL of MeOH at 0°C, and then The mixture was concentrated under reduced pressure to give JD-5303051-6 (520 mg, crude product) of 7-fluoro-6-{[(4-methyl-1,3-thiazeolan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepane as a brown oil.

LC-MS [M+H] ⁺ = 281.0.

Step 6 Preparation of 3-{[(7-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-1-carboxylic acid 2-methylpropane-2-yl ester JD-5303051-7

7-Fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin JD-5303051-6 (50.0 mg, 178 μmol, 1.00 eq) and 2-methylprop-2-yl 3-aminopiperidine-1-carboxylate JD-5303002a (107 mg, 535 μmol, 3.00 eq) were added to a THF (1.00 mL) solution, and BTC (26.4 mg, 89.1 μmol, 0.50 eq) and DIEA (69.1 mg, 535 μmol, 93.2 μL, 3.00 eq) were added respectively, and the mixture was stirred at 90° C. for 12 hours. The reaction mixture was quenched with H ₂ O (10.0 mL) and extracted with EtOAc (10.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high-performance liquid chromatography to obtain 2-methylpropane-2-yl 3-{[(7-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303051-7 (5.00 mg, 9.87 μmol, yield 5.53%) as a white solid.

LC-MS [M+H] ⁺ = 507.1.

Step 7 Preparation of 7-fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303051

To a solution of 2-methylpropan-2-yl 3-{[(7-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303051-7 (5.00 mg, 9.87 μmol, 1.00 eq) in TFE (1.00 mL) was added TMSCl (2.14 mg, 19.7 μmol, 2.51 μL, 2.00 eq). The mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to give 7-fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303051 (3.66 mg, 8.26 μmol, yield 83.7%, purity 98.52%, HCl) as a yellow solid.

LC-MS [M+H] ⁺ = 407.1.

¹ H NMR: (400MHz, METHANOL-d4) δppm 1.54-1.90 (m, 2H) 1.97-2.14 (m, 2H) 2.44 (s, 3H) 2.78-2.99 (m, 2H) 3.34 (br d, J＝3.50Hz, 1H) 3.49 (br dd,J＝11.94,3.69Hz,1H)3.66-3.83(m,2H)3.92-4.05(m,1H)4.13-4.26(m, 2H)5.24(s,2H)6.69(d,J＝11.76Hz,1H)7.39(d,J＝8.63Hz,1H)8.93(s,1H).

Example 58 Preparation of 2-(hexahydropyridin-3-yl)-1-(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)ethan-1-one JD-5303052

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303052-1 to prepare 2-(hexahydropyridin-3-yl)-1-(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)ethan-1-one JD-5303052 (16 mg, yield 44.7%, purity 99.2%) as a yellow solid.

LC-MS ([M+H] ⁺ )=388.1.

¹ H NMR (400MHz, DMSO-d ₆ )δ＝8.92(s,1H),7.52(s,1H),6.82(d,J＝8.9Hz,1H),6.76(dd,J＝8.9,2.9Hz,1H),5.21(s,2H),4.27–4.16(m,2H),3.92–3.77(m,2H),3.32–3 .25(m,1H),3.22–3.17(m,1H),2.82–2.73(m,1H),2.69–2.59(m,3H), 2.41(s,3H),2.35–2.23(m,1H),1.85–1.66(m,3H),1.32–1.26(m,1H).

Example 59 Preparation of N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxamide JD-5303053

Step 1 Preparation of 6-bromo-3,4-dihydro-2H-chromene-4-carbonitrile JD-5303053-2

6-Bromo-3,4-dihydro-2H-chromen-4-one JD-5303053-1 (5.0 g, 22.02 mmol, 1.0 eq) and Tosmic (6.45 g, 33.03 mmol, 1.5 eq) were dissolved in DME (250 mL) and EtOH (10 mL). The mixture was cooled to 0°C under nitrogen and t-BuOK (5.43 g, 48.44 mmol, 2.2 eq) was added. The reaction mixture was allowed to react at room temperature for 15 hours. The mixture was quenched by the addition of aqueous ammonium chloride (40 mL) at room temperature and then extracted with ethyl acetate (60 mL, 30.0 mL x 2). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 30/1) to give 6-bromo-3,4-dihydro-2H-chromene-4-carbonitrile JD-5303053-2 (2.4 g, yield 45.7%) as a white solid.

¹ H NMR (400MHz, CDCl ₃ )δ＝7.42(d,J＝2.4Hz,1H),7.31(dd,J＝8.8,2.4Hz,1H),6.75(d,J＝8.8Hz,1H),4 .38–4.29(m,1H),4.27–4.20(m,1H),3.99(t,J＝6.0Hz,1H),2.39–2.28(m,2H).

Step 2 Preparation of methyl 6-bromo-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-3

6-Bromo-3,4-dihydro-2H-chromene-4-carbonitrile JD-5303053-2 (600 mg, 2.52 mmol, 1.0 eq) was dissolved in MeOH (14 mL) _{and H₂SO₄} (6.18 g, 63.0 mmol, 25.0 eq) was added. The reaction mixture was reacted at 100°C under a nitrogen atmosphere for 15 hours. The mixture was quenched by the addition of water (10 mL) at room temperature and then extracted with ethyl acetate (30 mL, 15.0 mL x 2). The combined organic phases were washed with saturated _Na₂CO₃ solution (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate _, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 5/1 to 3/1) to give methyl 6-bromo-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-3 (550 mg, 80.5% yield) as a colorless oil.

LC-MS ([M+H] ⁺ ) = 271.0.

¹ H NMR (300MHz, CDCl ₃ )δ＝7.37(dd,J＝2.4,0.6Hz,1H),7.24(dd,J＝8.7,2.4Hz,1H),6.72(d,J＝8.7Hz,1 H),4.30–4.21(m,2H),3.80–3.70(m,4H),2.38–2.27(m,1H),2.16–2.00(m,1H).

Step 3 Preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-4

Methyl 6-bromo-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-3 (550 mg, 2.03 mmol, 1.0 eq) was dissolved in dioxane (8.0 mL). BPD (1.03 g, 4.06 mmol, 2.0 eq), AcOK (400 mg, 4.06 mmol, 2.0 eq), and Pd(dppf) _Cl₂ (73 mg, 0.10 mmol, 0.05 eq) were added. The reaction mixture was reacted at 100°C for 3 hours. The mixture was quenched by the addition of water (10 mL) at room temperature and then extracted with ethyl acetate (30 mL, 15.0 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 50/1 to 15/1) to give methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-4 (900 mg, crude, BPD residue on NMR) as a yellow oil.

LC-MS ([M+H] ⁺ )=319.0.

¹ H NMR (300MHz, CDCl ₃ )δ＝7.66(s,1H),7.61(dd,J＝8.1,1.5Hz,1H),6.83(d,J＝8.1Hz,1H),4.32–4.24(m,2H) ,3.85–3.78(m,1H),3.73(s,3H),2.37–2.24(m,1H),2.18–2.06(m,1H),1.32(s,12H).

Step 4 Preparation of methyl 6-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-5

Methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-4 (800 mg, 2.51 mmol, 1.0 eq) was dissolved in THF (4.0 mL) and _H₂O (4.0 mL). AcOH (755 mg, 12.57 mmol, 5.0 eq) and _H₂O₂ (2.85 g, 25.14 mmol, 10.0 _eq ) (30%) were added at 0°C. The reaction mixture was allowed to react at room temperature for 15 hours. The mixture was quenched by the addition of saturated _{aqueous Na₂SO₃} (10 mL) at 0°C and then extracted with ethyl acetate (30 mL, 15.0 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 20/1 to 5/1) to give methyl 6-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-5 (350 mg, yield 66.8%) as a yellow oil.

LC-MS ([M+H] ⁺ )=209.0.

¹ H NMR (400MHz, DMSO-d ₆ )δ=8.87(s,1H),6.63–6.50(m,3H),4.15–4.02(m,2H),3.81(t,J=5.6Hz,1H),3.67(s,3H),2.18–2.08(m,1H),2.07–1.95(m,1H).

Step 5 Preparation of methyl 6-{[(4-methyl-1,3-thiazolyl-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-6

Methyl 6-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-5 (100 mg, 0.48 mmol _, 1.0 eq) was dissolved in DMF (2.0 mL). 5-(Chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (92 mg, 0.62 mmol, 1.3 eq) and _K₂CO₃ (133 mg, 0.96 mmol, 2.0 eq) were added. The reaction mixture was reacted at 50°C for 2 hours. The mixture was quenched by the addition of water (10 mL) at room temperature and then extracted with ethyl acetate (30 mL, 15.0 mL*2). The collected organic phase was washed with water (24 mL, 8.0 mL*3) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 3/1) to give methyl 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-6 (100 g, yield 65.2%) as a yellow oil.

LC-MS ([M+H] ⁺ )=320.1.

¹ H NMR (400MHz, CDCI ₃ )δ=8.70(s,1H),6.90–6.75(m,3H),5.11(s,2H),4.28–4.15(m,2H),3.82–3 .76(m,1H),3.73(s,3H),2.47(s,3H),2.37–2.26(m,1H),2.15–2.05(m,1H).

Step 6 Preparation of 6-{[(4-methyl-1,3-thiazolyl-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylic acid JD-5303053-7

Methyl 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-6 (100 mg, 0.31 mmol, 1.0 eq) was dissolved in MeOH (0.5 mL), THF (0.5 mL), and H ₂ O (0.5 mL). LiOH (39 mg, 0.93 mmol, 3.0 eq) was added, and the reaction mixture was reacted at room temperature for 2 hours. Saturated aqueous potassium bisulfate was added to the mixture at room temperature to adjust the pH to 3, and the mixture was diluted with ethyl acetate (5 mL). The mixture was filtered and the filter cake was collected to give 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylic acid JD-5303053-7 (70 mg, yield 73.1%) as a white solid.

LC-MS ([M+H] ⁺ )=306.1.

¹ H NMR (300MHz, DMSO-d ₆ )δ=12.68(brs,1H),8.97(s,1H),6.92–6.79(m,2H),6.74–6.67(m,1H),5.18(s,2H),4.2 0–4.00(m,2H),3.72(t,J=5.4Hz,1H),2.39(s,3H),2.22–2.10(m,1H),2.08–1.93(m,1H).

Step 7 Preparation of 2-methylpropane-2-yl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromen-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303053-8

6-{[(4-Methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylic acid JD-5303053-7 (60 mg, 0.20 mmol, 1.0 eq) was dissolved in DCM (2.0 mL). (COCl) ₂ (75 mg, 0.59 mmol, 3.0 eq) and one drop of DMF were added at 0°C. The reaction mixture was allowed to react at room temperature for 0.5 hours. The mixture was concentrated to obtain a residue. The residue was then diluted with DCM (2 mL). 6 (40 mg, 0.15 mmol, 1.0 eq) and TEA (46 mg, 0.46 mmol, 3.0 eq) were added to the mixture. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction system was quenched with water (15 mL) and extracted with dichloromethane (10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 200/1 to 100/1) to afford 2-methylpropan-2-yl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromen-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303053-8 (70 mg, 73.4% yield) as a yellow oil.

LC-MS ([M+H] ⁺ )=488.2.

¹ H NMR (300 MHz, CDCl ₃ )δ＝8.72(d,J＝1.5Hz,1H),6.90–6.77(m,2H),6.67(d,J＝2.1Hz,1H),5.75–5 .60(m,1H),5.18–5.05(m,2H),4.27–4.16(m,1H),4.13–3.90(m,2H),3.63–3 .56(m,1H),3.50–3.40(m,1H),3.38–3.15(m,3H),2.48(d,J＝3.3Hz,3H),2.4 4–2.32(m,1H),2.27–1.74(m,3H),1.60–1.49(m,2H),1.41(d,J=2.1Hz,9H).

Step 8 Preparation of N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolyl-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxamide JD-5303053

3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromen-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid-2-methylpropane-2-yl ester JD-5303053-8 (70 mg, 0.14 mmol, 1.0 eq) was dissolved in DCM (2.5 mL), Dioxane/HCl (4 M, 0.7 mL, 2.8 mmol, 20.0 eq) was added to the mixture, and the reaction mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 9 with sodium bicarbonate, then extracted with DCM (10 mL*2), and the collected organic phase was purified by HPLC. After washing with brine (8 mL) and drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (dichloromethane/methanol = 8/1) to afford N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxamide JD-5303053 (23 mg, 41.0% yield, 94.0% purity) as a white solid.

LC-MS ([M+H] ⁺ )=388.2.

¹ H NMR (300MHz, CDCl ₃ )δ＝8.70(d,J＝0.9Hz,1H),6.90–6.80(m,2H),6.78–6.70(m,1H),6.55(brs,1H),5.11(s,2H),4.28–4.12(m,2H),4.12–4.00(m,1H),3.70–3 .56(m,1H),3.09–2.97(m,2H),2.89–2.79(m,2H),2.78–2.64(m,1H), 2.46(s,3H),2.42–2.27(m,1H),2.19–2.02(m,1H),1.80–1.52(m,4H).

Example 60 Preparation of 5-fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303054

Step 1 Preparation of 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303054-2

To a solution of 6-bromo-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303054-1 (900 mg, 3.66 mmol, 1.00 eq) and BPD (1.86 g, 7.32 mmol, 2.00 eq) in dioxane (9.00 mL) were added KOAc (897 mg, 9.15 mmol, 2.50 eq) and Pd(dppf)Cl ₂ (535 mg, 731 μmol, 0.20 eq), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was partitioned into _H2O (20.0 mL) and EtOAc (20.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to give 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303054-2 (2.90 g, crude) as a black solid.

LC-MS [M+H] ⁺ = 168.1.

Step 2 Preparation of 5-fluoro-6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303054-3

To a solution of 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303054-2 (2.90 g, 9.89 mmol, 1.00 eq) in THF (29.0 mL) and _H₂O (29.0 mL) was added _NaBO₃ (4.57 g, 29.6 mmol, 5.71 mL, 3.00 eq), and the mixture was stirred at 0°C for 3 hours. The reaction mixture was washed with _H₂O (40.0 mL) and extracted with EtOAc (50.0 mL). The organic phase was separated, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , petroleum ether/ethyl acetate = 1/1). 5-Fluoro-6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one JD-5303054-3 (450 mg, 2.46 mmol, yield 24.8%) was obtained as a yellow solid.

LC-MS [M+H] ⁺ = 184.0.

Step 3 Preparation of 5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303054-4

5-Fluoro-6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303054-3 (253 mg, 1.72 mmol, 0.90 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (253 mg, 1.72 mmol, 0.9 eq) were dissolved in DMF (3.00 mL) and K ₂ CO ₃ (528 mg, 3.82 mmol, 2.00 eq) was added. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was washed with H 2 O (10.0 mL) and extracted with EtOAc (20.0 mL). The organic phase was separated, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to give 5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303054-4 (60.0 mg, 203 μmol, yield 10.6%) as a white solid.

LC-MS [M+H] ⁺ = 295.0.

Step 4 Preparation of 5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303054-5

BMS (10M, 135 μL, 5.00 eq) was added to a solution of 5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-3-one JD-5303054-4 (80.0 mg, 271 μmol, 1.00 eq) in THF (1.00 mL) and stirred at 50°C for 8 hours. The reaction mixture was quenched by the addition of 5 mL of MeOH at 0°C and then concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to give 5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303054-5 (10.0 mg, 35.6 μmol, yield 13.12%) as a white solid.

LC-MS [M+H] ⁺ = 281.1.

Step 5 Preparation of 3-{[(5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-1-carboxylic acid 2-methylpropane-2-yl ester JD-5303054-6

5-Fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303054-5 (5.00 mg, 17.8 μmol, 1.00 eq) and 2-methylprop-2-yl 3-aminopiperidine-1-carboxylate JD-5303002a (10.7 mg, 53.5 μmol, 3.00 eq) were added to a THF (1.00 mL) solution, followed by DIEA (4.61 mg, 35.6 μmol, 6.21 μL, 2.00 eq) and BTC (2.12 mg, 7.13 μmol, 0.40 eq), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was partitioned between _H2O (10.0 mL) and EtOAc (10.0 mL), and the organic phase was separated, filtered, and concentrated under reduced pressure to give 2-methylpropane-2-yl 3-{[(5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303054-6 (15.0 mg, crude) as a colorless oil.

LC-MS [M+H] ⁺ = 507.2.

Step 6 Preparation of 5-fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303054

To a solution of 2-methylpropane-2-yl 3-{[(5-fluoro-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303054-6 (15.0 mg, 29.6 μmol, 1.00 eq) in TFE (1.00 mL) was added TMSCl (6.43 mg, 59.2 μmol, 7.52 μL, 2.00 eq), and the mixture was stirred at 25°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to give 5-fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303054 (9.66 mg, 21.8 μmol, yield 73.6%, purity 99.64% HCl) as a yellow solid.

LC-MS [M+H] ⁺ = 407.2.

¹ H NMR: (400MHz, DMSO-d6) δppm 1.42-1.71 (m, 2H) 1.85 (br d, J＝10.51Hz, 2H) 2.37 (s, 3H) 2.63-2.84 (m, 2H) 3.12-3.30 (m, 2H) 3.69 (br s,1H)3.77-3.93(m,2H)4.12(t,J＝4.38Hz,2H)5.25(s,2H)6.64(dd,J＝9.19,1.56H z, 1H) 6.97 (t, J = 8.94Hz, 1H) 7.18 (d, J = 7.38Hz, 1H) 8.54-8.80 (m, 2H) 8.99 (s, 1H).

Example 61 Preparation of N-(2-methylpyrazol-3-yl)-7-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303072

Referring to the synthesis method of Example 1, compound JD-5303001-1 was replaced with JD-5303072-1, and compound JD-5303001d was replaced with JD-5303014a to prepare N-(2-methylpyrazol-3-yl)-7-{[(4-methyl-1,3-thiazolyl-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303072 (6.8 mg, 27.28 mmol, yield 81.39%) as a white solid.

LC-MS [389+H] ⁺ = 384.0.

¹ H NMR: (400MHz, MeOD) δ8.75 (s, 1H), 7.39 (s, 1H) 6.94 (d, J = 8.40Hz, 1H) 6.43-6.39 (m, 2H) 6.2 1(s,1H)4.61(d,J=6.00Hz,4H)3.74(s,3H)2.70-2.76(m,2H)2.46(s,3H)1.93-2.00(m,2H).

Example 62 Preparation of N-[3-(3-hydroxypropyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303073

Step 1 Preparation of 2-methylpropane-2-yl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-(prop-2-enyl)piperidin-1-carboxylate JD-5303073-1

The intermediate of Example 17, 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-(prop-2-enyl)piperidin-1-carboxylic acid-2-methylpropan-2-yl ester JD-5303017- 1 (60 mg, 0.113 mmol, 1.0 eq) was dissolved in THF (2.0 mL), and BH ₃ -DMS (0.17 mL, 0.339 mmol, 3.0 eq) (2N) was added at 0°C, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then cooled to 0°C, and NaOH (1.0 mL) (3N), H ₂ O ₂ (1.0 mL), and EtOH (1.0 mL) were added, and the mixture was stirred at room temperature for 4 hours. The mixture was quenched by the addition of water (5 mL), and then extracted with EtOAC (20 mL, 10 mL * 2). The collected organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-(prop-2-enyl)piperidin-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303073-1 (60 mg, crude) as a white solid.

LC-MS ([M+H] ⁺ ) = 547.5.

Step 2 Preparation of N-[3-(3-hydroxypropyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303073

2-Methylprop-2-yl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-(prop-2-enyl)piperidine-1-carboxylate JD-5303073-1 (60 mg, 0.110 mmol, 1.0 eq, crude) was dissolved in DCM (2 mL). TFA (0.6 mL) was added to the mixture, and the reaction mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was stirred at room temperature with 15% sodium hydroxide solution (5 mL) for 1 hour, then extracted with DCM (20 mL, 10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25%-35%, 6 min) to give N-[3-(3-hydroxypropyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303073 (11.3 mg, two-step yield 19.6%, purity 98.6%) as a white solid.

LC-MS ([M-FA+H] ⁺ ) = 447.3.

¹ H NMR (400MHz, MeOD) δ = 8.88 (s, 1H), 8.38 (brs, 1.34H), 7.30–7.25 (m, 1H), 6.82 (d,J＝8.8Hz,1H),6.72–6.67(m,1H),5.19(s,2H),4.29–4.14(m,3H),3.95–3.8 6(m,1H),3.74–3.64(m,1H),3.59–3.53(m,2H),3.36–3.31(m,1H),3.07–2.92 (m,2H),2.44(s,3H),2.18–2.05(m,2H),2.01–1.80(m,2H),1.66–1.44(m,4H).

Example 63 Preparation of 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-3-carboxamide JD-5303074

Step 1 Preparation of 2,4-dioxy-1,3,7-triazaspiro[4.5]decane-7-carboxylic acid benzyl ester JD-5303074-2

Benzyl 3-oxodipyridinium-1-carboxylate JD-5303074-1 (3.0 g, 12.86 mmol, 1.0 eq) was dissolved in MeOH (22.5 mL) and _H₂O (22.5 mL). ( _NH₄ ) _₂CO₃ (2.6 g, 27.0 mmol, 2.1 eq) and TMSCN (2.55 _g , 25.72 mmol, 2.0 eq) were added, and the reaction mixture was reacted at 80°C for 15 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was filtered to collect the filter cake to obtain benzyl 2,4-dioxodipyridinium-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (3.4 g, 87.1% yield, 92% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )=304.4.

¹ H NMR (400MHz, DMSO-d ₆ )δ＝10.71(s,1H),8.52(d,J＝21.6Hz,1H),7.45–7.26(m,5H),5.17–5.00(m,2H),3.90–3.60(m ,2H),3.30–3.11(m,1H),3.05(dd,J＝13.2,6.8Hz,1H),1.93–1.76(m,1H),1.76–1.56(m,3H).

Step 2 Preparation of 7-[(benzyloxy)carbonyl]-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-3-carboxylic acid-2-methylprop-2-yl ester JD-5303074-3

Benzyl 2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (2.2 g, 7.25 mmol, 1.0 eq) was dissolved in DME (70.0 mL). TEA (734 mg, 7.25 mmol, 1.0 eq), (Boc) ₂ O (6.33 g, 29.0 mmol, 4.0 eq), and DMAP (89 mg, 0.725 mmol, 0.1 eq) were added. The reaction mixture was reacted at room temperature for 15 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 5/1 to 3/1) to give 2-methylprop-2-yl 7-[(benzyloxy)carbonyl]-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3 (1.5 g, yield 41.0%, purity 94%) as a white solid.

LC-MS ([M+H ₂ O] ⁺ ) = 521.3.

¹ H NMR (400 MHz, CDCl ₃ )

δ＝7.39–7.27(m,5H),5.18–4.95(m,2H),4.42–4.29(m,1H),4.20(d,J＝13.6Hz,1H),3.96–3.77(m,1H) ,2.92–2.59(m,2H),2.41–2.25(m,1H),1.94(d,J=13.2Hz,1H),1.74–1.66(m,1H),1.59–1.52(m,18H).

Step 3 Preparation of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4

2-Methylprop-2-yl-7-[(benzyloxy)carbonyl]-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3 (1.5 g, 2.98 mmol, 1.0 eq) was dissolved in THF (15.0 mL) and _H₂O (24.0 mL). LiOH (1.0 g, 23.83 mmol, 8.0 eq) was added, and the reaction mixture was allowed to react at room temperature for 15 hours. The mixture was adjusted to pH 3 by adding saturated _KHSO₄ solution at room temperature, and then extracted with ethyl acetate (20 mL, 10.0 mL x 2). The collected organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was filtered (dichloromethane/methanol = 10/1 (30 mL, 10.0 mL*3)) and the collected filtrate was concentrated under reduced pressure to give 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude product) as a white solid.

LC-MS ([M+H] ⁺ )=279.3.

Step 4 Preparation of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid methyl ester JD-5303074-5

3-Amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude product, 1.0 eq) was dissolved in MeOH (8.0 mL), and _MeSO₃H (2.0 mL) was added. The reaction mixture was reacted at 65°C for 15 hours. The mixture was concentrated under reduced pressure, then adjusted to pH 9 with saturated sodium carbonate solution, and finally extracted with dichloromethane/methanol = 10/1 (30 mL, 10.0 mL x 3). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5 (400 mg, 45.9% yield over two steps, 92% purity) as a white solid.

LC-MS ([M+H] ⁺ )=293.1.

Step 5 Preparation of 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-1-carboxylic acid benzyl ester JD-5303074-6

6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303001-4 (310 mg, 1.18 mmol, 1.0 eq) and TEA (598 mg, 5.91 mmol, 5.0 eq) were dissolved in DCM (3.0 mL), and (COCl ₂ ) ₃ (175 mg, 0.59 mmol, 0.5 eq) was added. The reaction mixture was allowed to react at room temperature for 0.5 hours. Methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5 (380 mg, 1.30 mmol, 1.1 eq) was then dissolved in DCM (1 mL) and added to the mixture, which was stirred at room temperature for 48 hours. The reaction system was quenched with water (10 mL) and extracted with DCM (20 mL, 10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 150/1 to 100/1) to afford benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303074-6 (350 mg, 51.0% yield, 92% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )=581.2.

Step 6 Preparation of 1-[(benzyloxy)carbonyl]-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-3-carboxylic acid JD-5303074-7

Benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303074-6 (100 mg, 0.17 mmol, 1.0 eq) was dissolved in MeOH (1.0 mL), THF (1 mL) and H ₂ O (1 mL), and LiOH (22 mg, 0.52 mmol, 3.0 eq) was added. The reaction mixture was reacted at room temperature for 15 hours. The reaction system was adjusted to pH 3 with saturated KHSO ₄ solution, extracted with DCM (20 mL, 10 mL * 2), and the collected organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1-[(benzyloxy)carbonyl]-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-3-carboxylic acid JD-5303074-7 (90 mg, crude) as a yellow solid.

LC-MS ([M+H] ⁺ )=567.2.

Step 7 3-Formamido-3-{[(6-{[(4-methyl-1,3-thiazolyl-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4] Preparation of [4-oxazacyclohexan-4-yl]carbonyl]amino]hexahydropyridine-1-carboxylic acid benzyl ester JD-5303074-8

1-[(Benzyloxy)carbonyl]-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-3-carboxylic acid JD-5303074-7 (90 mg, 0.16 mmol, 1.0 eq) was dissolved in DCM (3 mL), and DIEA (62 mg, 0.48 mmol, 3.0 eq), HATU (73 mg, 0.2 mmol, 1.2 eq), DMAP (2 mg, 0.016 mmol, 0.1 eq) and NH ₄ Cl (13 mg, 0.24 mmol, 1.5 eq) were added, and the reaction mixture was reacted at room temperature for 3 hours. The reaction system was quenched with water (10 mL) and extracted with DCM (20 mL, 10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (dichloromethane/methanol = 15/1) to afford benzyl 3-formamido-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303074-8 (50 mg, 51.3% yield over two steps, 93% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )=565.9.

Step 7 Preparation of 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-3-carboxamide JD-5303074

Benzyl 3-formamido-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303074-8 (45 mg, 0.08 mmol, 1.0 eq) was dissolved in DCM (2 mL). TMSI (48 mg, 0.24 mmol, 3.0 eq) was added to the mixture, and the reaction mixture was allowed to react at room temperature for 4 hours. The mixture was quenched with water (0.5 mL), followed by the addition of PTSA (10 mg) and stirring for 5 minutes. The pH was then adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted with DCM (15 mL, 5 mL x 2). The collected organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% H ₃ PO ₄ )-acetonitrile]; B%: 25%-45%, 6 min) to obtain a residue, which was then adjusted to pH 9 with sodium hydroxide (15%) solution, and extracted with DCM (15 mL, 5 mL*2). The collected organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl] Hexahydropyridine-3-carboxamide JD-5303074 (3.5 mg, yield 10.1%, purity 95.2%) was obtained as a white solid.

LC-MS ([M+H] ⁺ )=432.3.

¹ H NMR (400MHz, MeOD) δ = 8.88 (s, 1H), 7.39 (d, J = 2.8Hz, 1H), 6.82 (d, J = 8.8Hz, 1H),6.68(dd,J＝8.8,2.8Hz,1H),5.21(s,2H),4.20(t,J＝4.0Hz,2H),3.83–3 .76(m,2H),3.40(d,J＝12.4Hz,1H),3.00(d,J＝12.8Hz,1H),2.82(q,J＝5.0Hz ,2H),2.44(s,3H),2.09–2.02(m,1H),2.00–1.92(m,1H),1.71–1.63(m,2H).

Example 64 Preparation of N-[3-(hydroxymethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroacetate JD-5303075

Reference Example 63 Synthesis Method: Step 1 Preparation of Benzyl 2,4-dioxy-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2

Benzyl 3-oxodipyridinium-1-carboxylate JD-5303074-1 (3.0 g, 12.86 mmol, 1.0 eq) was dissolved in MeOH (22.5 mL) and _H₂O (22.5 mL). ( _NH₄ ) _₂CO₃ (2.6 g, 27.0 mmol, 2.1 eq) and TMSCN (2.55 _g , 25.72 mmol, 2.0 eq) were added, and the reaction mixture was reacted at 80°C for 15 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was filtered to collect the filter cake to obtain benzyl 2,4-dioxodipyridinium-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (3.4 g, 87.1% yield, 92% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )=304.4.

¹ H NMR (400MHz, DMSO-d ₆ )δ＝10.71(s,1H),8.52(d,J＝21.6Hz,1H),7.45–7.26(m,5H),5.17–5.00(m,2H),3.90–3.60(m ,2H),3.30–3.11(m,1H),3.05(dd,J＝13.2,6.8Hz,1H),1.93–1.76(m,1H),1.76–1.56(m,3H).

Step 2 Preparation of 7-[(benzyloxy)carbonyl]-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-3-carboxylic acid-2-methylprop-2-yl ester JD-5303074-3

Benzyl 2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (2.2 g, 7.25 mmol, 1.0 eq) was dissolved in DME (70.0 mL). TEA (734 mg, 7.25 mmol, 1.0 eq), (Boc) ₂ O (6.33 g, 29.0 mmol, 4.0 eq), and DMAP (89 mg, 0.725 mmol, 0.1 eq) were added. The reaction mixture was reacted at room temperature for 15 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 5/1 to 3/1) to give 2-methylprop-2-yl 7-[(benzyloxy)carbonyl]-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3 (1.5 g, yield 41.0%, purity 94%) as a white solid.

LC-MS ([M+H ₂ O] ⁺ ) = 521.3.

¹ H NMR (400 MHz, CDCl ₃ )

δ＝7.39–7.27(m,5H),5.18–4.95(m,2H),4.42–4.29(m,1H),4.20(d,J＝13.6Hz,1H),3.96–3.77(m,1H) ,2.92–2.59(m,2H),2.41–2.25(m,1H),1.94(d,J=13.2Hz,1H),1.74–1.66(m,1H),1.59–1.52(m,18H).

Step 3 Preparation of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4

2-Methylprop-2-yl-7-[(benzyloxy)carbonyl]-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3 (1.5 g, 2.98 mmol, 1.0 eq) was dissolved in THF (15.0 mL) and _H₂O (24.0 mL). LiOH (1.0 g, 23.83 mmol, 8.0 eq) was added, and the reaction mixture was allowed to react at room temperature for 15 hours. The mixture was adjusted to pH 3 by adding saturated _KHSO₄ solution at room temperature, and then extracted with ethyl acetate (20 mL, 10.0 mL x 2). The collected organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was filtered (dichloromethane/methanol = 10/1 (30 mL, 10.0 mL*3)) and the collected filtrate was concentrated under reduced pressure to give 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude product) as a white solid.

LC-MS ([M+H] ⁺ )=279.3.

Step 4 Preparation of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid methyl ester JD-5303074-5

3-Amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude product, 1.0 eq) was dissolved in MeOH (8.0 mL), and _MeSO₃H (2.0 mL) was added. The reaction mixture was reacted at 65°C for 15 hours. The mixture was concentrated under reduced pressure, then adjusted to pH 9 with saturated sodium carbonate solution, and finally extracted with dichloromethane/methanol = 10/1 (30 mL, 10.0 mL x 3). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5 (400 mg, 45.9% yield over two steps, 92% purity) as a white solid.

LC-MS ([M+H] ⁺ )=293.1.

Reference Example 1 Synthesis Method: Step 5 Preparation of 5-(Chloromethyl)-4-methyl-1,3-thiazolylcyclopentane JD-5303001c

(4-Methyl-1,3-thiazolin-5-yl)methanol JD-5303001b (400 mg, 3.10 mmol, 1.00 eq) and _SOCl₂ were dissolved in THF (25.0 mL), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with _H₂O (30.0 mL) and extracted with EtOAC (30.0 mL). The organic phase was collected, separated, filtered, and concentrated under reduced pressure to afford 5-(chloromethyl)-4-methyl-1,3-thiazolin-5-yl)methanol JD-5303001c (500 mg, crude) as a colorless oil.

Step 6 Preparation of JD-5303001-4 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin

3,4-Dihydro-2H-benzo[b][1,4]oxazepin-6-ol JD _- 5303001-3 (0.20 g, 1.32 mmol, 1.00 eq) was dissolved in DMF (2 mL). _K₂CO₃ (365 mg, 2.65 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolinone JD-5303001c (292 mg, 1.98 mmol, 1.50 eq) were added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was washed with _H₂O (10 mL) and ethyl acetate (10 mL, 5 mL x 2). The organic phase was collected and concentrated under reduced pressure to yield a residue. The residue was purified by preparative chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1:1) to give JD-5303001-4 (0.12 g, 457 μmol, yield 34.5%) of 6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-5-ol) as a colorless oil.

LC-MS [M+H] ⁺ = 263.1.

Step 7 Preparation of 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-1-carboxylic acid benzyl ester JD-5303074-6

6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303001-4 (310 mg, 1.18 mmol, 1.0 eq) and TEA (598 mg, 5.91 mmol, 5.0 eq) were dissolved in DCM (3.0 mL), and (COCl ₂ ) ₃ (175 mg, 0.59 mmol, 0.5 eq) was added. The reaction mixture was allowed to react at room temperature for 0.5 hours. Methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5 (380 mg, 1.30 mmol, 1.1 eq) was then dissolved in DCM (1 mL) and added to the mixture, which was stirred at room temperature for 48 hours. The reaction system was quenched with water (10 mL) and extracted with DCM (20 mL, 10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 150/1 to 100/1) to afford benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303074-6 (350 mg, 51.0% yield, 92% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )=581.2.

Step 8 Preparation of 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-3-carboxylic acid methyl ester JD-5303075-1

Benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303074-6 (150 mg, 0.258 mmol, 1.2 eq) was dissolved in DCM (2 mL), TMSI (155 mg, 0.774 mmol, 3.0 eq) was added, and the mixture was stirred at room temperature for 3 hours. Water (5 mL) was added to the mixture to quench it. The mixture was then extracted with DCM (10 mL, 5 mL*2). The aqueous phase was adjusted to pH 9 with saturated sodium bicarbonate solution and then extracted with DCM/MeOH = 8/1 (27 mL, 9 mL*3). The collected organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-3-carboxylic acid methyl ester JD-5303075-1 (70 mg, yield 60.8%, purity 90%) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 447.4.

Step 9 Preparation of N-[3-(hydroxymethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroacetate JD-5303075

Methyl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-3-carboxylate JD-5303075-1 (70 mg, 0.157 mmol, 1.0 eq) was dissolved in THF (2 mL). _LiAlH₄ (1.0 M in THF) (0.314 mL, 0.314 mmol, 2.0 eq) was added to the mixture at 0°C. The reaction mixture was reacted at 0°C for 1 hour. The mixture was quenched by the dropwise addition of 15% NaOH solution (0.1 mL) at 0°C and dried _{over Na₂SO₄} . The filtrate was collected by filtration and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 25%-45%, 6 min) to give N-[3-(hydroxymethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303075 (20.7 mg, yield 31.5%, purity 95.7%) as a pink solid.

LC-MS([M-TFA+H] ⁺ )=419.2.

¹ H NMR (300 MHz, DMSO-d ₆ )δ＝8.97(s,1H),8.29(d,J＝2.4Hz,1H),7.36(d,J＝2.7,Hz,1H),6.78(d,J＝9.0H z,1H),6.62(dd,J＝9.0,3.0Hz,1H),6.24(d,J＝5.1Hz,1H),5.17(s,2H),4.21–4 .08(m,2H),3.81–3.71(m,1H),3.71–3.61(m,2H),3.49–3.33(m,2H),3.05–2.8 9(m,1H),2.76–2.52(m,2H),2.39(s,3H),2.17–2.08(m,1H),1.66–1.37(m,3H).

Chiral separation of JD-5303075: JD-5303075 was split using the following splitting method to obtain JD-5303075A and JD-5303075B.

JD-5303075 splitting method

2.1 Instrument: Shimadzu high performance liquid chromatograph (HPLC-Z)

Column:Chiralpak IC 50*4.6mm 3μm

Mobile phase: A is hexane (0.1% diethanolamine), B is isopropanol/methyl naphthalene chloride = 2/1

Slope: B 60%

Flow rate: 1mL/min

Back pressure: 100 bar

Column temperature:35℃

Wavelength: 220nM

Cycle time: about 7 minutes

2.2 Sample preparation: Dissolve the compound in ~150 ml of ethanol/hydroxyethyl cellulose. Injection method: 12 ml per needle.

Post-treatment: After separation, the product was dried using a rotary evaporator at 40°C to obtain the target isomers JD-5303075A and JD-5303075B.

MS and NMR of isomer JD-5303075A:

LC-MS([M-TFA+H] ⁺ )=419.2.

¹ H NMR (300 MHz, DMSO-d ₆ )δ＝8.97(s,1H),7.31(d,J＝3.0Hz,1H),6.80(d,J＝9.0,Hz,1H),6.38(d,J＝3.0H z,1H),6.35(dd,J＝9.0,3.0Hz,1H),6.24(d,J＝5.1Hz,1H),5.17(s,2H),4.21–4 .08(m,2H),3.81–3.71(m,1H),3.71–3.61(m,2H),3.75–3.69(m,2H),3.67–3.3 1(m,1H),2.96–2.75(m,2H),2.50(s,3H),2.51–2.39(m,1H),1.42–1.29(m,3H).

MS and NMR of isomer JD-5303075B:

LC-MS ([M-TFA+H]+) = 419.2.

1H NMR (300MHz, DMSO-d6) δ＝8.97(s,1H),7.31(d,J＝2.1Hz,1H),6.79(d,J＝6.9,Hz,1 H),6.63(d,J＝2.1Hz,1H),6.35(dd,J＝9.0,3.0Hz,1H),6.24(d,J＝5.1Hz,1H),5.17(s, 2H),4.15–4.11(m,2H),3.81–3.71(m,1H),3.71–3.61(m,2H),3.75–3.68(m,2H),3.6 7–3.31(m,1H),2.94–2.75(m,2H),2.50(s,3H),2.44–2.38(m,1H),1.40–1.29(m,3H).

Example 65 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(4-methyl-1,3-thiazolin-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303076

Referring to the synthesis method of Example 52, compound JD-5303047a was replaced with JD-5303076a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(4-methyl-1,3-thiazolin-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide hydrochloride JD-5303076 (14.6 mg, 36.9 μmol, yield 45.8%, purity 96.49%) as an off-white solid.

LC-MS [396+1]+=397.

¹ H NMR: (400MHz, DMSO-d ₆ )δ＝9.59-10.24(m,2H),8.68(s,1H),7.45-7.68(m,2H),6.87(d,J＝8.88Hz,1H),6.68(dd,J＝8.88,3. 00Hz,1H),4.69-4.89(m,1H),4.17-4.27(m,2H),3.64-3.88(m,5H),3.35-3.46(m,1H),2.22(s,3H).

Example 66 Preparation of 6-[(3-cyclopropylphenyl)oxy]-N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303077

Referring to the synthetic method of Example 52, compound JD-5303047a was replaced with JD-5303077a to prepare 6-[(3-cyclopropylphenyl)oxy]-N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303077 (3.84 mg, 9.24 μmol, yield 47.7%, purity 100.00%) as an off-white solid.

LC-MS [415+H] ⁺ =416.

¹ H NMR: (400MHz, DMSO-d ₆ )δ=0.64(dd,J=4.94,2.06Hz,2H),0.89-0.99(m,2H),1.23(s,1H)1.83-1.91(m,1H),3.62-3.71(m,2H),3.71-3.79(m,2H),3.82(br dd,J＝5.44,3.19Hz,1H),4.13-4.27(m,2H),4.67-4.81(m,1H),6.62-6.71(m,3H),6.76(d,J＝7.75Hz,1H) ,6.88(d,J＝8.88Hz,1H),7.19(t,J＝7.82Hz,1H),7.42(d,J＝2.75Hz,1H),7.53(d,J＝8.25Hz,1H),9.68(br d,J＝2.00Hz,2H).

Example 67 Preparation of N-(hexahydropyridin-3-yl)-6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303079

Step 1 Preparation of 2-methylpropane-2-yl 6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylate JD-5303079-1

6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-ol 2-Methylpropane-2-yl formate JD-5303046-4 (350 mg, 0.97 mmol, 1.0 eq) was dissolved in DMF (4.0 mL). NaH (60%) (232 mg, 5.8 mmol, 6.0 eq) was added at 0°C and stirred for 0.5 hours. Mel (824 mg, 5.8 mmol, 6.0 eq) was then added to the mixture and stirred at room temperature for 2.5 hours. The mixture was quenched by the addition of saturated NH ₄ Cl solution (10 mL) at 0°C. It was then extracted with ethyl acetate (30 mL, 10 mL * 3), and the collected organic phase was washed with water (30 mL, 10 mL * 3), washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxylic acid-2-methylprop-2-yl ester JD-5303079-1 (350 mg, crude) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 376.2.

Step 2 Preparation of 6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepine JD-5303079-2

2-Methylpropane-2-yl 6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxylate JD-5303079-1 (350 mg, 0.93 mmol, 1.0 eq) was dissolved in DCM (3.0 mL), and Dioxane/HCl (2.33 ml, 9.32 mmol, 10.0 eq) (4 N) was added at room temperature. The mixture was concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 10 with sodium hydroxide solution (3 mL) (15%), then extracted with DCM (20 mL, 10 mL * 2), and the collected organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303079-2 (200 mg, crude) as a yellow solid.

LC-MS ([M+H] ⁺ ) = 276.1.

Step 3 Preparation of 2-methylpropane-2-yl 3-{[(6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-1-carboxylate JD-5303079-3

6-{Methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303079-2 (200 mg, 0.73 mmol, 1.0 eq) was dissolved in DCM (2.0 mL), and TEA (220 mg, 2.18 mmol, 3.0 eq) and (COCl ₂ ) ₃ (108 mg, 0.36 mmol, 0.5 eq) were added. The reaction mixture was reacted at room temperature for 0.5 h. 3A (174 mg, 0.87 mmol, 1.2 eq) was dissolved in DCM (1.0 mL) and added to the reaction system. The reaction was allowed to react at room temperature for 11.5 h. The mixture was quenched by addition of water (5 mL) at room temperature and then extracted with dichloromethane (20 mL, 10.0 mL x 2). The collected organic phase was washed with brine (10 mL) and anhydrous After drying over sodium sulfate, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 3/1 to 1/1) to obtain 2-methylpropane-2-yl 3-{[(6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303079-3 (80 mg, 16.5% yield over three steps, 93% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )＝502.4

¹ H NMR (300MHz, DMSO-d ₆ )δ＝8.80(s,1H),7.03(d,J＝3.0Hz,1H),6.73(d,J＝8.7Hz,1H),6.62–6.55(m,1H),6.53(dd,J＝9.0,2.7Hz,1H),4. 54(s,2H),4.12–4.07(m,2H),3.78–3.45(m,7H),2.93–2.76(m,3H),2.38(s,3H),1.84–1.56(m,4H),1.37(s,9H).

Step 4 Preparation of N-(hexahydropyridin-3-yl)-6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303079

2-Methylpropane-2-yl 3-{[(6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303079-3 (80 mg, 0.16 mmol, 1.0 eq) was dissolved in DCM (3 mL). Dioxane/HCl (0.4 mL, 1.6 mmol, 10.0 eq, 4 N) was added to the mixture, and the reaction mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 10 with sodium hydroxide solution (3 mL, 15%) and then extracted with DCM (10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 15%-25%, 6 min) to give N-(hexahydropyridin-3-yl)-6-{methyl[(4-methyl-1,3-thiazolin-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide formate JD-5303079 (25.4 mg, yield 34.4%, purity 98.4%) as a yellow solid.

LC-MS([M-1.3FA+H] ⁺ )=402.4.

¹ H NMR (300 MHz, DMSO-d ₆ )δ＝8.80(s,1H),8.30(brs,1H),7.07(d,J＝2.7Hz,1H),6.82(d,J＝7.2Hz,1H ),6.72(d,J＝8.7Hz,1H),6.52(dd,J＝8.7,2.7Hz,1H),4.53(s,2H),4.17–4. 02(m,2H),3.88–3.75(m,1H),3.75–3.58(m,2H),3.17–2.92(m,2H),2.74(s ,3H),2.70–2.55(m,2H),2.37(s,3H),1.88–1.67(m,2H),1.65–1.39(m,2H).

Example 68 Preparation of N-[(1S,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303080

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303080a to prepare N-[(1S,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303080 (111 mg, 254 μmol, yield 51.2%, purity 99.92% HCl) as an off-white solid.

LC-MS [415+H] ⁺ = 403.2.

¹ H NMR: (400MHz, DMSO-d6) δppm 1.21-1.42(m,2H)1.43-1.53(m,2H)1.62(br s,4H)2.38(s,3H)3.67(br d,J＝4.63Hz,2H)3.81-3.99(m,2H)4.03-4.18(m,2H)5.16(s,2H)6.53-6.60(m, 1H)6.61-6.72(m,1H)6.75(d,J＝8.76Hz,1H)7.31(d,J＝2.50Hz,1H)8.97(s,1H).

Example 69 Preparation of N-[(1R,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303081

Referring to the synthesis method of Example 1, compound JD-5303001d was replaced with JD-5303081a to prepare N-[(1R,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303081 (111 mg, 254 μmol, yield 51.2%, purity 98.43% HCl) as an off-white solid.

LC-MS [415+H] ⁺ = 403.2.

¹ H NMR(400MHz,DMSO-d6)δppm 1.21-1.42(m,2H)1.43-1.53(m,2H)1.62(br s,4H)2.38(s, 3H)3.67(br d,J＝4.63Hz,2H)3.81-3.99(m,2H)4.03-4.18(m,2H)5.16(s,2H)6.53-6.60(m, 1H)6.61-6.72(m,1H)6.75(d,J＝8.76Hz,1H)7.31(d,J＝2.50Hz,1H)8.97(s,1H).

Example 70 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide formate JD-5303091

Referring to the synthetic method of Example 64, compound JD-5303001c was replaced with JD-5303028a to prepare 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide formate JD-5303091 (30 mg, 18.7%) as a white solid.

LCMS: 416.2 ([M-FA+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d6): δ8.29(s,1H),7.53(td,J＝7.5,1.8Hz,1H),7.47–7.33(m ,2H),7.28–7.20(m,2H),6.78(d,J＝9.0Hz,1H),6.62(dd,J＝9.0,3.0Hz,1H),6.2 3(s,1H),5.04(s,2H),4.21–4.06(m,2H),3.83–3.59(m,3H),3.50–3.25(m,2H), 3.03–2.86(m,1H),2.75–2.51(m,2H),2.12(d,J=12.6Hz,1H),1.82–1.15(m,3H).

Example 71 Preparation of N-[3-(hydroxymethyl)piperidin-3-yl]-6-{[(2-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303109

Referring to the synthetic method of Example 64, compound JD-5303001c was replaced with JD-5303109a to prepare N-[3-(hydroxymethyl)piperidin-3-yl]-6-{[(2-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303109 (31.7 mg, yield 26.8%, purity 98.0%) as a white solid.

LC-MS ([M+H] ⁺ )=419.1.

¹ H NMR (300 MHz, DMSO-d ₆ )δ＝7.66(s,1H),7.29(d,J＝3.0Hz,1H),6.79(d,J＝9.0Hz,1H),6.61(dd,J＝9.0 ,3.0Hz,1H),6.11(s,1H),5.26–5.10(m,2H),4.78(brs,1H),4.13(t,J＝4.5Hz, 2H),3.80–3.60(m,3H),3.50–3.37(m,2H),3.03(d,J＝12.0Hz,1H),2.87–2.77 (m,1H),2.63(s,3H),2.50–2.40(m,1H),2.20–2.06(m,1H),1.62–1.17(m,4H).

Example 72 Preparation of N-[3-(hydroxymethyl)piperidin-3-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide 2,2,2-trifluoroacetate JD-5303110

Referring to the synthetic method of Example 64, compound JD-5303001c was replaced with JD-5303031b to prepare N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide 2,2,2-trifluoroacetate JD-5303110 (21.7 mg, yield 12.3%, purity 98.2%) as a white solid.

LC-MS([M-TFA+H] ⁺ )=467.2.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝8.85(d,J＝11.7Hz,1H),8.72(d,J＝4.5Hz,1H),8.28–8.09(m,2H),7.78(dd,J＝8.1,4. 8Hz,1H),7.44(d,J＝2.7Hz,1H),6.80(d,J＝8.7Hz,1H),6.63(dd,J＝9.0,3.0Hz,1H),6.28( s,1H),5.17(s,2H),4.23–4.09(m,2H),3.95–3.81(m,2H),3.72–3.56(m,2H),3.47(d,J＝ 10.8Hz,1H),3.23–3.08(m,1H),3.02–2.79(m,2H),2.12–1.98(m,1H),1.92–1.50(m,3H).

Example 73 Preparation of 6-{[(2,3-difluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303107

Referring to the synthetic method of Example 64, compound JD-5303001c was replaced with JD-5303036b to prepare 6-{[(2,3-difluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303107 (35 mg, yield 24.8%, purity 95.1%) as a white solid.

LC-MS ([M+H] ⁺ )=434.2.

¹ H NMR: (300MHz, DMSO-d ₆ )δ＝7.46–7.31(m,3H),7.28–7.20(m,1H),6.80(d,J＝9.0Hz,1H),6.64(dd,J＝ 9.0,3.0Hz,1H),6.12(s,1H),5.11(s,2H),4.89–4.54(m,1H),4.21–4.05(m, 2H),3.77–3.61(m,3H),3.40(d,J＝10.8Hz,1H),2.97(d,J＝12.3Hz,1H),2.85 –2.74(m,1H),2.49–2.40(m,2H),2.13(d,J＝12.9Hz,1H),1.53–1.23(m,3H).

Example 74 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2-methylthien-3-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide 2,2,2-trifluoroacetate JD-5303101

Reference Example 52: The synthetic method was used to replace compound JD-5303047a with JD-5303101a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2-methylthiophen-3-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide 2,2,2-trifluoroacetate JD-5303101 (6 mg, yield 26.5%, purity 99.8%) as a white solid.

LC-MS([M-TFA+H] ⁺ )=396.1.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝9.48(brs,2H),7.41(d,J＝8.4Hz,1H),7.32–7.22(m,2H),6.3(d,J＝9.0Hz,1H),6.73(d,J＝5.4Hz,1H),6.55( dd,J＝9.0,3.0Hz,1H),4.92–4.68(m,1H),4.28–4.09(m,2H),3.92–3.60(m,5H),3.42–3.24(m,1H),2.23(s,3H).

Example 75 Preparation of 6-[(cyclohexylmethyl)oxy]-N-[3-(hydroxymethyl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303103

Referring to the synthetic method of Example 64, compound JD-5303001c was replaced with JD-5303103a to prepare 6-[(cyclohexylmethyl)oxy]-N-[3-(hydroxymethyl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303103 (30 mg, 45.7%) as a yellow solid.

LCMS: 404.4 ([M+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d6): δ7.22(d,J＝2.9Hz,1H),6.75(d,J＝8.9Hz,1H),6.52(dd,J＝8.9,2.9Hz,1H),6.17(s,1H),4.21–4.02(m,2H),3.78–3.59 (m,5H),3.47–3.35(m,2H),3.03–2.92(m,1H),2.77–2.52(m,2H),2.21 –2.02(m,1H),1.85–1.45(m,9H),1.33–1.10(m,4H),1.08–0.93(m,2H).

Example 76 Preparation of 7-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)piperidin-3-yl]-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303099

Referring to the synthetic method of Example 70, compound JD-5303001-1 was replaced with JD-5303072-1 to prepare 7-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303099 (5.8 mg, 24.8%) as a white solid.

LCMS: 414.2 ([M+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.53–8.00(m,1H),7.58–7.49(m,1H),7.47–7.38(m,1H),7.31–7.19( m,3H),7.02(d,J＝8.4Hz,1H),6.64(dd,J＝8.4,2.7Hz,1H),6.02(s,1H),5. 06(s,2H),3.76–3.51(m,4H),3.49–3.40(m,1H),3.13–3.02(m,1H),2.88– 2.71(m,2H),2.64(t,J＝6.3Hz,2H),2.13–2.00(m,1H),1.92–1.33(m,6H).

Example 77 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-methylphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303083

Referring to the synthetic method of Example 52, compound JD-5303047a was replaced with JD-5303083a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-methylphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303083 (13.9 mg, 32.7 μmol, 80.1%, HCl) as an off-white solid.

LCMS [389+H] ⁺ =390.

¹ H NMR (400MHz, DMSO-d6) δ = 2.26 (s, 3H) 3.34-3.39 (m, 1H) 3.57-3.89 (m, 5H) 4.12-4.30 (m, 2H) 4.66-4.82 (m, 1H) 6.65 (dd, J = 8.82, 2.8 1Hz,1H)6.70-6.78(m,2H)6.84-6.91(m,2H)7.20(t,J＝7.82Hz,1H)7.42(d,J＝2.88Hz,1H)7.50(d,J＝8.38Hz,1H)9.48-9.76(m,2H).

Example 78 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-(1,3-thiazolin-5-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroacetate JD-5303088

Referring to the synthetic method of Example 52, compound JD-5303047a was replaced with JD-5303088a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-(1,3-thiazolin-5-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide trifluoroacetate JD-5303088 (19.7 mg, 39.7 μmol, yield 19.1%, FA) as an off-white solid.

LCMS [382+H] ⁺ =383.

¹ H NMR: (400MHz, DMSO-d6)δ=ppm 3.38(dd,J＝11.69,9.69Hz,1H)3.67-3.90(m,5H)4.13-4.28(m,2H)4.72-4.88 (m,1H)6.80(dd,J＝8.88,2.88Hz,1H)6.91(d,J＝9.01Hz,1H)7.41-7.68(m,3H) 8.68(d,J＝0.88Hz,1H)9.41-9.90(m,2H).

Example 79 Preparation of N-[(1S,3R)-3-aminocyclohexyl]-6-[(4-methyl-1,3-thiazolin-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303089

Referring to the synthetic method of Example 65, compound JD-5303001d was replaced with JD-5303022a to prepare N-[(1S,3R)-3-aminocyclohexyl]-6-[(4-methyl-1,3-thiazolin-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303089 (16.1 mg, 25.3%) as a white solid.

LCMS: 389.2 ([M+H] ⁺ ).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ8.70(s,1H),8.18–7.57(m,2H),7.48(d,J＝3.0Hz,1H),7.03(d,J＝7.8H z,1H),6.84(d,J＝9.0Hz,1H),6.63(dd,J＝8.7,2.7Hz,1H),4.21–4.10(m,2H ),3.74–3.65(m,2H),3.58–3.50(m,1H),3.05–2.94(m,1H),2.22(s,3H),2 .13–2.02(m,1H),1.91–1.83(m,1H),1.78–1.68(m,2H),1.34–1.16(m,4H).

Example 80 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2-fluorophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303092

Referring to the synthetic method of Example 52, compound JD-5303047a was replaced with JD-5303092a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2-fluorophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303092 (19.2 mg, 44.2 μmol, yield 14.5%, purity 99.1%, HCl) as a white solid.

LCMS [393+H] ⁺ =394.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = ppm 3.36-3.42(m,1H)3.62-3.88(m,5H)4.12-4.28(m,2H)4.65-4.85(m,1H)6.65(dd,J＝8.88,2.88Hz,1H)6. 88(d,J＝8.88Hz,1H)7.03-7.10(m,1H)7.11-7.21(m,2H)7.30-7.38(m,1H)7.44(d,J＝2.88Hz,1H)7.57(br d,J＝8.13Hz,1H)9.57-10.03(m,2H).

Example 81 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[2-(trifluoromethyl)pyridin-3-yl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303097

Referring to the synthetic method of Example 52, compound JD-5303047a was replaced with JD-5303031b to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[2-(trifluoromethyl)pyridin-3-yl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303097 (70.0 mg, 145 μmol, 99.0%, HCl) as a white solid.

LC-MS [444+H] ⁺ =445.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 3.39 (br t,J＝9.69Hz,1H),3.62-3.72(m,2H),3.73-3.81(m,2H),3.82-3.91(m,1H),4.16-4.29(m,2H),4.67-4.82(m,1H),6.77(dd,J＝ 8.76, 2.88Hz, 1H), 6.95 (d, J = 8.76Hz, 1H), 7.45-7.58 (m, 2H), 7.61-7.77 (m, 2H), 8.42 (d, J = 4.25Hz, 1H), 9.77-10.31 (m, 2H).

Example 82 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2,5-dimethylthiophen-3-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303098

Referring to the synthetic method of Example 52, compound JD-5303047a was replaced with JD-5303098a to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2,5-dimethylthiophen-3-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303098 (9.3 mg, 29.3%) as a white solid.

LCMS: 410.1 ([M+H] ⁺ ).

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.23(d,J＝3.2Hz,1H),7.08(d,J＝8.4Hz,1H),6.81(d,J＝8.8Hz,1H),6.52(dd,J＝8.8,2.8Hz,1H),6.44(s,1H),4.37–4.26(m ,1H),4.18–4.12(m,2H),3.76–3.68(m,2H),3.27–3.20(m,2H),3.04–2.90(m,1H),2.83–2.75(m,1H),2.32(s,3H),2.15(s,3H).

Example 83 Preparation of N-[3-(hydroxymethyl)piperidin-3-yl]-6-[(4-methyl-1,3-thiazolin-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303090

Referring to the synthetic method of Example 65, compound JD-5303001d was replaced with JD-5303074-6 to prepare N-[3-(hydroxymethyl)piperidin-3-yl]-6-[(4-methyl-1,3-thiazolin-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303090 (20 mg, 42.8%) as a white solid.

LCMS: 405.1 ([M+H] ⁺ ).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ8.65(s,1H),7.47(d,J＝3.0Hz,1H),6.86(d,J＝8.7Hz,1H),6.65(dd,J＝9. 0,3.0Hz,1H),6.17(s,1H),5.16–4.61(m,1H),4.25–4.09(m,2H),3.94–3.79( m,1H),3.69–3.59(m,2H),3.44–3.35(m,2H),3.30–3.25(m,1H),2.96–2.84( m,1H),2.68–2.54(m,2H),2.22(s,3H),2.09–1.99(m,1H),1.57–1.38(m,3H).

Example 84 Preparation of N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303104

Step 1 Preparation of 2-methylpropane-2-yl ({1-[(benzyloxy)carbonyl]-4-hydroxyhexahydropyridin-3-yl}amino)methane ester JD-5303104-2

Benzyl hexahydrooxalo[2,3-c]pyridine-3-carboxylate JD-5303104-1 (7.0 g, 30.01 mmol, 1.0 eq) was dissolved in EtOH (35.0 mL), and NH ₃ ·H ₂ O (35.0 mL) was added. The reaction mixture was reacted in an autoclave at 70°C for 15 hours. The mixture was then concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM (70.0 mL), and TEA (4.0 g, 39.01 mmol, 1.3 eq) and Boc ₂ O (7.2 g, 33.01 mmol, 1.1 eq) were added. The mixture was reacted at room temperature for 15 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica, petroleum ether/ethyl acetate = 1/1) to give 2-methylpropane-2-yl({1-[(benzyloxy)carbonyl]-4-hydroxyhexahydropyridin-3-yl}amino)methane JD-5303104-2 (3.2 g, yield 30.4%, purity 92%) as a transparent oil.

LC-MS ([M-56+H] ⁺ ) = 295.1.

¹ H NMR: (300MHz, CDCl ₃ )δ＝7.46–7.27(m,5H),5.26–5.04(m,2H),4.68(brs,1H),4.25–4.00(m,1H),3.99–3.78(m,1H), 3.74–3.57(m,1H),3.54–3.30(m,1H),3.25–2.80(m,2H),2.05–1.86(m,1H),1.67–1.32(m,10H).

Step 2 Preparation of 2-methylpropane-2-yl ({1-[(benzyloxy)carbonyl]-4-oxyylidenehexahydropyridin-3-yl}amino)methane ester JD-5303104-3

2-Methylpropane-2-({1-[(benzyloxy)carbonyl]-4-hydroxyhexahydropyridin-3-yl}amino)methane JD-5303104-2 (3.2 g, 9.13 mmol, 1.0 eq) was dissolved in DCM (35.0 mL), and DMP (5.8 g, 13.70 mmol, 1.5 eq) was added. The reaction mixture was allowed to react at room temperature for 15 hours. The reaction mixture was quenched by the addition _{of NaHCO₃ (40 mL) and Na₂S₂O₃ ( 10 mL} ), and then extracted with DCM (150 mL, 50 mL x 3). The collected organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 8/1) to give 2-methylpropane-2-yl({1-[(benzyloxy)carbonyl]-4-oxoylidenehexahydropyridin-3-yl}amino)methane JD-5303104-3 (2.7 g, yield 84.9%, purity 90%) as a yellow oil.

LC-MS ([M-56+H] ⁺ ) = 293.1.

¹ H NMR: (400MHz, CDCl ₃ )δ=7.52–7.30(m,5H),5.44(s,1H),5.29–5.10(m,2H),4.97–4.80(m,1H),4.51(s,1H), 4.30(s,1H),3.22–3.00(m,1H),2.73(t,J＝11.6Hz,1H),2.67–2.45(m,2H),1.45(s,9H).

Step 3 Preparation of 2-methylpropane-2-ylbis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methane] JD-5303104-4

2-Methylpropane-2-yl ({1-[(benzyloxy)carbonyl]-4-oxyylidenehexahydropyridin-3-yl}amino)methane JD-5303104-3 (300 mg, 0.86 mmol, 1.0 eq) was dissolved in DCM (5.0 mL), and DAST (1.4 g, 8.61 mmol, 10.0 eq) was slowly added at 0°C under nitrogen. The reaction mixture was reacted at 30°C for 72 hours. The reaction mixture was quenched by the addition of saturated aqueous _NaHCO₃ (40 mL) at room temperature and then extracted with DCM (60 mL, 20 mL*3). The collected organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 10/1) to give 2-methylpropane-2-yl bis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methane] JD-5303104-4 (150 mg, yield 47.0%, purity 89%) as a yellow oil.

LC-MS ([M-56+H] ⁺ )=315.1.

¹ H NMR: (300MHz, CDCl ₃ )δ=7.43–7.29(m,5H),5.26–5.04(m,2H),4.84–4.66(m,1H),4.13–3.95(m, 2H),3.27–2.95(m,2H),2.25–2.07(m,1H),2.05–1.82(m,1H),1.45(s,9H).

Step 4 Preparation of 2-methylpropane-2-ylbis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methane] JD-5303104-5

2-Methylpropane-2-ylbis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methane] JD-5303104-4 (150 mg, 0.41 mmol, 1.0 eq) was dissolved in DCM (3.0 mL). Dioxane/HCl (1.01 mL, 4.05 mmol, 10.0 eq) was added, and the reaction mixture was allowed to react at room temperature for 15 hours. The mixture was then concentrated under reduced pressure to afford 2-methylpropane-2-ylbis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methane] JD-5303104-5 (150 mg, crude) as a yellow solid.

LC-MS([M-HCl+H] ⁺ )=271.1.

Step 5 Preparation of 4,4-difluoro-3-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}piperidin-1-carboxylic acid benzyl ester JD-5303104-6

2-Methylpropane-2-ylbis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methane] JD-5303104-5 (40 mg, 0.14 mmol, 1.0 eq) was dissolved in DCM (4.0 mL), and TEA (137 mg, 1.35 mmol, 10.0 eq) and (COCl ₂ ) ₃ (20 mg, 0.07 mmol, 0.5 eq) were added. The reaction mixture was stirred at 30°C for 0.5 h. 70-5 (50 mg crude, 0.14 mmol, 1.0 eq) dissolved in DCM (1.0 mL) was added to the reaction system and stirred at 30°C for 14.5 h. The mixture was quenched by addition of water (10 mL) at room temperature and then extracted with DCM (20 mL, 10 mL*2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 3/1) to obtain benzyl 4,4-difluoro-3-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303104-6 (40 mg, total yield of 53.3% over two steps, purity 85%) as a white solid.

LC-MS ([M+H] ⁺ )=556.2.

Step 6 Preparation of N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303104

Benzyl 4,4-difluoro-3-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303104-6 (40 mg, 0.07 mmol, 1.0 eq) was dissolved in DCM (3.0 mL), TMSI (72 mg, 0.36 mmol, 5.0 eq) was added, and the mixture was stirred at room temperature for 3 hours. Water (5 mL) was added to the mixture to quench it. The mixture was then extracted with DCM (20 mL, 10 mL*2). The aqueous phase was adjusted to pH 10 with saturated sodium bicarbonate solution and then extracted with DCM (20 mL, 10 mL*2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (DCM/MeOH=15/1) to give N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303104 (6.6 mg, yield 21.8%, purity 95.2%) as a white solid.

LC-MS ([M+H] ⁺ )=422.1.

¹ H NMR: (300MHz, CD ₃ OD)δ＝7.56–7.43(m,1H),7.42–7.29(m,1H),7.23–7.04(m,3H),6.81(d,J＝9.0Hz,1H),6.68(dd,J＝9.0,3.0Hz,1H),5.05( s,2H),4.38–4.19(m,2H),4.17–4.00(m,2H),3.57–3.43(m,1H),3.21–3.02(m,2H),2.90–2.68(m,2H),2.30–1.88(m,2H).

Example 85 Preparation of N-[3-(Formylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303100

Compound 1 (100 mg, 0.25 mmol, 1.0 eq), HCOOH (65 mg, 1.24 mmol, 5.0 eq), HATU (471 mg, 1.24 mmol, 5.0 eq), and DIEA (321 mg, 2.48 mmol, 10.0 eq) were added to DCM (2.0 mL). The mixture was stirred at room temperature for 15 hours, diluted _{with K₂CO₃} solution (5 mL), and extracted with DCM (10 mL x 2). The collected organic phase was washed with brine (10 mL ₎ , dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a residue, which was purified by thin-layer chromatography (DCM/MeOH = 8/1) to afford JD-5303100 (70 mg, 65.4%) as a yellow solid.

LCMS: 431.2 ([M+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.97(s,1H),8.18(d,J＝8.1Hz,1H),7.97–7.91(m,1H),7.32(d,J＝3.0Hz,1H),6.79–6.68(m,2H),6.58(dd,J＝8.7 ,2.7Hz,1H),5.16(s,2H),4.14–4.04(m,3H),3.99–3.75(m,1H),3.69–3.63(m,2H),2.38(s,3H),1.77–1.34(m,8H).

Example 86 Preparation of (2S)-2-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-hydroxypropionamide JD-5303084

Refer to the synthesis method of Example 33, replacing compound JD-5303028b with JD-5303084a to prepare (2S)-2-{[(6-{[(2-fluorophenyl) [4-Methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-hydroxypropanamide JD-5303084 (82 mg, 65.2%) was obtained as a white solid.

LCMS: 390.1 ([M+H] ⁺ ).

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.60–7.35(m,4H),7.30–7.19(m,2H),7.13(s,1H),6.80(d,J＝8.8Hz,1H),6.71(d,J＝7.6Hz,1H),6.6 4(dd,J＝9.2,3.2Hz,1H),5.10–5.00(m,2H),4.94(t,J＝5.6Hz,1H),4.25–4.08(m,3H),3.85–3.61(m,4H).

Example 87 Preparation of N-[(1S,3R)-3-aminocyclohexyl]-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303086

Referring to the synthetic method of Example 33, compound JD-5303028b was replaced with JD-5303022a to prepare N-[(1S,3R)-3-aminocyclohexyl]-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303086 (43.7 mg, 55.0%) as a white solid.

LCMS: 400.3 ([M+H] ⁺ ).

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.62–7.32(m,5H),7.27–7.20(m,2H),6.97(d,J＝7.6Hz,1H),6.76(d,J＝8.8Hz,1H),6.59(dd,J＝8.8,2.8Hz,1H),5.02(s, 2H),4.75–4.05(m,2H),3.75–3.52(m,3H),3.05–2.94(m,1H),2.11(d,J＝11.6Hz,1H),1.92–1.71(m,3H),1.39–1.08(m,4H).

Example 88 Preparation of N-[(1S,3R)-3-aminocyclohexyl]-6-{[(2,6-difluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303087

Referring to the synthetic method of Example 22, JD-5303001d was replaced with JD-5303035a to prepare N-[(1S,3R)-3-aminocyclohexyl]-6-{[(2,6-difluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303087 (78.2 mg, 69.3%) as a white solid.

LCMS: 418.3 ([M+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.58–7.46(m,1H),7.37(d,J＝2.7Hz,1H),7.17(t,J＝7.8Hz,2H),6.94( d,J＝7.8Hz,1H),6.76(d,J＝9.0Hz,1H),6.59(dd,J＝8.7,2.7Hz,1H),4.99( s,2H),4.11(t,J＝4.5Hz,2H),3.70–3.63(m,2H),3.61–3.41(m,3H),2.86– 2.72(m,1H),2.00(d,J＝12.0Hz,1H),1.83–1.64(m,3H),1.34–1.06(m,4H).

Example 89 Preparation of N-[3-(hydroxymethyl)-2-oxo-3-ylpiperidin-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303095

Step 1 Preparation of ethyl 3-azido-2-oxyylidenehexahydropyridine-3-carboxylate JD-5303095-2

To a solution of ethyl 2-azidopyridinium-3-carboxylate JD-5303095-1 (3.0 g, 17.52 mmol, 1.0 eq) in DCM (30 mL), DBU (2.94 g, 19.28 mmol, 1.1 eq) and TsN₃ (3.80 g, 19.28 mmol, 1.1 eq) were added. The mixture was stirred at room temperature for 72 hours, diluted with water (15 mL), and extracted with DCM (15 mL x 2). The collected organic phase was washed with brine (10 mL), dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain a residue. Purification by silica gel column chromatography (DCM) afforded ethyl 3-azidopyridinium-3-carboxylate JD-5303095-2 (3.0 g, 80.6%) as a yellow solid.

LCMS: 213.1 ([M+H] ⁺ ).

¹ H NMR (400MHz, CDCl ₃ ): δ6.36 (s, 1H), 4.41–4.22 (m, 2H), 3.46–3.33 (m, 2H), 2.26–2.14 (m, 1H), 1.97–1.82 (m, 3H), 1.33 (t, J = 7.2Hz, 3H).

Step 2 Preparation of ethyl 3-amino-2-oxypyridinium-3-carboxylate JD-5303095-3

To a solution of ethyl 3-azido-2-oxo-pyridinium-3-carboxylate JD-5303095-2 (1.0 g, 4.71 mmol, 1.0 eq) in toluene (7 mL) was added _PPh₃ (989 mg, 3.77 mmol, 0.8 eq). After 5 minutes, 5% HCl (7 mL) was added. The mixture was stirred at room temperature for 12 hours, diluted with water (15 mL), and extracted with DCM (10 mL*2). The aqueous phase was adjusted to pH 9 with NaOH solution and extracted with DCM/MeOH = 10/1 (11 mL*3). The combined organic phases were washed with brine (10 _mL ), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to afford ethyl 3-amino-2-oxo-pyridinium-3-carboxylate JD-5303095-3 (160 mg, crude) as a yellow oil.

LCMS: 187.1 ([M+H] ⁺ ).

Step 3 Preparation of ethyl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-2-oxoylidenepiperidine-3-carboxylate JD-5303095-4

6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin JD-5303001-4 (120 mg, 0.46 mmol, 1.0 eq) and TEA (231 mg, 2.29 mmol, 5.0 eq) were dissolved in DCM (4.0 mL), and (COCl2)3 (68 mg, 0.23 mmol, 0.5 eq) was added. The reaction mixture was allowed to react at room temperature for 0.5 hours. Ethyl 3-amino-2-oxo-pyridin-3-carboxylate JD-5303095-3 (127 mg, 0.69 mmol, 1.4 eq) was dissolved in DCM (0.5 mL) and added to the mixture, which was stirred at 40°C for 15 hours. The reaction system was quenched with water (10 mL) and extracted with DCM (20 mL, 10 mL x 2). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 50/1) to afford ethyl 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-2-oxopyridin-3-carboxylate JD-5303095-4 (120 mg, 55.3% yield, 90% purity) as a white solid.

LCMS: 475.2 ([M+H] ⁺ ).

¹ H NMR (400MHz, CDCl ₃ ): δ8.71(s,1H),7.22(d,J＝2.7Hz,1H),7.14(s,1H),6.85(d,J＝9.0Hz,1H),6.68(dd,J＝9 .0,3.0Hz,1H),6.04(d,J＝3.0Hz,1H),5.16(s,2H),4.37–4.14(m,4H),3.93–3.75(m,2H), 3.66–3.56(m,1H),3.47–3.33(m,1H),2.60–2.47(m,4H),2.37–2.20(m,2H),1.95–1.87(m,1H),1.28(t,J＝7.2Hz,3H).

Step 4 Preparation of N-[3-(hydroxymethyl)-2-oxo-pyridin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303095

Compound 3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-2-oxopyridinium-3-carboxylate JD-5303095-4 (120 mg, 0.25 mmol, 1.0 eq) was stirred in THF (3 mL), and _LiAlH₄ (1.0 M, THF) (0.75 mL, 0.75 mmol, 3.0 eq) was added at 0°C. The mixture was stirred at 0°C for 2 h, quenched with 15% NaOH solution (0.1 mL) at 0°C, and dried _{over Na₂SO₄} . The mixture was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by pre-thin layer chromatography (DCM/MeOH=8:1) to obtain JD-5303095 (15 mg, 13.7%) as a white solid. LCMS: 433.1 ([M+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d6): δ8.98(s,1H),7.53(d,J＝2.7Hz,1H),7.32(d,J＝2.7Hz ,1H),6.79(d,J＝2.7Hz,1H),6.70–6.58(m,2H),5.27–5.04(m,3H),4.11(t,J＝4 .2Hz,2H),3.77–3.58(m,3H),3.56–3.49(m,1H),3.24–3.13(m,1H),3.12–3.03 (m,1H),2.39(s,3H),2.25–2.09(m,2H),1.75–1.69(m,1H),1.45–1.40(m,1H).

Example 90 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)-2-oxo-pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303102

Referring to the synthesis method of Example 89, compound JD-5303001-4 was replaced with JD-5303028-3 to prepare 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)-2-oxoylidenehexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303102 (40 mg, 46.3%) as a white solid.

LCMS: 430.2 ([M+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d ₆ ): δ7.59–7.48(m,2H),7.48–7.38(m,1H),7.34(d,J＝3.0Hz,1H),7.30– 7.17(m,2H),6.79(d,J＝8.7Hz,1H),6.69–6.58(m,2H),5.14(t,J＝6.3Hz,1H),5.04(s,2H),4.11(t,J＝4. 5Hz,2H),3.78–3.48(m,4H),3.28–3.14(m,1H),3.14–3.00(m,1H),2.23–2.02(m,2H),1.87–1.64(m,2H).

Example 91 Preparation of N-[3-(hydroxymethyl)piperidin-3-yl]-7-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303094

Referring to the synthetic method of Example 76, compound JD-5303028a was replaced with JD-5303001d to prepare N-[3-(hydroxymethyl)piperidin-3-yl]-7-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303094 (7.5 mg, 5.0%) as a white solid.

LCMS: 417.2 ([M+H] ⁺ ).

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.98(s,1H),7.26(d,J＝2.4Hz,1H),7.03(d,J＝8.4Hz,1H),6.64(dd,J＝8.0,2.4Hz,1 H),5.98(s,1H),5.21(s,2H),5.15–4.92(m,1H),3.68–3.62(m,2H),3.58–3.51(m,2H), 3.44(d,J＝10.8Hz,1H),3.06–2.97(m,1H),2.78–2.72(m,1H),2.72–2.66(m,1H),2.64( t,J＝6.8Hz,2H),2.40(s,3H),2.12–2.05(m,1H),1.85–1.77(m,2H),1.73–1.37(m,4H).

Example 92 Preparation of N-[3-(methoxymethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303093

Step 1 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid methyl ester JD-5303093-2

Compound 1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid methyl ester JD-530309-1 (500 mg, 2.055 mmol, 1.0 eq) was dissolved in THF (8 mL) and LDA (2.0 M in THF) (1.13 mL, 2.26 mmol, 1.1 eq) was added. The mixture was stirred at -65°C under a nitrogen atmosphere. The mixture was stirred at -65°C for 0.5 h, and MOMBr (308 mg, 2.46 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 15 h. The mixture was diluted with saturated NH4Cl solution (15 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (15 mL) and dried _{over Na2SO4} . The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1) to give compound 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid methyl ester JD-5303093-2 (500 mg, 84.6%) as a yellow oil.

LCMS: 232.1 ([M-56+H] ⁺ ).

¹ H NMR (300MHz, CDCl ₃ ): δ3.80–3.65(m,4H), 3.58–3.23(m,8H), 2.03–1.82(m,1H), 1.73–1.64(m,1H), 1.62–1.52(m,2H), 1.46(s,9H).

Step 2 Preparation of 3-(methoxymethyl)-1-{[(2-methylprop-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid JD-5303093-3

To the compound methyl 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylate JD-5303093-2 (500 mg, 1.74 mmol, 1.0 eq) in THF (3 ml) and H₂O (3 ml) was added LiOH· _H₂O (219 mg, 5.22 mmol, 3.0 eq). The mixture was stirred at room temperature for 15 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 2). The aqueous phase was adjusted to pH 3 with KHSO₄ solution and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with brine (10 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give compound 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid JD-5303093-3 (420 mg, crude) as a colorless oil.

LCMS: 218.3 ([M-56+H] ⁺ ).

Step 3 Preparation of benzyl {[3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl]amino}methane ester JD-5303093-4

To a solution of 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid JD-5303093-3 (420 mg, 1.54 mmol, 1.0 eq) in toluene (4 mL) and BnOH (0.8 mL) were added TEA (311 mg, 3.08 mmol, 2.0 eq) and DPPA (550 mg, 2.00 mmol, 1.3 eq). The mixture was then stirred at 90°C _for 15 hours. The mixture was diluted with water (8 mL) and extracted with ethyl acetate (8 mL x 2). The collected organic phase was washed with brine (8 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15:1) to give benzyl {[3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl]amino}methane JD-5303093-4 (650 mg, crude) as a colorless oil.

LCMS: 323.1 ([M-56+H] ⁺ ).

Step 4 Preparation of 2-methylpropane-3-(methoxymethyl)piperidin-1-carboxylate JD-5303093-5

To a solution of 2-methylpropane-2-yl 3-amino-3-(methoxymethyl)piperidin-1-carboxylate JD-5303093-5 (650 mg, crude, 1.54 mmol, 1.0 eq) in MeOH (5 mL) was added Pd/C (65 mg, 10%). The mixture was then stirred with hydrogenation at room temperature for 15 h. The mixture was filtered, and the filtrate was concentrated to yield 480 _mg of a crude product. The crude product was diluted with water (5 mL) and DCM (5 mL). The mixture was adjusted to pH 3 with 1N HCl and extracted with DCM (5 mL x 2). The aqueous phase was adjusted to pH 8 with _Na₂CO₃ solution and extracted with DCM (5 mL x 3). The collected organic phases were washed with brine (5 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give compound 3-amino- _3- (methoxymethyl)piperidine-1-carboxylic acid 2-methylpropane-2-yl ester JD-5303093-5 (220 mg, 51.7%, three steps) as a colorless oil.

LCMS: 245.2 ([M+H] ⁺ ).

Referring to the synthetic method of Example 1, compound JD-3503001d was replaced with JD-5303093-5 to prepare N-[3-(methoxymethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303093 (53 mg, 65.4%) as a yellow solid.

LCMS: 433.2 ([M+H] ⁺ ).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ8.98(s,1H),7.32(d,J＝3.0Hz,1H),6.78(d,J＝9.0Hz,1H),6.63(dd,J＝9.0 ,3.0Hz,1H),6.40(s,1H),5.17(s,2H),4.23–4.06(m,2H),3.87–3.77(m,1H),3 .75–3.58(m,3H),3.46(d,J＝9.0Hz,1H),3.33(s,1H),3.28(s,3H),3.17–3.00 (m,1H),2.90–2.68(m,2H),2.39(s,3H),2.22–2.18(m,1H),1.83–1.47(m,3H).

Example 93 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(methoxymethyl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303096

Referring to the synthetic method of Example 92, compound JD-3503001c was replaced with JD-5303028a to prepare 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(methoxymethyl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303096 (51 mg, 39.4%) as a white solid.

LCMS: 430.2 ([M+H] ⁺ ).

¹ H NMR (300MHz, DMSO-d ₆ ): δ8.28 (brs, 1H), 7.53 (td, J = 7.2, 1.5Hz, 1H), 7.46–7.37 (m, 1H), 7.34 (d,J＝2.7Hz,1H),7.29–7.16(m,2H),6.78(d,J＝9.0Hz,1H),6.63(dd,J＝9.0,3.0Hz,1H),6.41(s,1H),5.03(s,2H),4.24–4.03(m,2H),3.90–3. 77(m,1H),3.75–3.56(m,3H),3.46(d,J＝9.3Hz,1H),3.28(s,3H),3.15 –3.00(m,1H),2.90–2.65(m,2H),2.22–2.08(m,1H),1.86–1.43(m,3H).

Example 94 Preparation of N-[3-amino-1-(hydroxymethyl)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303108

Step 1 Preparation of benzyl [(2,4-dioxyylidene-1,3-diazaspiro[4.5]dec-7-yl)amino]methane ester JD-5303108-2

Benzyl [(3-oxyylidenecyclohexyl)amino]methane JD-5303108-1 (5.0 g, 20.22 mmol, 1.0 eq) was dissolved in MeOH (30 mL) and _H₂O (30 mL). ( _NH₄ ) _₂CO₃ (5.8 g, 60.66 mmol, 3.0 _eq ) and TMSCN (4.0 g, 40.44 mmol, 2.0 eq) were added, and the reaction mixture was reacted at 80°C for 15 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was collected by filtration to obtain benzyl [(2,4-dioxyylidene-1,3-diazaspiro[4.5]dec-7-yl)amino]methane JD-5303108-2 (5.5 g, crude) as a yellow solid. LC-MS ([M+H] ^⁺ ) = 318.1.

Step 2 Preparation of 7-(7,7-dimethyl-3,5-dioxy-1-phenyl-4-aza-2,6-dioxaoctane-4-yl)-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxy-1,3-diazaspiro[4.5]decane-3-carboxylic acid-2-methylprop-2-yl ester JD-5303108-3

Benzyl [(2,4-dioxyylidene-1,3-diazaspiro[4.5]dec-7-yl)amino]methane JD-5303108-2 (5.5 g, 17.33 mmol, 1.0 eq) was dissolved in dioxane (60 mL), and TEA (10.5 g, 103.99 mmol, 6.0 eq), (Boc) ₂ O (18.9 g, 86.66 mmol, 5.0 eq), and DMAP (212 mg, 1.73 mmol, 0.1 eq) were added. The reaction mixture was reacted at 70°C for 15 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 20/1) to give 7-(7,7-dimethyl-3,5-dioxyylidene-1-phenyl-4-aza-2,6-dioxaoct-4-yl)-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3-diazaspiro[4.5]decane-3-carboxylic acid -2-Methylpropan-2-yl ester JD-5303108-3 (6.2 g, two-step yield 49.6%, purity 94%) was obtained as a yellow oil.

LC-MS ([M+H ₂ O] ⁺ ) = 635.3.

¹ H NMR: (300MHz, CDCl ₃ )δ＝7.45-7.28(m,5H),5.35-5.24(m,2H),4.49-4.44(m,1H),2.71(t,J＝6.3Hz,1H),2.61-2.50(m,1H),2.14(d, J＝10.8Hz,1H),2.06-1.95(m,1H),1.89-1.76(m,2H),1.58-1.55(m,2H),1.54-1.47(m,18H),1.46-1.41(m,9H).

Step 3 Preparation of 1-amino-3-(7,7-dimethyl-3,5-dioxy-1-phenyl-4-aza-2,6-dioxaoctane-4-yl)cyclohexane-1-carboxylic acid JD-5303108-4

7-(7,7-Dimethyl-3,5-dioxyylidene-1-phenyl-4-aza-2,6-dioxaoctane-4-yl)-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,4-dioxyylidene-1,3-diazaspiro[4.5]decane-3-carboxylic acid-2-methylprop-2-yl ester JD-5303108-3 (6.2 g, 10.04 mmol, 1.0 eq) was dissolved in THF (30 mL) and _H2O (30 mL) ^, LiOH.H2O (3.37 g, 80.30 mmol, 8.0 eq) was _added , and the reaction mixture was reacted at room temperature for 15 hours. The mixture was concentrated under reduced pressure to give 1-amino-3-(7,7-dimethyl-3,5-dioxyidene-1-phenyl-4-aza-2,6-dioxaocan-4-yl)cyclohexane-1-carboxylic acid JD-5303108-4 (7.0 g, crude) as a white solid.

LC-MS ([MH] ⁻ )=391.2.

Step 4 Preparation of 1-amino-3-{[(benzyloxy)carbonyl]amino}cyclohexane-1-carboxylic acid JD-5303108-5

1-Amino-3-(7,7-dimethyl-3,5-dioxyylidene-1-phenyl-4-aza-2,6-dioxaocan-4-yl)cyclohexane-1-carboxylic acid JD-5303108-4 (7.0 g crude, 10.04 mmol, 1.0 eq) was dispersed in DCM (50 mL). HCl/Dioxane (4.0 M) (75.3 mL, 301.2 mmol, 30.0 eq) was added, and the reaction mixture was allowed to react at room temperature for 15 hours. The mixture was concentrated under reduced pressure to afford 1-amino-3-(7,7-dimethyl-3,5-dioxyylidene-1-phenyl-4-aza-2,6-dioxaocan-4-yl)cyclohexane-1-carboxylic acid JD-5303108-5 (8.0 g crude) as a white solid.

LC-MS ([M+H] ⁺ )=293.1.

Step 5 Preparation of 1-amino-3-{[(benzyloxy)carbonyl]amino}cyclohexane-1-carboxylic acid methyl ester JD-5303108-6

1-amino-3-(7,7-dimethyl-3,5-dioxyidene-1-phenyl-4-aza-2,6-dioxaoctane-4-yl)cyclohexane-1-carboxylic acid JD- 5303108- (4.0 g crude product, 5.02 mmol, 1.0 eq) was dissolved in MeOH (50 mL), and _MeSO₃H (2.5 mL) was added. The reaction mixture was reacted at 65°C for 15 hours. The pH of the mixture was adjusted to 9 with saturated sodium carbonate solution and then concentrated under reduced pressure to obtain a residue. The residue was washed with dichloromethane/methanol = 10/1 (90 mL, 30.0 mL x 3). The filtrate was collected by filtration and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 80/1) to obtain methyl 1-amino-3-{[(benzyloxy)carbonyl]amino}cyclohexane-1-carboxylate JD-5303108-6 (170 mg, 11.1% yield over three steps, 90% purity) as a yellow oil.

LC-MS ([M+H] ⁺ )=307.1.

¹ H NMR: (300MHz, CDCl ₃ ) δ = 7.38-7.31 (m, 5H), 5.07 (s, 2H), 4.63 (d, J = 6.3Hz, 1H), 4.04-3.89 (m, 1H), 3.70 (s, 3H), 2.02 -1.79(m,3H),1.70-1.56(m,6H),1.20-1.07(m,1H).

Step 6 Preparation of benzyl {[3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}cyclohexyl]amino}methane JD-5303108-7

Methyl 1-amino-3-{[(benzyloxy)carbonyl]amino}cyclohexane-1-carboxylate JD-5303108-6 (140 mg, 0.46 mmol, 1.2 eq) and TEA (193 mg, 1.91 mmol, 5.0 eq) were dissolved in DCM (2.0 mL), and ( _COCl₂ ) _₃ (57 mg, 0.19 mmol, 0.5 eq) was added. The reaction mixture was reacted at room temperature for 0.5 h. Int-1 (100 mg, 0.38 mmol, 1.0 eq) was then dissolved in DCM (1 mL) and added to the mixture, which was stirred at 40°C for 15 h. The reaction was quenched with water (5 mL) and extracted with DCM (10 mL, 5 mL x 2). The collected organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 1/1) to give benzyl {[3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}cyclohexyl]amino}methane JD-5303108-7 (150 mg, yield 66.1%, purity 90%) as a yellow solid.

LC-MS ([M+H] ⁺ )=595.2.

Step 7 Preparation of 3-amino-1-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}cyclohexane-1-carboxylic acid methyl ester JD-5303108-8

Benzyl {[3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}cyclohexyl]amino}methane JD-5303108-7 (150 mg, 0.25 mmol, 1.0 eq) was dissolved in DCM (5 mL), TMSI (151 mg, 0.75 mmol, 3.0 eq) was added, and the mixture was stirred at room temperature for 4 hours. Water (5 mL) was added to the mixture to quench it. The mixture was then extracted with DCM (10 mL, 5 mL*2). The aqueous phase was adjusted to pH 9 with saturated sodium bicarbonate solution and then extracted with DCM/MeOH = 8/1 (27 mL, 9 mL*3). The collected organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 20/1) to obtain methyl 3-amino-1-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}cyclohexane-1-carboxylate JD-5303108-8 (60 mg, 51.7% yield, 90% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )=461.2.

Step 8 Preparation of N-[3-amino-1-(hydroxymethyl)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303108

Compound 53-8 (60 mg, 0.13 mmol, 1.0 eq) was dissolved in THF (5 mL). _LiAlH₄ (1.0 M in THF) (0.26 mL, 0.26 mmol, 2.0 eq) was added to the mixture at 0°C, and the reaction mixture was allowed to react at 0°C for 1 hour. The mixture was quenched by the dropwise addition of 15% NaOH solution (0.1 mL) at 0°C and dried _{over Na₂SO₄} . The filtrate was collected by filtration and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25 mm*5 mm; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 25%-45%, 6 min) to obtain the product. The product was dissolved in water (5 mL), adjusted to pH 9 with saturated aqueous sodium hydroxide, and extracted with DCM (5 mL*2). The collected organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give JD01-LHNY-53 (4.5 mg, yield 8.0%, purity 95.3%) as a white solid.

LC-MS ([M+H] ⁺ )=433.3.

¹ H NMR: (300MHz, DeOD) δ = 8.89 (s, 1H), 7.17 (d, J = 3.0Hz, 1H), 6.82 (d, J = 9.0Hz, 1H), 6.69 (dd, J = 9.0,3.0Hz,1H),5.19(s,2H),4.22-4.15(m,2H),3.87-3.60(m,4H),2.93-2.80(m,1H),2.53- 2.41(m,4H),2.12(d,J＝13.2Hz,1H),1.93(d,J＝11.7Hz,1H),1.74-1.63(m,1H),1.60-1.45(m,1H),1.26-1.09(m,3H).

Example 95 Preparation of N-[3-amino-1-(hydroxymethyl)cyclohexyl]-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303111

Referring to the synthetic method of Example 94, compound JD-5303001-4 was replaced with JD-5303028-3 to prepare N-[3-amino-1-(hydroxymethyl)cyclohexyl]-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303111 (19 mg, yield 20.2%, purity 95.9%) as a white solid.

LC-MS ([M+H] ⁺ )=430.3.

¹ H NMR: (300MHz, DMSO-d6) δ = 7.53 (td, J = 7.5, 1.5Hz, 1H), 7.48-7.34 (m, 1H), 7.30-7.14 (m, 3 H),6.77(d,J＝9.0Hz,1H),6.61(dd,J＝8.7,2.7Hz,1H),6.28-5.80(m,2H),5.02(s,2H),4.2 3-4.00(m,2H),3.87-3.70(m,1H),3.68-3.57(m,1H),3.55-3.45(m,2H),3.38(s,2H),3.08 -2.88(m,1H),2.14-1.95(m,1H),1.93-1.74(m,1H),1.70-1.38(m,2H),1.35-0.97(m,4H).

Example 96 Preparation of benzyl 4,4-difluoro-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303105

Referring to step 5 of the synthetic method of Example 84, compound JD-5303104-5 was replaced with JD-5303001-4 to prepare 4,4-difluoro-3-{[(6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid benzyl ester JD-5303105 (95 mg, yield 69.4%, purity 99%) as a white solid.

LC-MS ([M+H] ⁺ )=559.2.

¹ H NMR: (300MHz, DMSO-d ₆ δ＝8.87(s,1H),7.42–7.23(m,5H),7.17(d,J＝3.0Hz,1H),6.81(d,J＝9.0Hz,1H),6.66(dd,J＝9.0,2.7Hz,1H),5.16(s,2H), 5.12(s,2H),4.38–4.19(m,2H),4.17–3.95(m,4H),3.57–3.40(m,1H),3.28–3.06(m,2H),2.42(s,3H),2.30–1.90(m,2H).

Example 97 Preparation of N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303106

Referring to the synthetic method of Example 84, compound JD-5303104-5 was replaced with JD-5303001-4 to prepare N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303106 (10 mg, yield 18.8%, purity 99%) as a white solid.

LC-MS ([M+H] ⁺ )=425.2.

¹ H NMR: (300MHz, DMSO-d ₆ )δ＝8.98(s,1H),7.27(d,J＝3.0Hz,1H),6.96(d,J＝9.0Hz,1H),6.79(d,J＝9.0Hz,1H),6.62(dd,J＝9.0,3.0Hz,1H),5.16(s,2H), 4.30–3.98(m,3H),3.97–3.82(m,1H),3.60–3.45(m,1H),2.98–2.80(m,2H),2.70–2.56(m,2H),2.38(s,3H),2.17–1.73(m,2H).

Example 98 Preparation of N-methyl-N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303082

Step 1 Preparation of N-methyl-N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303082

N-(3-Aminocyclohexyl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303008 (100 mg, 0.25 mmol, 1.0 eq) was dissolved in MeOH (2 mL), and (HCHO) _n (11 mg, 0.37 mmol, 1.5 eq) was added to the mixture. The reaction mixture was reacted at room temperature for 0.5 h, and then _NaBH3CN (31 mg, 0.5 mmol, 2.0 eq) was added to the mixture and stirred at 50 °C for 11.5 h. The mixture was concentrated to yield a crude product, which was diluted with water (8 mL) and extracted with dichloromethane (20 mL, 10 mL x 2). The collected organic phase was washed with brine (8 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (silica, dichloromethane/methanol = 30/1 to 10/1) to yield N-methyl-N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepan-4-carboxamide JD-5303082 (12.9 mg, 12.1% yield, 97% purity) as a yellow solid.

LC-MS ([M+H] ⁺ )=431.2.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝10.43(brs,1H),8.97(s,1H),7.34(d,J＝3.0Hz,1H),6.76(d,J＝8.7Hz,1H),6.70(d,J＝5.7Hz,1H),6.60(dd,J＝9. 0,3.0Hz,1H),5.17(s,2H),4.18–4.00(m,3H),3.79–3.60(m,2H),2.73–2.56(m,6H),2.39(s,3H),2.10–1.41(m,8H).

Comparative Example 1 Preparation of N-(hexahydropyridin-3-yl)-7-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazepin-1-carboxamide trifluoroacetate JD-5303065

Referring to the synthesis method of Example 1, the compound JD-5303001-1 was replaced with JD-5303065-1 to prepare N-(hexahydropyridin-3-yl)-7-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazepin- 1-Formamide trifluoroacetate JD-5303065 (1.42 mg, 3.57 μmol, yield 34.9%, purity 98%) was obtained as a yellow gum.

LCMS [389+H] ⁺ =390.

¹ H NMR(400MHz, DMSO-d ₆ )δppm 1.47-1.70(m,2H)1.82-1.95(m,2H)2.40(s,3H)2.70-2.84(m,2H)3.18(br d,J＝11.51Hz,1H)3.28-3.31(m,1H)3.64-3.77(m,2H)3.84-3.96(m,1H)4.20-4.32(m,2H)5.27(s,2H)7.09(br d,J＝7.13Hz,1H)7.62(d,J＝2.63Hz,1H)7.94(d,J＝2.75Hz,1H)8.55(br s,2H)9.00(s,1H).

Comparative Example 2 Preparation of N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazepin-4-carboxamide JD-5303066

Referring to the synthesis method of Example 1, compound JD-5303001-1 was replaced with JD-5303066-1 to prepare N-(hexahydropyridin-3-yl)-7-{[(4-methyl-1,3-thiazolin-5-yl)methyl]oxy}-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazepin-1-carboxamide trifluoroacetate JD-5303066 (22.4 mg, purity 98.83%) as a yellow gum.

LC-MS [389+H] ⁺ =390.

¹ H NMR: (400MHz, METHANOL-d ₄ ) δ = 1.55 (qd, J = 11.63, 3.38Hz, 1H), 1.63-1.74 (m, 1H) 1.81-1.90 (m, 1H), 1.98-2.08 (m, 1H), 2.42 (s, 3H), 2.81 (br d,J＝11.13Hz,2H),3.19(br d,J＝12.01Hz,1H),3.42(br d,J＝10.26Hz,1H),3.89(br dd,J＝6.44,3.06Hz,1H),3.95-4.04(m,2H),4.12-4.23(m,2H),5.41(d,J＝3.38Hz,2H),6.53(d, J=8.63Hz, 1H), 7.39 (d, J=8.63Hz, 1H), 8.54-8.83 (m, 2H), 9.01 (s, 1H), 9.26 (d, J= 6.75Hz, 1H).

Biological test cases

1. hTRPM3 calcium flux assay

This test uses Calcium 5 Assay Kit was used to screen small molecules. HeLa cells transfected with human TRPM3 protein for about 24 hours were plated onto 96-well plates for adherent culture. After growing to an appropriate density, the culture medium was discarded. A membrane-permeable calcium ion concentration indicator (FLIPR Calcium 5 Assay kit) prepared with extracellular buffer was added and incubated with the cells at 37°C and 5% CO2 for 50 minutes. Then, small molecule solutions and positive inhibitors of varying concentrations were added to the 96-well plates. A blank control was set up and incubated for another 15 minutes. The small molecule was prepared as a 10mM stock solution with DMSO and then diluted to the required concentration with the pharmaceutical solvent (10% DMSO + 90% HBSS). The blank control was an extracellular buffer solution containing the corresponding concentration of the co-solvent DMSO. The whole process was kept away from light. After the incubation was completed, the 96-well plate was placed on the FlexStation3 multi-function plate reader. The TRPM3-specific agonist pregnenolone sulfate (PregS) sample plate was loaded into the sampler of the microplate reader in advance. The concentration was set to 60μM (the final concentration in the well was 15uM). The test program was set to excite cell fluorescence at 485nM and detect fluorescence emission at 525nM. The test time for each well was 90s, and the data acquisition interval was 1.52s. After recording for 25s, the positive agonist PregS (final concentration 15uM) was added by the instrument's liquid adding arm, and the remaining data points were continued to be collected. After all well plate tests were completed, the fluorescence increments of all wells before and after the addition of the agonist were calculated based on the quantified fluorescence intensity change curve output by the machine, and normalized with the fluorescence increments of the corresponding blank control wells to obtain the inhibition rate of fluorescence intensity under the action of different concentrations of small molecules. The inhibition curve of the logarithm of concentration against the inhibition rate was obtained by curve fitting in GraphPad (Y = 100/(1 + 10^((LogIC50-X)*HillSlope))). All charts were generated by GraphPad Prism version 8.0.

Table 1 hTRPM3 calcium flux test results


“A”: IC ₅₀ ≤ 1 μM; “B”: 1 μM < IC ₅₀ ≤ 10 μM; “C” > 10 μM.

The test results show that the compounds of the present invention exhibit good hTRPM3 inhibitory effects, and some of the compounds can achieve an hTRPM3 inhibitory effect of 1 μM.

Claims (14)

A compound I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
in, X is N or CH; Y is O or -CH ₂ -; ^L1 is -L ^a -L ^b -L ^c -L ^d -; L ^a , L ^b , L ^c and L ^d are each independently a connecting bond, O, S or ^{And La} , ^Lb , ^Lc and ^Ld are not simultaneously connected bonds ^{; O} , ^S and The number of is 1 or 2; R ⁶ , R ^6a and R ^6b are each independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl substituted with one or more R ^6-1 ; R ^6-1 are each independently hydroxy, halogen, amino, -NHC ₁ -C ₆ alkyl or -N(C ₁ -C ₆ alkyl) ₂ ; U is 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , 5-10 membered heteroaryl substituted by one or more R ^9-2 , or 3-8 membered cycloalkyl substituted by one or more R ^9-a ; R ^9-1 , R ^9-2 and R ^9-a are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, Oxo, -O-(3-8 membered cycloalkyl) or C ₁ -C ₆ alkyl substituted by one or more R ^9-4 ; R ^9-3 are each independently H, C ₁ -C ₆ alkyl or 3-8 membered cycloalkyl; R ^9-4 are each independently hydroxy, halogen or C ₁ -C ₆ alkoxy; R ¹ , R ² and R ³ are each independently H, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkyl substituted by one or more halogens; R ⁴ , R ^4a , R ^5a and R ⁵ are each independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl or C ₁ -C ₆ alkyl substituted by one or more halogens; Alternatively, R ⁴ and R ^4a together with their adjacent carbon atoms form a 3-8 membered cycloalkyl group; W is L ² R ⁷ ; L ² is a linking bond, -CH ₂ -, -NH- or -N(C ₁ -C ₆ alkyl)-; R ⁷ is 3-8 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , C ₁ -C ₆ alkyl substituted by one or more R ^7-3 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 ; R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, hydroxy, oxo, amino, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, -O-(3-8 membered cycloalkyl), C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ; R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxy, amino, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , R ^7-3 are each independently halogen, hydroxy, amino, C ₁ -C ₆ alkoxy, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , R ^7-2-1 are each independently H, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, or C ₁ -C ₆ alkyl substituted by one or more C ₆ -C ₁₀ aryl groups; The heteroatoms in the 3-12 membered heterocycloalkyl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3; The heteroatoms in the 5-10 membered heteroaryl group are selected from one or more of N, O and S; and the number of heteroatoms is 1, 2 or 3. Compound I, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: ^L1 is Wherein end a is connected to U; U is 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , or 5-10 membered heteroaryl substituted by one or more R ^9-2 ; R ^9-1 and R ^9-2 are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, Oxo, -O-(3-8 membered cycloalkyl) or C ₁ -C ₆ alkyl substituted by one or more R ^9-4 ; R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, hydroxy, oxo, amino, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, -O-(3-8 membered cycloalkyl), C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ; R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxy, amino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , R ^7-2-1 are each independently H, C ₁ -C ₆ alkyl or 3-8 membered cycloalkyl. Compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the compound I satisfies one or more of the following conditions: (1) Each C ₁ -C ₆ alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (2) Each C ₂ -C ₆ alkenyl group is independently vinyl, propenyl, allyl, butenyl or pentenyl, preferably vinyl; (3) Each C ₂ -C ₆ alkynyl group is independently ethynyl, propynyl, propargyl, butynyl or pentynyl; (4) Each C ₁ -C ₆ alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy; (5) Each halogen is independently fluorine, chlorine, bromine or iodine; (6) The heteroatom in each 3-12 membered heterocycloalkyl group is independently nitrogen; the number of heteroatoms is independently 1 or 2; (7) each 3-12 membered heterocycloalkyl group is independently a 4-10 membered heterocycloalkyl group; (8) Each 3-12 membered heterocyclic group is independently a monocyclic or bicyclic ring, and the bicyclic ring may be a bridged ring or a spiro ring; (9) Each C ₆ -C ₁₀ aryl group is independently phenyl or naphthyl, preferably phenyl; (10) each 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group; (11) The heteroatoms in each 5-10 membered heteroaryl group are independently N, S or O; the number of heteroatoms can be 1 or 2; (12) Each 5-10 membered heteroaryl group is independently monocyclic or bicyclic; (13) Each 3-8 membered cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl; (14) The pharmaceutically acceptable salt is hydrochloride, formate or trifluoroacetate. Compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the compound I satisfies one or more of the following conditions: (1) X is N; (2) Y is O; (3) L ¹ is Preferably Wherein end a is connected to U; (4) R ⁶ , R ^6a and R ^6b are each independently H or C ₁ -C ₆ alkyl, preferably H; (5) U is C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , or 5-10 membered heteroaryl substituted ^{by one or more R 9-2 ;} (6) R ^9-1 and R ^9-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, or C ₁ -C ₆ alkyl substituted by one or more R ^9-4 ; (7) R ^9-3 are each independently H or C ₁ -C ₆ alkyl, preferably H; (8) R ^9-4 is halogen; (9) R ¹ , R ² and R ³ are each independently H or halogen; preferably, R ¹ and R ³ are H, and R ² is H or halogen; (10) R ^4a is H; (11) R ⁵ and R ^5a are H; (12) R ⁴ is H or C ₁ -C ₆ alkyl, preferably H; (13) L ² is a linking bond, -CH ₂ - or -NH-, preferably -NH-; (14) R ⁷ is 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 ; Preferably, R ⁷ is a 3-12 membered heterocycloalkyl group or a 3-12 membered heterocycloalkyl group substituted by one or more R ^7-1 groups; More preferably, R ⁷ is piperidinyl, tetrahydropyrrolyl, tetrahydropyrrolyl substituted by one or more halogens, or piperidinyl substituted by one or more halogens; More preferably, R ⁷ is piperidinyl substituted by 1 or 2 F groups or tetrahydropyrrolyl substituted by 1 or 2 F groups; (15) R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, amino, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 (16) R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxyl, C ₂ -C ₆ alkenyl, (17) R ^7-2-1 are each independently H or C ₁ -C ₆ alkyl; and (18) When ^L2 is a connecting bond, ^R7 is a 3-12 membered heterocycloalkyl group or a 3-12 membered heterocycloalkyl group substituted by one or more ^R7-1 ; the 3-12 membered heterocycloalkyl group is preferably a spirocyclic ring; preferably, the heteroatom of the 3-12 membered heterocycloalkyl group may be N, and the number of heteroatoms may be 1 or 2; more preferably, the N atom in the 3-12 membered heterocycloalkyl group is connected to ^L2 . Compound I, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the Compound I satisfies one or more of the following conditions: (1) L ¹ is Wherein end a is connected to U; (2) U is (3)W is Compound I, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: X is N or CH; Y is O or -CH ₂ -; ^L1 is Wherein end a is connected to U; R ⁶ , R ^6a and R ^6b are each independently H or C ₁ -C ₆ alkyl; U is C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , or 5-10 membered heteroaryl substituted by one or more R ^9-2 ; R ^9-1 and R ^9-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, or C ₁ -C ₆ alkyl substituted by one or more halogens; R ^9-3 are each independently H or C ₁ -C ₆ alkyl R ¹ , R ² and R ³ are each independently H, halogen or C ₁ -C ₆ alkyl; R ⁴ and R ^4a are each independently H or C ₁ -C ₆ alkyl; Alternatively, R ⁴ and R ^4a together with their adjacent carbon atoms form a 3-8 membered cycloalkyl group; W is L ² R ⁷ ; L ² is a linking bond, -CH ₂ - or -NH-; R ⁷ is 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 ; R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, amino, -NHC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ; R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxyl, C ₂ -C ₆ alkenyl, R ^7-2-1 are each independently H or C ₁ -C ₆ alkyl; The heteroatoms in the 3-12 membered heterocycloalkyl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3; The heteroatoms in the 5-10 membered heteroaryl group are selected from one or more of N, O and S; and the number of heteroatoms is 1, 2 or 3. Compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the compound I satisfies one or more of the following conditions: (1) O, S and L in L ^a , L ^b , L ^c and L ^d The number of is 1; (2) U is a 3-8 membered cycloalkyl group; (3) R ^9-a is independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, or C ₁ -C ₆ alkyl substituted by one or more R ^9-4 ; (4) L ² is a linking bond, -NH- or -N(CH ₃ )-; (5) R ⁷ is a C ₁ -C ₆ alkyl group substituted by one or more R ^7-3 ; (6) R ^7-3 is hydroxy or (7) R ^7-1 , R ^7-2 and R ^7-4 are each independently (8) R ^7-1-1 and R ^7-1-2 are each independently a C ₁ -C ₆ alkoxy group; and (9) R ^7-2-1 are each independently a 3-8 membered cycloalkyl group or a C ₁ -C ₆ alkyl group substituted with one or more C ₆ -C ₁₀ aryl groups. Compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the compound I satisfies one or both of the following conditions: (1) U is (2)W is Compound I, its stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the compound I satisfies any one of the following schemes: Option 1: X is N or CH; Y is O or -CH ₂ -; ^L1 is Wherein end a is connected to U; R ⁶ , R ^6a and R ^6b are each independently H or C ₁ -C ₆ alkyl; U is C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, C ₆ -C ₁₀ aryl substituted by one or more R ^9-1 , or 5-10 membered heteroaryl substituted by one or more R ^9-2 ; R ^9-1 and R ^9-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-8 membered cycloalkyl, or C ₁ -C ₆ alkyl substituted by one or more halogens; R ^9-3 are each independently H or C ₁ -C ₆ alkyl R ¹ , R ² and R ³ are each independently H, halogen or C ₁ -C ₆ alkyl; R ⁴ and R ^4a are each independently H or C ₁ -C ₆ alkyl; Alternatively, R ⁴ and R ^4a together with their adjacent carbon atoms form a 3-8 membered cycloalkyl group; ^R5 and ^R5a are H; W is L ² R ⁷ ; L ² is a linking bond, -CH ₂ - or -NH-; R ⁷ is 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl substituted by one or more R ^7-1 , 5-10 membered heteroaryl substituted by one or more R ^7-2 , C ₁ -C ₆ alkyl substituted by one or more R ^7-3 , or 3-8 membered cycloalkyl substituted by one or more R ^7-4 ; R ^7-1 , R ^7-2 and R ^7-4 are each independently halogen, amino, -NHC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl substituted by one or more R ^7-1-1 or C ₁ -C ₆ alkoxy substituted by one or more R ^7-1-2 ; R ^7-1-1 and R ^7-1-2 are each independently halogen, hydroxy, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, R ^7-3 are each independently hydroxyl or R ^7-2-1 are each independently H, C ₁ -C ₆ alkyl, or C _{1 -C 6} alkyl substituted with one or more C ₆ -C ₁₀ aryl groups; The heteroatoms in the 3-12 membered heterocycloalkyl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3; The heteroatoms in the 5-10 membered heteroaryl group are selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3; Option 2: The compound I is compound I-1, I-2 or I-3,
Compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the compound I or its stereoisomer is selected from any one of the following compounds:







The pharmaceutically acceptable salt of Compound I is selected from any one of the following compounds:



a compound II,
wherein R ¹ , R ² , R ³ , R ⁴ , R ^4a , R ⁵ , R ^5a , L ¹ and U are as defined in any one of claims 1 to 10. A pharmaceutical composition comprising Compound I according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. A use of Compound I according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating pain; the pain is preferably inflammatory pain. A use of Compound I according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the preparation of a medicament for preventing and/or treating a TRPM3-mediated disease; the TRPM3-mediated disease is preferably pain, more preferably inflammatory pain.