Benzomorpholine compound and application thereof

Abstract

The invention discloses a benzomorpholine compound and an application thereof. Specifically disclosed are compounds I, stereoisomers thereof, or pharmaceutically acceptable salts thereof. The compound provided by the invention has good TRPM3 inhibitory activity and is expected to treat related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a benzomorpholine compound and its application. Background Art

[0002] The TRP superfamily consists of proteins with six transmembrane domains (6TM), which assemble as homo- or heterotetramers to form cation-permeable ion channels.

[0003] TRP channel dysfunction is directly involved in the etiology of various genetic and acquired diseases. In fact, loss-of-function and gain-of-function mutations in TRP channel genes have been identified as the direct cause of genetic diseases, including short QT syndrome, hypomagnesemia with secondary hypocalcemia, polycystic kidney disease, mucopolysaccharidosis type IV, and familial focal segmental glomerulosclerosis. In addition, TRP channel function / dysfunction has been directly associated with a wide range of pathological conditions, including chronic pain, hypertension, cancer, and neurodegenerative disorders.

[0004] TRPM3 (transient receptor potential melastatin 3) represents a promising pharmacological target. TRPM3 is highly expressed in a large subset of small diameter sensory neurons from dorsal root and trigeminal ganglia and is involved in thermal sensing. The neurosteroid pregnenolone sulfate is a known potent activator of TRPM3. 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 analgesic drugs to combat pain, such as inflammatory pain.

[0005] There is still a great medical need for new, alternative, and / or better therapeutic agents for the prevention or treatment of TRPM3-mediated disorders, more specifically for pain (such as inflammatory pain). There is an urgent need for therapeutic agents that have good potency against a certain type of pain, low or no side effects, and / or good or better pharmacokinetic or kinetic properties. Summary of the Invention

[0006] The present invention provides a novel class of 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.

[0007] The present invention provides a compound I, its stereoisomers, or its pharmaceutically acceptable salts,

[0008]

[0009] wherein,

[0010] X is N or CH;

[0011] Y is O or -CH2-;

[0012] L 1 -L a -L b -L c -L d -;

[0013] L a , L b , L c and L d Each is independently a connecting key, O, S or And L a , L b , L c and L d Not a connecting key at the same time; L a , L b , L c and L d O, S and The number of is 1 or 2;

[0014] R 6 、R 6a and R 6b Each independently represents H, C1-C6 alkyl or is replaced by one or more R 6-1 Substituted C1-C6 alkyl;

[0015] R 6-1 Each is independently hydroxy, halogen, amino, -NHC1-C6 alkyl or -N(C1-C6 alkyl)2;

[0016] U is a 3-12 membered heterocycloalkyl group, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 9-1 Substituted C6-C 10 Aryl, one or more R 9-2 substituted 5-10 membered heteroaryl or one or more R 9-a substituted 3-8 membered cycloalkyl;

[0017] R 9-1 、R 9-2 and R 9-a Each is independently halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, Oxo, -O-(3-8 membered cycloalkyl) or one or more R 9-4 Substituted C1-C6 alkyl;

[0018] R9-3 Each is independently H, a C1-C6 alkyl group, or a 3- to 8-membered cycloalkyl group;

[0019] R 9-4 Each is independently a hydroxyl group, a halogen, or a C1-C6 alkoxy group;

[0020] R 1 、R 2 and R 3 Each is independently H, a halogen, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 alkyl group substituted with one or more halogens;

[0021] R 4 、R 4a 、R 5a and R 5 Each is independently H, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered cycloalkyl group, or a C1-C6 alkyl group substituted with one or more halogens;

[0022] Alternatively, R 4 and R 4a together with the adjacent carbon atom form a 3- to 8-membered cycloalkyl group;

[0023] W is L 2 R 7 ;

[0024] L 2 is a linking bond, -CH2-, -NH-, or -N(C1-C6 alkyl)-;

[0025] R 7 is a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocycloalkyl group substituted with one or more R 7-1 substituents, a 5- to 10-membered heteroaryl group substituted with one or more R 7-2 substituents, a C1-C6 alkyl group substituted with one or more R 7-3 substituents, or a 3- to 8-membered cycloalkyl group substituted with one or more R 7-4 substituents;

[0026] R 7-1 、R 7-2 and R 7-4 Each is independently a halogen, a hydroxyl group, an oxo group, an amino group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered cycloalkyl group, -O-(3- to 8-membered cycloalkyl group), a C1-C6 alkyl group substituted with one or more R 7-1-1 substituents, or a C1-C6 alkoxy group substituted with one or more R 7-1-2 substituents;

[0027] R 7-1-1 and R 7-1-2 each independently represents a halogen, a hydroxyl group, an amino group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2,

[0028] R 7-3 each independently represents a halogen, a hydroxyl group, an amino group, a C1-C6 alkoxy group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2,

[0029] R 7-2-1 each independently represents H, a C1-C6 alkyl group, a 3-8 membered cycloalkyl group or a C1-C6 alkyl group substituted by one or more C6-C 10 aryl groups;

[0030] 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;

[0031] 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.

[0032] In one embodiment,

[0033] L 1 is where the a end is connected to U;

[0034] U is a 3-12 membered heterocycloalkyl group, a C6-C 10 aryl group, a 5-10 membered heteroaryl group, a C6-C 9-1 aryl group substituted by one or more R 10 or a 5-10 membered heteroaryl group substituted by one or more R 9-2 groups;

[0035] R 9-1 and R 9-2 each independently represents a halogen, a cyano group, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3-8 membered cycloalkyl group, oxo, -O-(3-8 membered cycloalkyl) or a C1-C6 alkyl group substituted by one or more R 9-4 groups;

[0036] R 7-1 、R 7-2 and R 7-4Each is independently a halogen, a hydroxyl group, an oxo group, an amino group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, -O-(3-8 membered cycloalkyl), C1-C6 alkyl substituted by one or more R 7-1-1 or C1-C6 alkoxy substituted by one or more R 7-1-2 ;

[0037] R 7-1-1 and R 7-1-2 are each independently a halogen, a hydroxyl group, an amino group, C2-C6 alkenyl, C2-C6 alkynyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2,

[0038] R 7-2-1 are each independently H, C1-C6 alkyl or 3-8 membered cycloalkyl.

[0039] In one embodiment, each C1-C6 alkyl can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0040] In one embodiment, each C2-C6 alkenyl can independently be vinyl, propenyl, allyl, butenyl or pentenyl, preferably vinyl.

[0041] In one embodiment, each C2-C6 alkynyl can independently be ethynyl, propynyl, propargyl, butynyl or pentynyl.

[0042] In one embodiment, each C1-C6 alkoxy can independently be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0043] In one embodiment, each halogen can independently be fluorine, chlorine, bromine or iodine.

[0044] In one embodiment, each heteroatom in each 3-12 membered heterocycloalkyl can independently be N; the number of heteroatoms can independently be 1 or 2.

[0045] In one embodiment, each 3-12 membered heterocycloalkyl can independently be a 4-10 membered heterocycloalkyl.

[0046] In one embodiment, each 3-12 membered heterocyclic group can independently be monocyclic or bicyclic, and the bicyclic group can be a bridged ring or a spiro ring.

[0047] In one embodiment, each "plurality" can independently be 2 or 3.

[0048] In one embodiment, each C6-C 10Aryl groups independently may be phenyl or naphthyl, preferably phenyl.

[0049] In a certain embodiment, each 5-10 membered heteroaryl group can independently be a 5-6 membered heteroaryl group.

[0050] 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.

[0051] In one embodiment, each 5-10 membered heteroaryl group is independently monocyclic or bicyclic.

[0052] In one embodiment, each 3-8 membered cycloalkyl group can independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.

[0053] In one embodiment, the pharmaceutically acceptable salt may be hydrochloride, formate or trifluoroacetate.

[0054] In one embodiment, X is N.

[0055] In one embodiment, Y is O.

[0056] In one scenario, L 1 for Preferably The a end is connected to U.

[0057] In one scenario, L a , L b , L c and L d O, S and The number of is 1.

[0058] In one scenario, R 6 、R 6a and R 6b Each is independently H or C1-C6 alkyl, preferably H.

[0059] In one scheme, U is C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 9-1 Substituted C6-C 10 Aryl or one or more R 9-2 Substituted 5-10 membered heteroaryl.

[0060] In one scheme, U is C6-C 10 Aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 9-1 Substituted C6-C 10 Aryl or one or more R 9-2 Substituted 5-10 membered heteroaryl.

[0061] In one embodiment, U is a 3- to 8-membered cycloalkyl group.

[0062] In one embodiment, R 9-1 and R 9-2 are each independently halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, or C1-C6 alkyl substituted with one or more R 9-4 groups.

[0063] In one embodiment, R 9-1 , R 9-2 and R 9-a are each independently halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, or C1-C6 alkyl substituted with one or more R 9-4 groups.

[0064] In one embodiment, R 9-a is independently halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, or C1-C6 alkyl substituted with one or more R 9-4 groups.

[0065] In one embodiment, R 9-3 are each independently H or C1-C6 alkyl, preferably H.

[0066] In one embodiment, R 9-4 is halogen.

[0067] 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.

[0068] In one embodiment, R 4a is H.

[0069] In one embodiment, R 5 and R 5a are H.

[0070] In one embodiment, R 4 is H or C1-C6 alkyl, preferably H.

[0071] In one embodiment, L 2 is a linking bond, -CH2-, or -NH-, preferably -NH-.

[0072] In one embodiment, L 2 is a linking bond, -NH-, or -N(CH3)-.

[0073] In one embodiment, L 2 is -N(CH3)-.

[0074] In one embodiment, R 7 is 3- to 12-membered heteroalkyl, 5- to 10-membered heteroaryl, 3- to 12-membered heteroalkyl substituted with one or more R 7-1 , 5- to 10-membered heteroaryl substituted with one or more R 7-2 , or 3- to 8-membered cycloalkyl substituted with one or more R 7-4 .

[0075] In one embodiment, R 7 is C1-C6 alkyl substituted with one or more R 7-3 .

[0076] In one embodiment, R 7-3 is hydroxy or

[0077] In one embodiment, R 7-1 , R 7-2 and R 7-4 are each independently halogen, amino, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkyl substituted with one or more R 7-1-1 , or C1-C6 alkoxy substituted with one or more R 7-1-2 .

[0078] In one embodiment, R 7-1 , R 7-2 and R 7-4 are each independently halogen, amino, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkyl substituted with one or more R 7-1-1 , or C1-C6 alkoxy substituted with one or more R 7-1-2 .

[0079] In one embodiment, R 7-1 , R 7-2 and R 7-4 are each independently

[0080] In one embodiment, R 7-1-1 and R 7-1-2 are each independently halogen, hydroxy, C2-C6 alkenyl,

[0081] In one embodiment, R 7-1-1 and R 7-1-2 are each independently halogen, hydroxy, C1-C6 alkoxy, C2-C6 alkenyl,

[0082] In one embodiment, R 7-1-1 and R 7-1-2 are each independently C1-C6 alkoxy.

[0083] In one embodiment, R 7-2-1 are each independently H or C1-C6 alkyl.

[0084] In one embodiment, R 7-2-1 are each independently H, C1-C6 alkyl or C1-C6 alkyl substituted by one or more C6-C 10 aryl.

[0085] In one embodiment, R 7-2-1 are each independently 3- to 8-membered cycloalkyl or C1-C6 alkyl substituted by one or more C6-C 10 aryl.

[0086] In one embodiment, when L 2 is a linking bond, R 7 is 3- to 12-membered heterocycloalkyl or 3- to 12-membered heterocycloalkyl substituted by one or more R 7-1 ; the 3- to 12-membered heterocycloalkyl is preferably spiro;

[0087] Preferably, the heteroatom of the 3- to 12-membered heterocycloalkyl can be N, and the number of heteroatoms can be 1 or 2;

[0088] More preferably, the N atom in the 3- to 12-membered heterocycloalkyl is linked to L 2 .

[0089] In one embodiment, R 7 is 3- to 12-membered heterocycloalkyl or 3- to 12-membered heterocycloalkyl substituted by one or more R 7-1 ;

[0090] Preferably, R 7 is 5- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl substituted by one or more halogens; the heteroatom of the 5- to 6-membered heterocycloalkyl is N, and the number of heteroatoms can be 1 or 2;

[0091] More preferably, R 7 is piperidinyl, pyrrolidinyl, pyrrolidinyl substituted by one or more halogens or piperidinyl substituted by one or more halogens;

[0092] Further preferably, R 7 is a piperidinyl group substituted with one or two Fs or a pyrrolidinyl group substituted with one or two Fs.

[0093] In one embodiment, L 1 is where the a end is connected to U.

[0094] In one embodiment, U is

[0095] In one embodiment, U is

[0096] In one embodiment, U is, In one embodiment, W is

[0097]

[0098] In one embodiment, W is

[0099]

[0100] In one embodiment, W is

[0101] In one embodiment,

[0102] X is N or CH;

[0103] Y is O or -CH2-;

[0104] L 1 is where the a end is connected to U;

[0105] R 6 、R 6a and R 6b are each independently H or C1-C6 alkyl;

[0106] U is C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 9-1 aryl substituted with one or more Rs 10 or 5-10 membered heteroaryl substituted with one or more Rs 9-2 ;

[0107] R 9-1 and R 9-2Each independently is a halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered cycloalkyl group, or a C1-C6 alkyl group substituted by one or more halogens;

[0108] R 9-3 Each independently is H or a C1-C6 alkyl group

[0109] R 1 , R 2 and R 3 Each independently is H, a halogen or a C1-C6 alkyl group;

[0110] R 4 and R 4a Each independently is H or a C1-C6 alkyl group;

[0111] Or, R 4 and R 4a together with the adjacent carbon atom are connected to form a 3- to 8-membered cycloalkyl group;

[0112] R 5 and R 5a are H;

[0113] W is L 2 R 7 ;

[0114] L 2 is a linking bond, -CH2- or -NH-;

[0115] R 7 is a 3- to 12-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocycloalkyl group substituted by one or more R 7-1 a 5- to 10-membered heteroaryl group substituted by one or more R 7-2 or a 3- to 8-membered cycloalkyl group substituted by one or more R 7-4 ;

[0116] R 7-1 , R 7-2 and R 7-4 Each independently is a halogen, an amino group, -NHC1-C6 alkyl group, a C1-C6 alkyl group, -N(C1-C6 alkyl)2, a C1-C6 alkyl group substituted by one or more R 7-1-1 or a C1-C6 alkoxy group substituted by one or more R 7-1-2 ;

[0117] R 7-1-1 and R 7-1-2 Each independently is a halogen, a hydroxyl group, a C2-C6 alkenyl group,

[0118] R7-2-1 each independently is H or a C1-C6 alkyl group;

[0119] the heteroatoms in the 3- to 12-membered heterocycloalkyl group are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3;

[0120] the heteroatoms in the 5- to 10-membered heteroaryl group are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3.

[0121] In one embodiment,

[0122] X is N or CH;

[0123] Y is O or -CH2-;

[0124] L 1 is where the a end is connected to U;

[0125] R 6 、R 6a and R 6b each independently is H or a C1-C6 alkyl group;

[0126] U is a C6-C 10 aryl group, a 5- to 10-membered heteroaryl group, a 3- to 8-membered cycloalkyl group, a C6-C 9-1 aryl group substituted with one or more R 10 or a 5- to 10-membered heteroaryl group substituted with one or more R 9-2 ;

[0127] R 9-1 and R 9-2 each independently is a halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered cycloalkyl group, or a C1-C6 alkyl group substituted with one or more halogens;

[0128] R 9-3 each independently is H or a C1-C6 alkyl group

[0129] R 1 、R 2 and R 3 each independently is H, a halogen, or a C1-C6 alkyl group;

[0130] R 4 and R 4a each independently is H or a C1-C6 alkyl group;

[0131] Alternatively, R 4 and R 4a together with the adjacent carbon atom are connected to form a 3- to 8-membered cycloalkyl group;

[0132] R 5 and R 5a is H;

[0133] W is L 2 R 7 ;

[0134] L 2 is a connecting bond, -CH2- or -NH-;

[0135] R 7 is a 3-12 membered heterocycloalkyl, a 5-10 membered heteroaryl, or a 5-10 membered heteroaryl group, 7-1 substituted 3-12 membered heterocycloalkyl, substituted by one or more R 7-2 substituted 5-10 membered heteroaryl, substituted by one or more R 7-3 Substituted C1-C6 alkyl or one or more R 7-4 substituted 3-8 membered cycloalkyl;

[0136] R 7-1 、R 7-2 and R 7-4 Each is independently halogen, amino, -NHC1-C6 alkyl, C1-C6 alkyl, -N(C1-C6 alkyl)2, By one or more R 7-1-1 Substituted C1-C6 alkyl or one or more R 7-1-2 Substituted C1-C6 alkoxy;

[0137] R 7-1-1 and R 7-1-2 Each is independently halogen, hydroxy, C1-C6 alkoxy, C2-C6 alkenyl,

[0138] R 7-3 Each independently is hydroxyl or R 7-2-1 Each independently represents H, C1-C6 alkyl or substituted by one or more C6-C 10 Aryl-substituted C1-C6 alkyl;

[0139] 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;

[0140] 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.

[0141] In one embodiment, the compound I of the present invention is compound I-1, I-2 or I-3,

[0142]

[0143] Among them, R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , R 5a , L 1 , U and W are defined as described above. In one embodiment, the compound I or its stereoisomer is selected from any of the following compounds:

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] In one embodiment, the pharmaceutically acceptable salt of the compound I is selected from any of the following compounds:

[0151]

[0152]

[0153]

[0154] The present invention also provides a compound II,

[0155]

[0156] Among them, R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , R 5a , L 1 and U are defined as described above.

[0157] On the other hand, the present invention also provides a pharmaceutical composition, which comprises the compound I, its stereoisomer or its pharmaceutically acceptable salt as described above, and at least one pharmaceutical excipient.

[0158] On the other hand, the present invention also provides the use of the compound I as described above, its stereoisomers or its pharmaceutically acceptable salts, or the pharmaceutical composition as described above in the preparation of a medicament for treating pain; the pain is preferably inflammatory pain.

[0159] On the other hand, the present invention also provides the use of the compound I as described above, its stereoisomers or its pharmaceutically acceptable salts, or the pharmaceutical composition as described above in the preparation of a medicament for preventing and / or treating TRPM3-mediated diseases; the TRPM3-mediated diseases are preferably pain, and more preferably inflammatory pain.

[0160] On the other hand, the present invention also provides the use of the compound I as described above, its stereoisomers or its pharmaceutically acceptable salts, or the 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, mainly for experimental purposes, for example: provided as a standard or control sample for comparison, or made into a kit according to the conventional methods in the art to provide a rapid detection of the effect of antagonizing TRPM3.

[0161] The term

[0162] Unless otherwise specified, the definitions of the groups and terms described in the specification and claims of the present invention, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in the tables, definitions of specific compounds in the examples, etc., can be combined and combined with each other arbitrarily. The defined groups and compound structures after such combination and combination should fall within the scope described in the specification of the present invention.

[0163] The total number of carbon atoms present in certain chemical groups defined herein is represented by a simplified symbol in front of the group. For example, C1-C6 alkyl or C 1-6 alkyl refers to an alkyl as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0164] In this article, the numerical ranges defined in the substituents, such as 0 to 10, 1-6, 1-3, etc., indicate integers within that range, such as 1-6 being 1, 2, 3, 4, 5 or 6.

[0165] The term "plurality" means 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, preferably 2, 3 or 4.

[0166] The term "alkyl" refers to a straight-chain or branched-chain, saturated monovalent hydrocarbon group having a specified number of carbon atoms (for example, C1-C6 or C1-C4). Alkyl includes, but is not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0167] The term "alkenyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 double bonds. Alkenyl includes, but is not limited to: vinyl, etc.

[0168] The term "alkynyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 triple bonds. Alkynyl includes, but is not limited to: ethynyl, etc.

[0169] The term "alkoxy" refers to the group R X -O-, where the definition of R X is the same as that of the term "alkyl". Alkoxy includes, but is not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0170] The term "halogen" refers to F, Cl, Br, I.

[0171] The term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C 10 or C3-C6), which is a monocyclic ring. Cycloalkyl includes, but is not limited to: etc.

[0172] The term "oxo" refers to =O, where an oxygen atom replaces two hydrogens on the same carbon atom, that is, a carbonyl group replaces a methylene group, for example after oxo it becomes

[0173] The term "heterocycloalkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-12 membered, 4-10 membered, or 4-6 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is a monocyclic or polycyclic ring, and the polycyclic ring can be a bridged ring, a fused ring, or a spiro ring, and the polycyclic ring can also be a bicyclic or tricyclic ring. Heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes, but is not limited to: etc.

[0174] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-10 membered or 5-6 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, with two atoms and one bond shared between monocyclic rings, and each ring being aromatic. The heteroaryl is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms. Heteroaryls include, but are not limited to: etc.

[0175] 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 according to the circumstances.

[0176] The term "pharmaceutical excipient" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and is generally divided into two major categories: excipients and additives. For details, please refer to Pharmacopoeia of the People's Republic of China (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0177] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0178] The term "prevention" refers to reducing the risk of developing a disease.

[0179] The term "patient" refers to any animal that needs to receive treatment or prevention of a disease, usually a mammal, such as a human. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0180] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0181] The reagents and raw materials used in the present invention are all commercially available.

[0182] The positive and progressive effects of the present invention are as follows: The compounds provided by the present invention have good TRPM3 inhibitory activity and are expected to treat related diseases. Detailed Description of the Invention

[0183] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0184] Example 1 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303001

[0185]

[0186] Step 1 Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin JD-5303001-2

[0187]

[0188] Dissolve 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303001-1 (10 g, 46.72 mmol, 1.00 eq) in dioxane (200 mL). Add 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) to the reaction mixture. The reaction mixture is stirred at 100 °C for 2 hours. The mixture is filtered and concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303001-2 (12 g, 45.96 mmol, 98.37% yield) as a yellow oil.

[0189] LC-MS [M+H] + = 262.0.

[0190] Step 2 Preparation of 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ol JD-5303001-3

[0191]

[0192] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin JD-5303001-2 (11 g, 42.13 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (110 mL) and water (110 mL). AcOH (12.65 g, 210.63 mmol, 12.06 mL, 5.0 eq) and H2O2 (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 h. The reaction mixture was quenched by adding Na2SO3 (aq., 600 mL) at 0 °C, and then extracted with EtOAc (900 mL, 300 mL * 3). The organic layer was collected, 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 obtain 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ol JD-5303001-3 (4.17 g, 27.59 mmol, yield 65.49%) as a brown oil.

[0193] LC-MS [M] = 150.1.

[0194] Step 3 Preparation of (4-methyl-1,3-thiazol-5-yl)methanol JD-5303001b

[0195]

[0196] LAH (2.00 M, 29.2 mL, 2.00 eq) was dissolved in THF (50.0 mL). After stirring for 30 min, ethyl 4-methyl-1,3-thiazole-5-carboxylate JD-5303001a was added. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched by adding H2O (2.00 mL) at -10 °C, then diluted with 15% NaOH (2.00 mL) and H2O (6.00 mL), and stirred at 25 °C for 15 min. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain (4-methyl-1,3-thiazol-5-yl)methanol JD-5303001b (2.50 g, 19.3 mmol, yield 66.2%) as a yellow solid.

[0197] LC-MS [M + H] + = 130.3.

[0198] Step 4 Preparation of 5-(chloromethyl)-4-methyl-1,3-thiazolane JD-5303001c

[0199]

[0200] Dissolve (4-methyl-1,3-thiazolan-5-yl)methanol JD-5303001b (400 mg, 3.10 mmol, 1.00 eq) and SOCl2 in THF (25.0 mL), and stir the reaction mixture at 25 °C for 1 hour. Quench the reaction mixture with H2O (30.0 mL) and extract with EtOAC (30.0 mL). Collect the organic phase, separate, filter, and concentrate under reduced pressure to obtain 5-(chloromethyl)-4-methyl-1,3-thiazolane JD-5303001c (500 mg, crude product) as a colorless oil.

[0201] Step 5 Preparation of 6-{[(4-methyl-1,3-thiazolan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazinane JD-5303001-4

[0202]

[0203] Dissolve 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ol JD-5303001-3 (0.20 g, 1.32 mmol, 1.00 eq) in DMF (2 mL), add K2CO3 (365 mg, 2.65 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolane JD-5303001c (292 mg, 1.98 mmol, 1.50 eq). Stir the reaction mixture at 80 °C for 16 hours. Wash the reaction mixture with H2O (10 mL) and ethyl acetate (10 mL, 5 mL * 2). Collect the organic phase, separate and concentrate under reduced pressure to obtain a residue. Purify the residue by preparative chromatography (SiO2, petroleum ether / ethyl acetate = 1:1) to obtain 6-{[(4-methyl-1,3-thiazolan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazinane JD-5303001-4 (0.12 g, 457 μmol, yield 34.5%) as a colorless oil.

[0204] LC-MS [M+H] + = 263.1.

[0205] Step 6 Preparation of 2-methylpropan-2-yl 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}pyrrolidine-1-carboxylate JD-5303001-5

[0206]

[0207] Dissolve JD-5303001-4 (20.3 mg, 91.4 μmol, 1.20 eq) of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine and DIEA (39.4 mg, 304 μmol, 53.1 μL, 4.00 eq) in THF (1.00 mL), and exchange the gas with N2 three times. Cool the mixture to 0 °C. Add BTC (0.09 g, 303 μmol, 0.40 eq) to the mixture and stir at 25 °C for 1 hour. Then add 2-methylpropan-2-yl 4-amino-3,3-difluoropyrrolidine-1-carboxylate JD-5303001d (20.0 mg, 76.2 μmol, 1.00 eq) to the mixture. Stir the mixture at 25 °C for 2 hours. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.53) shows that the starting material is completely consumed and a new spot is formed. Quench the reaction mixture by adding 5 mL of H2O at 0 °C, then extract with 15 mL (5 mL * 3) of ethyl acetate, and concentrate under reduced pressure to obtain a residue. Purify by preparative high performance liquid chromatography to obtain 2-methylpropan-2-yl 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}pyrrolidine-1-carboxylate JD-5303001-5 (25.0 mg) as a white solid.

[0208] Step 7 Preparation of hydrochloride of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303001

[0209]

[0210] To 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303001-5 (40.0 mg, 78.3 μmol, 1.00 eq) in TFE (1.00 mL) was added TMSCl (17.0 mg, 156 μmol, 19.8 μL, 2 eq), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound JD-5303001 (23.0 mg, 51.4 μmol, yield 65.6%, HCl salt).

[0211] LC-MS [M+H] + = 411.0.

[0212] 1 1H NMR: (400 MHz, 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, 2.88 Hz, 1H), 6.79 (d, J = 8.88 Hz, 1H), 7.35 (d, J = 2.88 Hz, 1H), 7.61 (d, J = 8.38 Hz, 1H), 9.10 (s, 1H), 10.02 - 10.46 (m, 2H).

[0213] Example 2 Preparation of N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide hydrochloride JD-5303002

[0214]

[0215] Referring to the synthetic method of Example 1, compound JD-5303001d was replaced with JD-5303002a to prepare N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide hydrochloride JD-5303002 as a yellow gum (0.073 g, 181 μmol, yield 88.5%, purity 96.4%).

[0216] LC-MS [M+H] + = 389.2.

[0217] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 - 1.73 (m, 2H) 1.86 (br d, J = 10.88 Hz, 2H) 2.40 (s, 3H) 2.80 (br dd, J = 19.39, 9.51 Hz, 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, 2.88 Hz, 1H) 6.76 (d, J = 8.88 Hz, 1H) 7.17 (br d, J = 7.38 Hz, 1H) 7.40 (d, J = 2.88 Hz, 1H) 9.14 - 9.30 (m, 2H) 9.42 (br s, 1H).

[0218] Example 3 Preparation of N-[(3S)-hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303003

[0219]

[0220] Referring to the synthesis method of Example 1, replacing compound JD-5303001d with JD-5303003a, N-[(3S)-hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303003 was obtained as a yellow gum (48.9 mg, 124 μmol, yield 71.6%, purity 99.0%).

[0221] LC-MS [M+H] + = 389.1.

[0222] 11H NMR (400 MHz, DMSO-d6) δ ppm 1.50 - 1.70 (m, 2H) 1.81 - 1.95 (m, 2H) 2.39 (s, 3H) 2.77 (br t, J = 9.94 Hz, 2H) 3.18 (br d, J = 12.01 Hz, 1H) 3.30 (br d, J = 10.13 Hz, 1H) 3.69 (br d, J = 2.88 Hz, 2H) 3.85 - 3.96 (m, 1H) 4.13 (t, J = 4.57 Hz, 2H) 5.17 (s, 2H) 6.63 (dd, J = 8.88, 2.88 Hz, 1H) 6.78 (d, J = 8.88 Hz, 1H) 6.96 (d, J = 7.38 Hz, 1H) 7.36 (d, J = 2.88 Hz, 1H) 8.54 - 8.73 (m, 2H) 8.98 (s, 1H).

[0223] Example 4 Preparation of N-[(3R)-hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303004

[0224]

[0225]

[0226] Referring to the synthesis method of Example 1, replacing compound JD-5303001d with JD-5303004a, N-[(3R)-hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303004 was obtained as a yellow gum (39.11 mg, 99.67 μmol, yield 57.29%, purity 99%).

[0227] LC-MS [M+H] + = 389.0.

[0228] 11H NMR (400 MHz, DMSO-d6) δ ppm 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 = 12.38 Hz, 1H) 3.30 (br d, J = 9.76 Hz, 1H) 3.65 - 3.75 (m, 2H) 3.82 - 3.95 (m, 1H) 4.13 (t, J = 4.57 Hz, 2H) 5.17 (s, 2H) 6.63 (dd, J = 8.88, 2.88 Hz, 1H) 6.78 (d, J = 8.88 Hz, 1H) 6.97 (d, J = 7.38 Hz, 1H) 7.36 (d, J = 2.88 Hz, 1H) 8.52 - 8.76 (m, 2H) 8.98 (s, 1H).

[0229] Example 5 Preparation of N-(1-Methylhexahydropyridin-4-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide Trifluoromethanesulfonate JD-5303005

[0230]

[0231] Referring to the synthesis method of Example 1, replacing compound JD-5303001d with JD-5303005a, N-(1-Methylhexahydropyridin-4-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303005 was obtained as a yellow gummy compound (71.5 mg, 138 μmol, yield 36.3%, TFA salt).

[0232] LC-MS [M+H] + = 403.1.

[0233] 11H NMR: (400 MHz, DMSO-d6) δ ppm 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 = 11.76 Hz, 2H) 3.62 - 3.80 (m, 3H) 4.04 - 4.16 (m, 2H) 5.16 (s, 2H) 6.61 (dd, J = 8.88, 2.88 Hz, 1H) 6.74 - 6.80 (m, 1H) 7.04 (br d, J = 7.38 Hz, 1H) 7.34 - 7.39 (m, 1H) 8.99 (s, 1H) 9.27 - 9.57 (m, 1H).

[0234] Example 6 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(tetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303006

[0235]

[0236] Referring to the synthesis method of Example 1, replacing compound JD-5303001d with JD-5303006a, 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(tetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303006 (120 mg, 252 μmol, yield 66.3%) was obtained as a white solid.

[0237] LC-MS [M+H] + = 375.0.

[0238] 1 1H NMR: (400 MHz, DMSO-d6) 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).

[0239] Preparation of N-(5,5-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303007

[0240]

[0241] Using the synthetic method of Reference Example 1, replacing compound JD-5303001d with JD-5303007a, N-(5,5-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303007 (0.045 g, yield 69.9%, purity 97.92%) was obtained as a brown gum.

[0242] LC-MS [M+H] + = 425.2.

[0243] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 2.17 - 2.49 (m, 5H) 2.99 (br s, 1H) 3.30 (br d, J = 9.76 Hz, 1H) 3.46 (br d, J = 12.76 Hz, 1H) 3.58 - 3.68 (m, 1H) 3.70 - 3.79 (m, 2H) 4.08 - 4.23 (m, 3H) 5.19 (s, 2H) 6.63 (dd, J = 8.94, 2.94 Hz, 1H) 6.78 (d, J = 8.88 Hz, 1H) 7.30 - 7.46 (m, 2H) 9.21 (s, 1H) 9.83 (br s, 1H) 10.68 (br s, 1H).

[0244] Preparation of N-(3-aminocyclohexyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303008

[0245]

[0246] According to the method of Example 1, replace compound JD-5303001d with JD-5303008a to prepare N-(3-aminocyclohexyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303008 (75 mg, yield 62.4%, purity 98.8%) as a white solid.

[0247] LC-MS([M+H] + ) = 403.2.

[0248] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.92 (s, 1H), 7.35 (d, J = 2.9 Hz, 1H), 6.80–6.74 (m, 1H), 6.61 (dd, J = 8.8, 2.9 Hz, 1H), 6.39 (d, J = 6.8 Hz, 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).

[0249] Example 9 Preparation of N-(piperidin-4-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoromethanesulfonate JD-5303009

[0250]

[0251] According to the synthetic method of Example 1, replace JD-5303001d with JD-5303009a to prepare N-(piperidin-4-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoromethanesulfonate JD-5303009 (80 mg, 205.48 μmol, yield 83.66%, purity 99.78%) as a white solid.

[0252] LC-MS [M+H] + = 389.1.

[0253] 11H NMR: (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.80 - 8.92 (m, 1H), 8.67 - 8.78 (m, 1H), 7.37 (d, J = 2.88 Hz, 1H), 7.05 - 7.11 (m, 1H), 6.76 (d, J = 8.88 Hz, 1H), 6.60 (dd, J = 8.82, 2.94 Hz, 1H), 5.15 - 5.18 (m, 2H), 4.09 - 4.13 (m, 2H), 3.27 (br d, J = 12.26 Hz, 2H), 3.15 - 3.23 (m, 1H), 2.87 - 3.05 (m, 4H), 2.39 (s, 3H), 1.94 (br d, J = 12.26 Hz, 2H), 1.63 - 1.76 (m, 2H).

[0254] Example 10 Preparation of N-(5-Amino-2-methylcyclohexyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303010

[0255]

[0256] Step 1 Preparation of [(3-Amino-4-methylcyclohexyl)amino]methanoic acid 2-methylprop-2-yl ester JD-5303010b

[0257]

[0258] Dissolve 4-methylcyclohexane-1,3-diamine JD-5303010a (500 mg, 3.90 mmol, 1.0 eq) in dichloromethane (5.0 mL), add triethylamine (592 mg, 5.85 mmol, 1.5 eq) and (Boc)2O (851 mg, 3.90 mmol, 1.0 eq), and react the reaction mixture at room temperature for 15 hours. Quench the mixture by adding water (10 mL) at room temperature, and then extract with dichloromethane (30 mL, 10.0 mL * 3). Concentrate the collected organic phase under reduced pressure to obtain a residue. Purify the residue by column chromatography (silica gel, dichloromethane / methanol = 10 / 1) to obtain [(3-Amino-4-methylcyclohexyl)amino]methanoic acid 2-methylprop-2-yl ester JD-5303010b (150 mg, yield 16.8%) as a yellow oil.

[0259] LC-MS [M + H] + = 229.2.

[0260] 11H NMR (400 MHz, DMSO-d6): δ 7.00–6.43 (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).

[0261] Step 2 Preparation of N-(5-amino-2-methylcyclohexyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303010

[0262] Prepared N-(5-amino-2-methylcyclohexyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303010 (11.9 mg, yield 53.7%, purity 98.82%) as a white solid by replacing JD-5303001d with JD-5303010b according to the synthesis method of Example 1.

[0263] LC-MS [M+H] + = 417.2.

[0264] 1 1H NMR (400 MHz, DMSO-d6): δ 8.97 (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), 3.67–3.57 (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).

[0265] Example 11 Preparation of N-(azepan-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303011

[0266]

[0267] Using the synthesis method of Example 1, replace JD-5303001d with JD-5303011a to prepare N-(azepan-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303011 (58 mg, yield 48.3%, purity 98.9%) as a white solid.

[0268] LC-MS([M+H] + ) = 403.2.

[0269] 1 H NMR (300 MHz, DMSO-d6) δ = 8.98 (s, 1H), 7.38 (d, J = 2.9 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 8.9, 2.9 Hz, 1H), 5.17 (s, 2H), 4.13 (t, J = 4.4 Hz, 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).

[0270] Example 12 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(4-azabicyclo[2.2.2]octan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303012

[0271]

[0272]

[0273] Using the synthesis method of Example 1, replace JD-5303001d with JD-5303012a to prepare 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(4-azabicyclo[2.2.2]octan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303012 (13.8 mg, yield 8.7%, purity 97.71%) as a yellow solid.

[0274] LC-MS([M+H] + ) = 415.2.

[0275] 1 1H NMR (300 MHz, CDCl3): δ 8.70 (s, 1H), 7.42 (d, J = 3.0 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.70–6.59 (m, 2H), 5.12 (s, 2H), 4.30 (s, 1H), 4.21 (t, J = 4.8 Hz, 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 = 4.8 Hz, 1H), 2.25–2.16 (m, 1H), 2.04–1.96 (m, 2H), 1.82–1.73 (m, 1H).

[0276] Example 13 Preparation of N-(4-Fluoroperhydro-3-pyridinyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide Trifluoromethanesulfonate JD-5303013

[0277]

[0278] Prepared N-(4-Fluoroperhydro-3-pyridinyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide Trifluoromethanesulfonate JD-5303013 (4.6 mg, 11.3 μmol, yield 28.6%, purity 99.6%) as a white solid by replacing JD-5303001d with JD-5303013a according to the synthesis method of Example 1.

[0279] LC-MS [M+H] + = 407.0.

[0280] 11H NMR: (400 MHz, DMSO-d6) δ = 8.99 (s, 1H), 8.66 - 8.93 (m, 2H), 7.36 (d, J = 2.88 Hz, 1H), 7.14 - 7.19 (m, 1H), 6.78 - 6.83 (m, 1H), 6.65 (dd, J = 8.94, 2.94 Hz, 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).

[0281] Example 14 Preparation of N-(2H-Pyrazol-3-yl)-6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014

[0282]

[0283] Step 1 Preparation of 6-{[Dimethyl(2-methylpropan-2-yl)silyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303014-2

[0284]

[0285] Imidazole (45.0 mg, 661 μmol, 2.00 eq) was added to a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazin-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 the mixture was 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 obtain 6-{[Dimethyl(2-methylpropan-2-yl)silyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303014-2 (100 mg, crude) as a brown oil.

[0286] LC-MS [M+H] + = 266.1.

[0287] Step 2 Preparation of 6-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014-3

[0288]

[0289] 6-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin 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) were added to CDI (36.6 mg, 226 μmol, 1.20 eq) and DIEA (29.2 mg, 226 μmol, 39.3 μL, 1.20 eq) in THF (1.00 mL), and the mixture was stirred at 25 °C for 12 h. 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 obtain 6-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014-3 (110 mg, crude product) as a brown oil.

[0290] LC-MS [M+H] + = 389.4.

[0291] Step 3 Preparation of 6-hydroxy-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014-4

[0292]

[0293] To a solution of 6-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014-3 (50.0 mg, 128 μmol, 1.00 eq) in THF (1.00 mL) was added TBAF (50.4 mg, 193 μmol, 1.50 eq), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (10.0 mL) and extracted with EtOAc (10.0 mL). The organic layer was separated, filtered, and concentrated under reduced pressure to give 6-hydroxy-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014-4 (30.0 mg, crude) as a brown oil.

[0294] LC-MS [M+H] + = 275.0.

[0295] Step 4 Preparation of N-(2H-pyrazol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014

[0296]

[0297] 6-Hydroxy-N-(2-methylpyrazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014-4 (30.0 mg, 109 μmol, 1.00 eq) and (4-methyl-1,3-thiazol-5-yl)methanol JD-5303001a (28.2 mg, 218 μmol, 2.00 eq) were added to a solution of THF (1.00 mL). PPh3 (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 h. The reaction mixture was quenched with H2O (10.0 mL) and extracted with EtOAc (10.0 mL). The organic layer was separated, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative high performance liquid chromatography to give N-(2H-pyrazol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303014 (1.45 mg, 3.76 μmol, yield 3.44%) as a brown gum.

[0298] LC-MS [M+H] + = 386.1

[0299] 1 H NMR (300 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.98 (s, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.68 (dd, J = 9.0, 3.0 Hz, 1H), 6.11 (d, J = 2.1 Hz, 1H), 5.18 (s, 2H), 4.22 (t, J = 4.5 Hz, 2H), 3.85 (t, J = 4.5 Hz, 2H), 3.65 (s, 3H), 2.38 (s, 3H).

[0300] Example 15 Preparation of N-(5-chlorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide formate JD-5303015

[0301]

[0302] Step 1. Referring to the synthesis method of Example 1, replace compound JD-5303001d with JD-5303015a to prepare 6-[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid 2-methylpropan-2-yl ester JD-5303015-1 (150 mg, 92.2%) as a yellow solid.

[0303] LCMS: 487.2 ([M+H] + )

[0304] 1 H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 7.00 (d, J = 2.9 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.67 (dd, J = 8.9, 2.9 Hz, 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).

[0305]

[0306] Step 2. 6-[(6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid 2-methylpropan-2-yl ester JD-5303015 (150 mg, 0.31 mmol, 1.0 eq) was dissolved in DCM (2 mL), and Dioxane / HCl (1.5 mL, 6.2 mmol, 20.0 eq) was added to the mixture. The reaction mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was quenched with saturated sodium carbonate solution (3 mL), then extracted with dichloromethane (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 a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150 * 25 mm * 5 mm; 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.

[0307] LC-MS([M + H] + ) = 423.1.

[0308] 1 H NMR (300 MHz, MeOD) δ = 8.88 (s, 1H), 8.33 (brs, 0.74H), 7.24 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.67 (dd, J = 9.0, 2.8 Hz, 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), 3.43–3.32 (m, 2H), 2.91–2.77 (m, 1H), 2.69 (s, 1H), 2.44 (s, 3H), 2.34–2.09 (m, 2H).

[0309] Example 16 Preparation of 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-4-(1,6-diazaspiro[3.5]non-1-ylcarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine trifluoroacetate JD-5303016

[0310]

[0311] Prepared 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-4-(1,6-diazaspiro[3.5]nonan-1-ylcarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-carboxylate JD-5303016 (7.3 mg, yield 7.9%, purity 97.0%) as a white solid by replacing JD-5303001d with JD-5303016a according to the synthesis method of Reference Example 1.

[0312] LC-MS([M+H] + ) = 415.3.

[0313] 1 H NMR(400 MHz, MeOD) δ = 8.96(s, 1H), 6.85–6.78(m, 2H), 6.72(dd, J = 2.8 Hz, 8.8 Hz, 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).

[0314] Example 17 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-[3-(prop-2-en-1-yl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303017

[0315]

[0316] Step 1 Preparation of 3-amino-3-(prop-2-en-1-yl)piperidine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303017c

[0317]

[0318] Dissolve 2-methylpropan-2-yl 3-oxopiperidine-1-carboxylate JD-5303017a (400 mg, 2.0 mmol, 1.0 eq) in NH3 in MeOH (4.0 mL). After the reaction mixture was reacted at room temperature for 0.5 h, 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane JD-5303017b (439 mg, 2.6 mmol, 1.3 eq) was added to the reaction system and reacted at room temperature for 11.5 h. The mixture was adjusted to pH 10 by adding sodium hydroxide solution (15%) (5 mL) at room temperature, and then extracted with dichloromethane (20 mL, 10.0 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 a residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 50 / 1 to 30 / 1) to obtain 2-methylpropan-2-yl 3-amino-3-(prop-2-en-1-yl)piperidine-1-carboxylate JD-5303017c (310 mg, yield 64.2%, purity 92%) as a yellow oil.

[0319] LC-MS([M-56+H] + ) = 185.1.

[0320] 1 H NMR (300 MHz, DMSO-d6) 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).

[0321] Step 2 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-[3-(prop-2-en-1-yl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303017

[0322] Referring to the synthesis method of Example 1, replace compound JD-5303001d with JD-5303017c to prepare 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-[3-(prop-2-en-1-yl)piperidin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303017 (25.1 mg, yield 61.9%, purity 98.2%) as a white solid.

[0323] LC-MS([M+H]+ ) = 429.3.

[0324] 1 1H NMR (300 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.62–7.96 (m, 1H), 7.31 (d, J = 3.0 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.63 (dd, J = 9.0, 3.0 Hz, 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), 2.67–2.56 (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).

[0325] Preparation of Example 18 N-[3-(2-chloroethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303018

[0326]

[0327] Step 1 Preparation of 1-[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]-1,6-diazaspiro[3.5]nonane-6-carboxylic acid 2-methylpropan-2-yl ester JD-5303018-1

[0328]

[0329] Referring to the synthesis method of Example 1, replacing JD-5303001d with JD-5303018a, 1-[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]-1,6-diazaspiro[3.5]nonane-6-carboxylic acid 2-methylpropan-2-yl ester JD-5303018-1 (150 mg, yield 87.1%, purity 92%) was prepared as a yellow oil.

[0330] LC-MS ([M+H] +) = 515.2.

[0331] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 6.84 (d, J = 2.9 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.9, 2.9 Hz, 1H), 5.20 (s, 2H), 4.23–3.34 (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).

[0332] Step 2 Preparation of N-[3-(2-chloroethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303018

[0333]

[0334] 1-[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]-1,6-diazaspiro[3.5]nonane-6-carboxylic acid 2-methylpropan-2-yl ester JD-5303018-1 (150 mg, 0.29 mmol, 1.0 eq) was dissolved in DCM (2 mL), and Dioxane / HCl (1.46 mL, 5.93 mmol, 20.0 eq) was added to the mixture. 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), then extracted with DCM (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 a residue. The residue was purified by prep-TLC (dichloromethane / methanol = 10 / 1) to obtain N-[3-(2-chloroethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303018 (9 mg, yield 6.8%, purity 97.3%) as a yellow solid.

[0335] LC-MS ([M + H] + ) = 451.0.

[0336] 11H NMR (300 MHz, DMSO-d6) δ = 9.16 (s, 2H), 8.99 (s, 1H), 7.27 (d, J = 2.9 Hz, 1H), 7.02 (t, J = 5.6 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.63 (dd, J = 8.9, 2.9 Hz, 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).

[0337] Preparation of Ethyl (3-{[(6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridin-3-yl)acetate JD-5303019, Example 19

[0338]

[0339] Step 1 Preparation of Ethyl [(3E)-1-{[(2-Methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-ylidene]acetate JD-5303019c

[0340]

[0341] Diethyl (2-ethoxy-2-oxoethyl)phosphonate JD-5303019b (2.7 g, 12.05 mmol, 1.2 eq) was dissolved in tetrahydrofuran (20 mL). At 0 °C, NaH (482 mg, 12.05 mmol, 1.2 eq) was added and the mixture was stirred for 0.5 h. Then 2-Methylpropan-2-yl 3-oxohexahydropyridine-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 h. The mixture was quenched by adding saturated aqueous ammonium chloride solution (20 mL) at 0 °C. Then it was extracted with ethyl acetate (40 mL, 20 mL * 2). The collected organic phase was washed with brine (20 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 gel, petroleum ether / ethyl acetate = 200 / 1 to 50 / 1) to obtain 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.

[0342] LC-MS ([M+Na]) = 292.1.

[0343] 1 1H NMR (400 MHz, CDCl3): δ = 5.74 (s, 1H), 4.16 (q, J = 7.2 Hz, 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 = 7.2 Hz, 3H).

[0344] Step 2 Preparation of Ethyl (3-Amino-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)acetate JD-5303019d

[0345]

[0346] 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 ammonia water (1.2 mL) was added at room temperature. The mixture was stirred in an autoclave at 80 °C for 15 h. The mixture was concentrated under reduced pressure to obtain ethyl (3-amino-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)acetate JD-5303019d (500 mg, crude product) as a green oil.

[0347] LC-MS ([M+H] + ) = 287.3.

[0348] Step 3 Preparation of 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-N-[3-(prop-2-enyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide

[0349] Referring to the synthetic method of Example 1, compound JD-5303001d was replaced with JD-5303019d to prepare 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-[3-(prop-2-enyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303019 (8.9 mg, yield 30.7%, purity 95.6%) as a white solid.

[0350] LC-MS ([M+H] + ) = 475.3.

[0351] 1 1H NMR (300 MHz, DMSO-d6): δ = 8.97 (s, 1H), 8.07 (brs, 1H), 7.31 (d, J = 2.7 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 6.64 (dd, J = 9.0, 3.0 Hz, 1H), 6.38 (s, 1H), 5.18 (s, 2H), 4.22–4.06 (m, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.89–3.78 (m, 1H), 3.78–3.68 (m, 1H), 3.68–3.59 (m, 1H), 3.05 (d, J = 12.3 Hz, 1H), 2.92–2.82 (m, 2H), 2.77–2.66 (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 = 7.2 Hz, 3H).

[0352] Example 20 Preparation of N-(azetidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303020

[0353]

[0354] Prepared by replacing JD-5303001d with JD-5303020a according to the synthesis method of Reference Example 1, N-(azetidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303020 (55.28 mg, 135.90 μmol, yield 78.23%, purity 97.57%, HCl) was a yellow gum.

[0355] LC-MS [M+H] + = 361.1.

[0356] 11H NMR: (400 MHz, DMSO-d6) 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, 2.88 Hz, 1H), 6.77 (d, J = 8.88 Hz, 1H), 7.42 (d, J = 2.75 Hz, 1H), 7.92 (br d, J = 5.88 Hz, 1H), 9.25 (br s, 1H), 9.30 (s, 1H), 9.38 (br s, 1H).

[0357] Preparation of N-[(1R,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303021 in Example 21

[0358]

[0359] Referring to the synthesis method of Example 1, replace compound JD-5303001d with JD-5303021a to prepare N-[(1R,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303021 (60 mg, yield 74.8%, purity 99.72%) as a white solid.

[0360] LC-MS [M+H] + = 403.2.

[0361] 1 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.00 (s, 2H), 7.36 (d, J = 2.8 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 8.8, 2.8 Hz, 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 = 11.6 Hz, 1H), 1.89 (d, J = 12.0 Hz, 1H), 1.82–1.72 (m, 2H), 1.41–1.26 (m, 2H), 1.25–1.11 (m, 2H).

[0362] Preparation of 22N-[(1S,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide hydrochloride JD-5303022

[0363]

[0364] Referring to the synthesis method of Example 1, replace compound JD-5303001d with JD-5303022a to prepare 22N-[(1S,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide hydrochloride JD-5303022 (60 mg, yield 74.8%, purity 98.32%), which is a white solid.

[0365] LC-MS[M+H] + = 403.2.

[0366] 1 1H NMR (300 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.07 (s, 2H), 7.36 (d, J = 2.91 Hz, 1H), 6.97 (d, J = 7.86 Hz, 1H), 6.79–6.72 (m, 1H), 6.60 (dd, J = 8.85, 2.91 Hz, 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).

[0367] Preparation of 23N-(1H-imidazol-5-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303023

[0368]

[0369] The compound JD-5303001d was replaced with JD-5303023a according to the synthesis method of Example 1 to prepare N-(1H-imidazol-5-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303023 (3.00 mg, 8.05 μmol, yield 2.11%, purity 99.7%) as a white solid.

[0370] LC-MS[M+H] + = 372.1.

[0371] 1 1H NMR: (400 MHz, DMSO-d6) 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 = 8.75 Hz, 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).

[0372] Example 24 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(1,3-thiazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303024

[0373]

[0374]

[0375] The compound JD-5303001d was replaced with JD-5303024a according to the synthesis method of Example 1 to prepare 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(1,3-thiazol-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.

[0376] LC-MS[M+H] + = 388.9.

[0377] 11H NMR: (400 MHz, DMSO-d6) δ ppm 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, 2.88 Hz, 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).

[0378] Example 25 Preparation of N-(isoxazol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303025

[0379]

[0380] Referring to the synthesis method of Example 1, replacing compound JD-5303001d with JD-5303025a, N-(isoxazol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303025 (3.62 mg, 9.72 μmol, yield 12.7%, purity 97.56%) was obtained as an off-white solid

[0381] LC-MS [M + H] + = 373.1.

[0382] 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3H) 3.83 (br d, J = 4.38 Hz, 2H) 4.15 - 4.21 (m, 2H) 5.18 (s, 2H) 6.68 (dd, J = 8.88, 2.88 Hz, 1H) 6.81 (dd, J = 5.13, 3.63 Hz, 2H) 7.35 (d, J = 2.75 Hz, 1H) 8.75 (d, J = 1.25 Hz, 1H) 8.98 (s, 1H) 10.28 (s, 1H).

[0383] Example 26 Preparation of N-(1-ethylhexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303026

[0384]

[0385] N-(Hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303002 (50.0 mg, 128 μmol, 1.00 eq) was added to a solution of DMF (2 mL), and K2CO3 (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) were added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by adding H2O (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 high performance liquid chromatography (column: Welch xextreme C18 150 * 25 mm * 5 um; mobile phase: [water (TFA)-ACN]; gradient: 13% - 33% B over 10 minutes) to obtain N-(1-ethylhexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide trifluoroacetate JD-5303026 (20.0 mg, 48.0 μmol, yield 37.3%, recovery 99.41%) as a yellow gum.

[0386] LC-MS [M + H] + = 417.2.

[0387] 1 H NMR: (400 MHz, DMSO-d6) δ = 1.22 (t, J = 7.25 Hz, 3H), 1.46 - 1.83 (m, 2H), 1.92 (brd, J = 11.51 Hz, 2H), 2.39 (s, 3H), 2.59 - 2.80 (m, 2H), 3.11 - 3.

[0388] 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]oxazin-4-carboxamide Hydrochloride JD-5303027

[0389]

[0390]

[0391] K2CO3 (33.9 mg, 245 μmol, 2.00 eq) and DIEA (31.7 mg, 245 μmol, 42.7 μL, 2.00 eq) were added to a solution of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-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) in DMF (1.00 mL), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding H2O (2.00 mL), and then 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 high performance liquid chromatography gave N-(1-Ethyl-4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide N-(1-Ethyl-4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303027 (27.8 mg, 64.0 μmol, yield 52.1%, purity 99.41%) as a colorless gum.

[0392] LC-MS [M+H] + = 436.2.

[0393] 11H NMR: (400 MHz, DMSO-d6) δ ppm 1.18 (t, J = 7.19 Hz, 3H) 3.06 - 3.17 (m, 2H) 3.32 (br d, J = 5.88 Hz, 1H) 3.67 (ddd, J = 10.01, 6.69, 3.31 Hz, 2H) 3.79 (br dd, J = 5.38, 3.00 Hz, 1H) 3.81 - 3.84 (m, 1H) 3.94 (br d, J = 10.88 Hz, 1H) 4.10 - 4.20 (m, 2H) 4.71 - 4.89 (m, 1H) 5.03 (s, 2H) 6.68 (dd, J = 8.94, 2.94 Hz, 1H) 6.81 (d, J = 8.88 Hz, 1H) 7.19 - 7.27 (m, 2H) 7.33 (d, J = 2.88 Hz, 1H) 7.37 - 7.46 (m, 2H) 7.52 (td, J = 7.66, 1.44 Hz, 1H).

[0394] Example 28 Preparation of 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(3-propylhexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303056

[0395]

[0396] Step 1 Preparation of 2-Methylpropan-2-yl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-3-propylhexahydropyridine-1-carboxylate JD-5303056-1

[0397]

[0398] Dissolve the intermediate JD-5303017-1 (30 mg, 0.057 mmol, 1.0 eq) of Example 17 in MeOH (1.0 mL), add Pd / C (5 mg) (10%), degas the suspension, and purify it with hydrogen three times. Stir the mixture under a hydrogen (15 psi) atmosphere at room temperature for 15 hours. Filter the mixture and concentrate the filtrate to obtain 2-Methylpropan-2-yl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-3-propylhexahydropyridine-1-carboxylate JD-5303056-1 (26 mg, crude) as a yellow solid.

[0399] LC-MS([M+H] + ) = 531.2.

[0400] Step 2 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(3-propylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303056

[0401]

[0402] Dissolve 2-methylpropyl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-3-propylpiperidine-1-carboxylate JD-5303056-1 (26 mg, 0.049 mmol, 1.0 eq) in DCM (2 mL), add Dioxane / HCl (0.25 mL, 0.98 mmol, 20.0 eq) (4N) to the mixture, and the reaction mixture is reacted at room temperature for 2 hours. The mixture is concentrated under reduced pressure to obtain a residue. The residue is quenched with sodium hydroxide solution (15%) (3 mL), then extracted with DCM (20 mL, 10 mL * 2). The collected organic phase is washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue is purified by prep-HPLC (column: Welch Ul C18 150 * 25 mm * 5 mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25% - 35%, 6 min) to obtain 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-N-(3-propylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303056 (10.1 mg, two-step yield 39.6%, purity 98.2%) as a yellow solid.

[0403] LC-MS([M+H] + ) = 431.2.

[0404] 11H NMR (400 MHz, CDCl3) 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), 1.98–1.80 (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).

[0405] Preparation of N-[3-(2-Hydroxyethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide Formate JD-5303057

[0406]

[0407] Step 1 Preparation of 3-(2-Hydroxyethyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic Acid 2-Methylpropan-2-yl Ester JD-5303057-1

[0408]

[0409] The intermediate JD-5303019-1 (60 mg, 0.107 mmol, 1.0 eq) of Example 19 was dissolved in tetrahydrofuran (2.0 mL), and 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 adding 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 obtain 3-(2-hydroxyethyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303057-1 (30 mg, yield 52.3%) as a yellow solid.

[0410] LCMS: 533.2 ([M+H] + ).

[0411] Preparation of N-[3-(2-hydroxyethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-53030:

[0412]

[0413] 3-(2-Hydroxyethyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303057 (30 mg, 0.056 mmol, 1.0 eq) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (128 mg, 1.12 mmol, 20.0 eq) was added. The reaction mixture was reacted at room temperature for 2 h. Then the reaction solution was adjusted to pH 11 with aqueous potassium carbonate solution and extracted with dichloromethane (10 mL, 5.0 mL * 2). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150 * 19 mm * 5 mm; mobile phase: [water (FA)-acetonitrile]; B%: 25%-40%, 6 min) to obtain N-[3-(2-hydroxyethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303057 (7.0 mg, yield 28.5%, purity 97.9%) as a yellow solid.

[0414] LC-MS([M+H] + ) = 433.2.

[0415] 1 H NMR (300 MHz, MeOD): δ 8.88 (s, 1H), 7.27 (d, J = 3.0 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.69 (dd, J = 9.0, 3.0 Hz, 1H), 5.20 (s, 2H), 4.26–4.12 (m, 3H), 3.92–3.82 (m, 1H), 3.71 (t, J = 6.6 Hz, 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).

[0416] Example 30 Preparation of 2-(3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridin-3-yl)acetamide 2,2,2-trifluoroacetate JD-5303058

[0417]

[0418] Step 1 Preparation of 2-methylpropan-2-yl 3-(formamidomethyl)-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303058-1

[0419]

[0420] The intermediate JD-5303019-1 (40 mg, 0.073 mmol, 1.0 eq) from Example 19 was dissolved in dichloromethane (2.0 mL), and 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. The reaction mixture was reacted at room temperature for 3 hours. The mixture was quenched by adding water (10 mL) at room temperature and then extracted with dichloromethane (20 mL, 10.0 mL * 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 obtain 2-methylpropan-2-yl 3-(formamidomethyl)-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303058-1 (30 mg, yield 75.3%) as a yellow solid.

[0421] LC-MS([M+H] + ) = 546.2.

[0422] Step 2 Preparation of 2-(3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}piperidin-3-yl)acetamide 2,2,2-trifluoroacetate JD-5303058

[0423]

[0424] 3-(Formamidomethyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303058 (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 h. Then the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150*19 mm*5 mm; mobile phase: [water (TFA)-acetonitrile]; B%: 25%-45%, 6 min) to obtain 2-(3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridin-3-yl)acetamide 2,2,2-trifluoroacetate JD-5303058 (16.2 mg, yield 39.5%, purity 99.04%) as a yellow solid.

[0425] LC-MS([M+H] + ) = 446.1.

[0426] 1 1H NMR (300 MHz, MeOD): δ 8.94 (s, 1H), 7.33 (d, J = 2.7 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.70 (dd, J = 9.0, 3.0 Hz, 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 = 12.9 Hz, 1H), 3.07–2.96 (m, 1H), 2.85 (d, J = 14.4 Hz, 1H), 2.53 (d, J = 14.4 Hz, 1H), 2.45 (s, 3H), 2.33 (d, J = 13.2 Hz, 1H), 2.06–1.69 (m, 3H).

[0427] Preparation of N-[3-(dimethylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303059

[0428]

[0429]

[0430] The intermediate JD-5303060-1 (19 mg, 0.044 mmol, 1.0 eq) of Example 32 was dissolved in THF (1 mL), and BH3-THF (0.22 mL, 0.22 mmol, 5.0 eq) was added to the mixture. The reaction mixture was reacted at room temperature for 15 hours. After adding HCl (1 mL) (IN) and MeOH (2 mL) to the reaction system, it was stirred at room temperature for 20 minutes. The mixture was quenched with saturated sodium carbonate solution (5 mL), then extracted with ethyl acetate (18 mL, 6 mL * 3). The collected organic phase was washed with brine (6 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150 * 25 mm * 5 mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25%-35%, 6 min) to obtain N-[3-(dimethylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303059 (product 2.3 mg, yield 11.9%, purity 91.2%) as a yellow solid.

[0431] LC-MS([M+H] + ) = 431.2.

[0432] 1 H NMR (300 MHz, MeOD) δ = 8.88 (s, 1H), 7.16–7.11 (m, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.68 (dd, J = 3.0, 9.0 Hz, 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).

[0433] Preparation of N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303060 in Example 32

[0434]

[0435] Step 1 Preparation of N-[3-(formylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303060-1

[0436]

[0437] Dissolve the product JD-5303008 (70 mg, 0.17 mmol, 1.0 eq) of Example 8 in DCM (2 mL), add 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) to the mixture, and the reaction mixture is reacted at room temperature for 15 h. The mixture is quenched with saturated potassium carbonate solution (5 mL), then extracted with dichloromethane (20 mL, 10 mL * 2). The collected organic phase is washed with brine (10 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a residue. The residue is purified by prep-TLC (dichloromethane / methanol = 8 / 1) to obtain N-[3-(formylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303060-1 (50 mg, yield 66.7%, purity 94%) as a yellow solid.

[0438] LC-MS([M+H] + ) = 431.3.

[0439] 1 H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.95 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 6.59 (dd, J = 2.8, 8.8 Hz, 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).

[0440] Preparation of N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303060

[0441]

[0442] Dissolve N-[3-(formylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303060-1 (50 mg, 0.116 mmol, 1.0 eq) in THF (1 mL), add BH3-THF (0.58 mL, 0.58 mmol, 5.0 eq) to the mixture, and react the reaction mixture at room temperature for 15 h. After adding HCl (2 mL) (1 N) and MeOH (4 mL) to the reaction system, stir at room temperature for 20 min. Quench the mixture with saturated sodium carbonate solution (10 mL), then extract with ethyl acetate (30 mL, 10 mL * 3). Wash the collected organic phase with brine (10 mL) and dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain a residue. Purify the residue by prep-HPLC (column: Welch Ul C18 150 * 25 mm * 5 mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25%-35%, 6 min) to obtain N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303060 (3.1 mg, yield 5.9%, purity 99.8%) as a yellow solid.

[0443] LC-MS([M+H] + ) = 417.2.

[0444] 1 H NMR (400 MHz, 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).

[0445] Preparation of Example 33 N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide Hydrochloride JD-5303028

[0446]

[0447] Step 1 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303028-2

[0448]

[0449] To a solution of DMF (10.0 mL), 6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-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. The reaction mixture was stirred at 25 °C for 12 h. 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 give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303028-2 (250 mg, 914 μmol, yield 15.1%) as a white solid.

[0450] LC-MS [M+H] + = 274.1.

[0451] Step 2 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303028-3

[0452]

[0453] 6-{[(2-Fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303028-2 (250 mg, 914 μmol, 1.00 eq) was dissolved in THF solution (2.50 mL). At 0 °C, BH3-Me2S (10 M, 457 μL, 5.00 eq) was added to the mixture. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with MeOH (5.00 mL) at 0 °C and then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to give 6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin JD-5303028-3 (60.0 mg, 231 μmol, yield 25.2%) as a brown oil.

[0454] LC-MS [M+H] + = 260.0.

[0455] Step 3 Preparation of 3,3-difluoro-4-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303028-4

[0456]

[0457] 6-{[(2-Fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin JD-5303028-3 (50.0 mg, 192 μmol, 1.00 eq) and 4-amino-3,3-difluoropyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303028b (257 mg, 1.16 mmol, 6.00 eq) were dissolved in DMF (1.00 mL), and then CDI (69.7 mg, 430 μmol, 2.00 eq) was added. The mixture was stirred at 65 °C for 12 h. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography (column: Welch xextreme C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 46%-76% B over 10 min) to give 3,3-difluoro-4-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303028-4 (85.0 mg, 167 μmol, yield 86.8%) as a gray solid.

[0458] LC-MS [M+Na] = 530.1.

[0459] 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

[0460]

[0461] To TFE (1.00 mL) was added 3,3-difluoro-4-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}tetrahydro-1-pyrrolecarboxylic acid 2-methyl-2-propanyl ester 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). The mixture was stirred at 25 °C for 2 h. Filtration and concentration under reduced pressure gave 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.

[0462] LC-MS [M+Na] = 408.0.

[0463] 1 H NMR: (400 MHz, 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, 2.88 Hz, 1H), 6.80 (d, J = 8.88 Hz, 1H), 7.20 - 7.29 (m, 2H), 7.35 (d, J = 2.88 Hz, 1H), 7.38 - 7.46 (m, 1H), 7.49 - 7.61 (m, 2H), 9.87 - 10.31 (m, 1H).

[0464] Example 34 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303029

[0465]

[0466] Step 1 Preparation of (2-Methyl-1,3-oxazolidin-5-yl)methanol JD-5303029b

[0467]

[0468] Methyl 2-methyl-1,3-oxazolidine-5-carboxylate JD-5303029a (1.00 g, 7.09 mmol, 1.00 eq) was added to a solution of THF (10.0 mL). LAH (2.50 M, 4.25 mL, 1.50 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by adding H2O (0.40 mL) at -10 °C, then diluted with 15% NaOH (0.40 mL) and H2O (1.20 mL), and stirred at 25 °C for 15 min. The mixture was filtered under reduced pressure and concentrated to obtain (2-Methyl-1,3-oxazolidin-5-yl)methanol JD-5303029b (1.00 g, crude) as a yellow oil.

[0469] Step 2 Preparation of 5-(Chloromethyl)-2-methyl-1,3-oxazolidine JD-5303029c

[0470]

[0471] (2-Methyl-1,3-oxazolidin-5-yl)methanol JD-5303029b (1.00 g, 8.84 mmol, 1.00 eq) was added to SOCl2 (2.10 g, 17.6 mmol, 1.28 mL, 2.00 eq) in THF (10.0 mL), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with Na2CO3 to adjust the pH = 8. Then the reaction solution was slowly quenched in warm water and extracted twice with ethyl acetate. The mixture was concentrated under reduced pressure to obtain 5-(Chloromethyl)-2-methyl-1,3-oxazolidine JD-5303029c (1.00 g, crude) as a yellow oil.

[0472] Step 3 Preparation of N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-thiazolidin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303029

[0473] Using the synthetic method of Example 33, replace compound JD-5303028b with compound JD-5303029c to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303029 (51.2 mg, 124 μmol, yield 79.6%) as a gray gum.

[0474] LC-MS[M+H] + = 411.0.

[0475] 1 1H NMR: (400 MHz, DMSO-d6) 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, 2.88 Hz, 1H), 6.79 (d, J = 8.88 Hz, 1H), 7.36 (d, J = 2.75 Hz, 1H), 7.64 (br d, J = 8.38 Hz, 1H), 7.82 (s, 1H), 10.18 - 10.55 (m, 2H).

[0476] 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

[0477]

[0478] Example 35 Using the method of Example 37, prepare 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%) as a white solid.

[0479] LC-MS[M+H] + = 407.0.

[0480] 11H NMR: (400 MHz, 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 = 12.01 Hz, 1H), 5.00 - 5.09 (m, 1H), 5.14 (d, J = 12.13 Hz, 1H), 6.46 - 6.55 (m, 2H), 6.63 (dd, J = 8.88, 2.75 Hz, 1H), 6.79 (d, J = 8.88 Hz, 1H), 7.43 (br d, J = 5.50 Hz, 1H), 7.80 (dd, J = 6.94, 1.69 Hz, 1H), 12.13 - 12.55 (m, 1H).

[0481] 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]oxazin-4-carboxamide hydrochloride JD-5303031

[0482]

[0483] Step 1 Preparation of 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303031b

[0484]

[0485] Add [2-(trifluoromethyl)pyridin-3-yl]methanol JD-5303031a (1.00 g, 5.65 mmol, 1.00 eq) to a solution of THF (10.0 mL), add SOCl2 (1.34 g, 11.2 mmol, 820 μL, 2.50 eq), and stir at 25 °C for 12 h. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.58) showed complete consumption of the starting material and formation of a new spot. The reaction was checked to be clean by thin layer chromatography. The reaction mixture was quenched with Na2CO3 to adjust the pH = 8. Then the reaction solution was slowly quenched in warm water and then extracted twice with ethyl acetate. Concentration under reduced pressure gave 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303031b (1.18 g, crude) as a brown oil.

[0486] 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]oxazin-4-carboxamide hydrochloride JD-5303031

[0487] Replace compound JD-5303031b with the synthetic method of Example 33 to prepare JD-5303028a to obtain N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303031 (4.80 mg, 11.3 μmol, yield 8.45%, purity 96.2%) as a white solid.

[0488] LC-MS [M+H] + = 459.1.

[0489] 1H NMR: (400 MHz, DMSO-d6) δ ppm 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, 2.94 Hz, 1H) 6.82 (d, J = 8.88 Hz, 1H) 7.38 (d, J = 2.88 Hz, 1H) 7.58 (d, J = 8.38 Hz, 1H) 7.78 (dd, J = 7.88, 4.63 Hz, 1H) 8.21 (d, J = 7.75 Hz, 1H) 8.72 (d, J = 4.00 Hz, 1H) 10.04 (br s, 2H).

[0490] 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]oxazin-4-carboxamide trifluoroacetate JD-5303032 in Example 37

[0491]

[0492] Step 1 Preparation of 3-(chloromethyl)-2-methoxypyridine JD-5303032b

[0493]

[0494] Dissolve (2-methoxypyridin-3-yl)methanol JD-5303032a (1.00 g, 7.19 mmol, 1.00 eq) in THF (10.0 mL), then add SOCl2 (1.71 g, 14.3 mmol, 1.04 mL, 2.00 eq), and stir 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 and the formation of a new spot. Quench the reaction mixture with Na2CO3 to adjust the pH to 8. Then slowly quench the reaction solution in warm water and extract twice with ethyl acetate. Concentrate under reduced pressure to obtain 3-(chloromethyl)-2-methoxypyridine JD-5303032b (600 mg, crude) as a yellow oil.

[0495] Step 2 Preparation of 2-methylpropan-2-yl 3,3-difluoro-4-{[(6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}pyrrolidine-1-carboxylate JD-5303032-1

[0496]

[0497] Example 32 Using the method of Example 33, replace JD-5303028a with 3-(chloromethyl)-2-methoxypyridine JD-5303032b to prepare 2-methylpropan-2-yl 3,3-difluoro-4-{[(6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}pyrrolidine-1-carboxylate JD-5303032-1 (70.0 mg, 134 μmol, yield 45.7%, purity 99.09%) as a white solid.

[0498] LC-MS [M+H] + = 521.2.

[0499] 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]oxazine-4-carboxamide trifluoroacetate JD-5303032

[0500] To a solution of TFE (2.00 mL) was added compound 3,3-difluoro-4-{[(6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-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), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. Purification by preparative high performance liquid chromatography (column: Welch xextreme C18 150*25 mm*5 μm; mobile phase: [water (TFA)-ACN]; gradient: 14%-44% B over 14 min) afforded N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methoxypyridin-3-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide trifluoroacetate JD-5303032 (24.0 mg, 56.5 μmol, yield 42.0%, purity 99.1%) as a white solid.

[0501] LC-MS [M+H] + = 421.1.

[0502] 1 1H NMR (400 MHz, DMSO-d6) 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, 2.94 Hz, 1H), 6.80 (d, J = 8.88 Hz, 1H), 7.01 (dd, J = 7.19, 5.07 Hz, 1H), 7.33 (d, J = 2.88 Hz, 1H), 7.46 (d, J = 8.38 Hz, 1H), 7.76 (dd, J = 7.25, 1.75 Hz, 1H), 8.14 (dd, J = 4.94, 1.81 Hz, 1H).

[0503] Preparation of Example 38 N-(Hexahydropyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide hydrochloride JD-5303033

[0504]

[0505] Prepared according to the synthesis method of Example 33 by replacing compound JD-5303028a with JD-5303033a, 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%) is an off-white solid.

[0506] LC-MS [M+H] + = 436.3.

[0507] 1 H NMR: (400 MHz, DMSO-d6) δ = 1.50 - 1.73 (m, 2H), 1.81 - 1.91 (m, 2H), 2.77 (br d, J = 1.63 Hz, 2H), 3.14 (br d, J = 12.13 Hz, 1H), 3.26 (br d, J = 11.51 Hz, 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, 2.88 Hz, 1H), 6.79 (d, J = 8.88 Hz, 1H), 7.03 (d, J = 7.38 Hz, 1H), 7.40 (d, J = 2.75 Hz, 1H), 7.55 - 7.61 (m, 1H), 7.69 - 7.81 (m, 3H), 8.71 - 8.94 (m, 2H).

[0508] 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

[0509]

[0510] Step 1 Preparation of 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303034b

[0511]

[0512] Add [2-(trifluoromethyl)pyridin-3-yl]methanol JD-5303034a (90.0 mg, 508 μmol, 1.00 eq) to THF (2.00 mL), add SOCl2 (120 mg, 1.02 mmol, 73.8 μL, 2.00 eq) at 0 °C, and stir 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 and formation of a new spot. Quench the reaction mixture with Na2CO3 to adjust the pH to 8. Then slowly quench the reaction solution in warm water and extract twice with ethyl acetate. Collect the organic phase and concentrate it under reduced pressure to obtain 3-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303034b (50.0 mg, crude product) as a yellow oil.

[0513] Step 2 Preparation of N-(piperidin-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303034

[0514] Refer to the synthesis method of Example 33, replace the compound JD-5303028a with JD-5303034b to prepare N-(piperidin-3-yl)-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303034 (7.36 mg, 11.46 μmol, yield 61.47%) as a white solid.

[0515] LC-MS [M+H] + = 437.3.

[0516] 11H NMR: (400 MHz, DMSO-d6) δ = 1.50 - 1.61 (m, 1H), 1.63 - 1.74 (m, 1H), 1.86 (br d, J = 11.01 Hz, 2H), 2.78 (q, J = 9.30 Hz, 2H), 3.12 (br d, J = 12.13 Hz, 1H), 3.24 (br d, J = 9.88 Hz, 1H), 3.70 - 3.78 (m, 2H), 3.87 - 3.97 (m, 1H), 4.13 (t, J = 4.31 Hz, 2H), 5.18 (s, 2H), 6.62 (dd, J = 8.88, 3.00 Hz, 1H), 6.79 (d, J = 8.88 Hz, 1H), 7.09 (d, J = 7.50 Hz, 1H), 7.43 (d, J = 2.88 Hz, 1H), 7.78 (dd, J = 7.88, 4.75 Hz, 1H), 8.20 (d, J = 7.75 Hz, 1H), 8.72 (d, J = 4.38 Hz, 1H), 8.93 (br d, J = 9.26 Hz, 1H), 9.14 (br d, J = 7.00 Hz, 1H).

[0517] 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

[0518]

[0519] According to the synthesis method of Example 33, replacing compound JD-5303028a with JD-5303035a, 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%) was obtained as a white solid.

[0520] LC-MS [M + H] + = 404.1.

[0521] 1 1H NMR: (400 MHz, DMSO-d6)

[0522] δ = 1.52 - 1.72 (m, 2H), 1.81 - 1.92 (m, 2H), 2.79 (br t, J = 9.76 Hz, 2H), 3.11 (br d, J = 12.01 Hz, 1H), 3.25 (br d, J = 10.51 Hz, 1H), 3.73 (dt, J = 9.22, 4.46 Hz, 2H), 3.87 - 3.98 (m, 1H), 4.13 (t, J = 4.32 Hz, 2H), 4.99 (s, 2H), 6.62 (dd, J = 8.88, 2.88 Hz, 1H), 6.78 (d, J = 8.88 Hz, 1H), 7.09 - 7.22 (m, 3H), 7.39 (d, J = 2.88 Hz, 1H), 7.46 - 7.57 (m, 1H), 8.89 - 9.27 (m, 2H).

[0523] Example 41 Preparation of 6-{[(2,3-difluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide hydrochloride JD-5303036

[0524]

[0525] Step 1 Preparation of 3-(chloromethyl)-1,2-difluorobenzene JD-5303036b

[0526]

[0527] (2,3-Difluorophenyl)methanol JD-5303036a (1.50 g, 10.4 mmol, 1.17 mL, 1.00 eq) was added to a solution of THF (15 mL). SOCl2 (2.48 g, 20.8 mmol, 1.51 mL, 2.00 eq) was added at 25 °C, and 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 and the formation of a new spot. The reaction mixture was concentrated under reduced pressure to give 3-(chloromethyl)-1,2-difluorobenzene JD-5303036b (1.30 g, crude) as a brown solid.

[0528] Step 2 Preparation of 6-{[(2,3-difluorophenyl)methyl]oxy}-N-(hexahydropyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303036

[0529] Prepared 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 by replacing compound JD-5303028a with JD-5303036b according to the synthesis method of Example 33.

[0530] LC-MS [M+H] + = 404.2.

[0531] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 - 1.71 (m, 2H) 1.86 (br d, J = 6.75 Hz, 2H) 2.77 (br t, J = 10.88 Hz, 2H) 3.15 (br d, J = 12.51 Hz, 1H) 3.25 - 3.29 (m, 1H) 3.71 (br d, J = 2.75 Hz, 2H) 3.85 - 3.97 (m, 1H) 4.13 (t, J = 4.50 Hz, 2H) 5.07 (s, 2H) 6.63 (dd, J = 8.88, 3.00 Hz, 1H) 6.78 (d, J = 8.88 Hz, 1H) 7.04 (br d, J = 7.38 Hz, 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).

[0532] Example 42 Preparation of 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

[0533]

[0534] Prepared 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 by replacing compound JD-5303028a with JD-5303037a according to the synthesis method of Example 33.

[0535] LC-MS [M+H] + = 400.1.

[0536] 1 1H NMR: (400 MHz, DMSO-d6) δ = 8.34 - 8.70 (m, 2H), 7.26 - 7.47 (m, 2H), 6.89 - 7.13 (m, 3H), 6.77 (d, J = 8.88 Hz, 1H), 6.61 (dd, J = 8.88, 2.88 Hz, 1H), 4.86 - 5.07 (m, 2H), 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).

[0537] 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

[0538]

[0539] Prepared by replacing compound JD-5303028b with JD-5303002a according to the synthetic method of Reference Example 33, 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) was a yellow gum.

[0540] LC-MS [M+H] + = 386.2.

[0541] 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 1.47 - 1.73 (m, 2H) 1.86 (br d, J = 10.13 Hz, 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, 2.88 Hz, 1H) 6.77 (d, J = 8.88 Hz, 1H) 7.08 (d, J = 7.50 Hz, 1H) 7.20 - 7.29 (m, 2H) 7.37 - 7.45 (m, 2H) 7.49 - 7.56 (m, 1H) 8.92 (br d, J = 9.25 Hz, 1H) 9.13 (br d, J = 7.50 Hz, 1H).

[0542] Preparation of 44N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(4-methyl-1,3-thiazol-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide trifluoromethanesulfonate JD-5303039

[0543]

[0544] Step 1 Preparation of 1-(4-methyl-1,3-thiazol-5-yl)ethan-1-ol JD-5303039b

[0545]

[0546] 4-Methyl-1,3-thiazol-5-carbaldehyde JD-5303039a (2.50 g, 19.6 mmol, 1.00 eq) was added to MeMgBr (3 M, 7.86 mL, 1.20 eq) in THF (25 mL) at 0 °C under a N2 atmosphere and stirred at 0 - 25 °C for 16 h. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.42) indicated complete consumption of the starting material and formation of a new spot. The reaction was checked to be complete by thin layer chromatography. The reaction mixture was quenched with saturated NH4Cl (20 mL) solution at 0 °C, then diluted with H2O (40 mL) and extracted with ethyl acetate (60 mL, 30 mL * 2). The organic layer was collected and concentrated under reduced pressure to give 1-(4-methyl-1,3-thiazol-5-yl)ethan-1-ol JD-5303039b (2.65 g, crude) as a yellow oil.

[0547] Step 2 Preparation of 5-(1-bromoethyl)-4-methyl-1,3-thiazole JD-5303039c

[0548]

[0549] 1-(4-Methyl-1,3-thiazol-5-yl)ethan-1-ol JD-5303039b (1.00 g, 6.98 mmol, 1.00 eq) was added to PBr3 (945 mg, 3.49 mmol, 0.50 eq) in THF (10 mL) and stirred at 0 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 5-(1-bromoethyl)-4-methyl-1,3-thiazole JD-5303039c (1.40 g, crude) as an off-white solid. The reaction solution was used for the next step without further purification.

[0550] Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(4-methyl-1,3-thiazol-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide trifluoromethanesulfonate JD-5303039

[0551] Refer to Example 33, replace compound JD-5303028a with JD-5303039c to prepare N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[1-(4-methyl-1,3-thiazol-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide trifluoromethanesulfonate JD-5303039 (0.12 g, 376 μmol, yield 5.65%, purity 91.0%) as a white solid.

[0552] LC-MS [M+H] + = 425.1.

[0553] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J = 6.25 Hz, 3H) 2.36 (d, J = 2.00 Hz, 3H) 3.29 - 3.47 (m, 2H) 3.68 - 3.77 (m, 4H) 4.10 - 4.14 (m, 2H) 4.69 - 4.90 (m, 1H) 5.64 (q, J = 6.25 Hz, 1H) 6.57 (dd, J = 8.88, 2.25 Hz, 1H) 6.74 (d, J = 8.88 Hz, 1H) 7.28 (dd, J = 4.57, 2.94 Hz, 1H) 7.39 (br t, J = 8.13 Hz, 1H) 8.89 (s, 1H) 9.39 - 9.73 (m, 2H).

[0554] 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]oxazin-4-carboxamide hydrochloride JD-5303040

[0555]

[0556] Step 1 Preparation of 1-(2-fluorophenyl)ethan-1-ol JD-5303040b

[0557]

[0558] Dissolve 2-fluorobenzene-1-carbaldehyde JD-5303040a (2.50 g, 20.1 mmol, 2.11 mL, 1.00 eq) in THF (25 mL). Under a nitrogen atmosphere at 0 °C, add MeMgBr (3 M, 8.06 mL, 1.20 eq), and stir at 0 - 25 °C for 16 hours. Quench the reaction mixture with NH4Cl (aq, 30 mL) at 0 °C, then dilute with H2O (50 mL), extract with ethyl acetate (60 mL, 30 mL * 2), collect the organic layer, wash with NaCl (aq, 20 mL), and concentrate under reduced pressure to obtain 1-(2-fluorophenyl)ethan-1-ol JD-5303040b (2.30 g, crude product) as a yellow oil.

[0559] Step 2 Preparation of 1-(1-chloroethyl)-2-fluorobenzene JD-5303040c

[0560]

[0561] Dissolve 1-(2-fluorophenyl)ethan-1-ol JD-5303040b (1.20 g, 8.56 mmol, 1.00 eq) in THF (12 mL), add SOCl2 (3.06 g, 25.6 mmol, 1.87 mL, 3.00 eq), and stir the reaction mixture at 25 °C for 16 hours. Quench the reaction mixture with Na2CO3 to adjust the pH = 8. Then slowly quench the reaction solution in warm water, and then extract twice with ethyl acetate. Concentrate under reduced pressure to obtain 1-(1-chloroethyl)-2-fluorobenzene JD-5303040c (1.28 g, crude product) as a yellow oil.

[0562] 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]oxazin-4-carboxamide JD-5303040

[0563] Refer to the synthesis method of Example 33, replace compound JD-5303028a 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]oxazin-4-carboxamide JD-5303040 (7.33 mg, 16.70 μmol, yield 29.03%, purity 96%) as a yellow oil.

[0564] LC-MS [M + H] + = 422.2.

[0565] 11H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J = 6.25 Hz, 3H) 2.36 (d, J = 2.00 Hz, 3H) 3.29 - 3.47 (m, 2H) 3.68 - 3.77 (m, 4H) 4.10 - 4.14 (m, 2H) 4.69 - 4.90 (m, 1H) 5.64 (q, J = 6.25 Hz, 1H) 6.57 (dd, J = 8.88, 2.25 Hz, 1H) 6.74 (d, J = 8.88 Hz, 1H) 7.28 (dd, J = 4.57, 2.94 Hz, 1H) 7.39 (br t, J = 8.13 Hz, 1H) 8.89 (s, 1H) 9.39 - 9.73 (m, 2H).

[0566] 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

[0567]

[0568]

[0569] Prepared by replacing compound JD-5303028b with JD-5303041a according to the synthetic method of Reference Example 33, 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%) was a yellow solid.

[0570] LC-MS [M+H] + = 400.1.

[0571] 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 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, 3.00 Hz, 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, 1.50 Hz, 1H) 7.94 (br s, 3H).

[0572] Example 47 Preparation of 6-(Benzyloxy)-N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303042

[0573]

[0574] Prepared 6-(Benzyloxy)-N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303042 (7.50 mg, 19.2 μmol, yield 23.5%, purity 97.13%) as a white solid by replacing compound JD-5303028a with JD-5303042a according to the synthetic method of Reference Example 33.

[0575] LC-MS [M+H] + = 390.0.

[0576] 1 1H NMR: (400 MHz, DMSO-d6) δ = 2.78 (br dd, J = 11.57, 8.44 Hz, 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, 8.04 Hz, 1H), 4.98 (s, 2H), 6.61 (dd, J = 8.94, 2.81 Hz, 1H), 6.77 (d, J = 8.88 Hz, 1H), 7.09 (br d, J = 8.50 Hz, 1H), 7.29 - 7.47 (m, 6H).

[0577] 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]oxazin-4-carboxamide Hydrochloride JD-5303043

[0578]

[0579] Step 1 Preparation of [2-(Trifluoromethyl)pyridin-4-yl]methanol JD-5303043b

[0580]

[0581] BH3-THF (1 M, 10.4 mL, 2.00 eq) was added dropwise to a solution of 2-(trifluoromethyl)pyridine-4-carboxylic acid JD-5303043a (1.00 g, 5.23 mmol, 1.00 eq) in THF (10 mL) at 0 °C, and the mixture was stirred at 75 °C for 2 h. The reaction mixture was added to MeOH (50 mL) and quenched at 0 °C under N2. The mixture was stirred at 25 °C for 0.5 h and concentrated under reduced pressure to obtain [2-(trifluoromethyl)pyridin-4-yl]methanol JD-5303043b (1.00 g, crude) as a brown oil.

[0582] LC-MS [M+H] + = 178.0.

[0583] Step 2 Preparation of 4-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303043c

[0584]

[0585] [2-(Trifluoromethyl)pyridin-4-yl]methanol JD-5303043b (1.00 g, 5.65 mmol, 1.00 eq) was added to a solution of THF (10 mL), and SOCl2 (1.68 g, 14.1 mmol, 1.03 mL, 2.50 eq) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with aq Na2CO3 to adjust the pH to 8, and then the reaction solution was slowly quenched in warm water and extracted twice with ethyl acetate. The extract was concentrated under reduced pressure to obtain 4-(chloromethyl)-2-(trifluoromethyl)pyridine JD-5303043c (0.6 g, crude) as a brown solid.

[0586] 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]oxazin-4-carboxamide hydrochloride JD-5303043

[0587] Referring to the synthetic 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]oxazin-4-carboxamide hydrochloride JD-5303043 (0.024 g, 51.7 μmol, yield 96.4%, purity 99.0%) as a white solid.

[0588] LC-MS [M+H] + = 459.2.

[0589] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 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, 2.94 Hz, 1H) 6.83 (d, J = 8.88 Hz, 1H) 7.33 - 7.52 (m, 2H) 7.74 (d, J = 4.88 Hz, 1H) 7.91 (s, 1H) 8.77 (d, J = 5.00 Hz, 1H) 9.24 - 10.08 (m, 2H).

[0590] Example 49 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-oxazolidin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303044

[0591]

[0592] Step 1 Preparation of (2-methyl-1,3-oxazolidin-5-yl)methanol JD-5303044b

[0593]

[0594] Methyl 2-methyl-1,3-oxazolidine-5-carboxylate JD-5303044a (1.00 g, 7.09 mmol, 1.00 eq) was added to a solution of THF (10.0 mL). LAH (2.50 M, 4.25 mL, 1.50 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched by adding H2O (0.40 mL) at -10 °C, then diluted with 15% NaOH (0.40 mL) and H2O (1.20 mL), stirred at 25 °C for 15 min, and concentrated by vacuum filtration to obtain (2-methyl-1,3-oxazolidin-5-yl)methanol JD-5303044b (1.00 g, crude) as a yellow oil.

[0595] Step 2 Preparation of 5-(chloromethyl)-2-methyl-1,3-oxazolidine JD-5303044c

[0596]

[0597] (2-Methyl-1,3-oxazolidin-5-yl)methanol JD-5303044b (1.00 g, 8.84 mmol, 1.00 eq) was added to SOCl2 (2.10 g, 17.6 mmol, 1.28 mL, 2.00 eq) in THF (10.0 mL), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with Na2CO3 to adjust the pH to 8. Then the reaction solution was slowly quenched in warm water and extracted twice with ethyl acetate. The residue was concentrated under reduced pressure to obtain 5-(chloromethyl)-2-methyl-1,3-oxazolidine JD-5303044c (1.00 g, crude) as a yellow oil.

[0598] Step 3 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-oxazolidin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303044

[0599] N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(2-methyl-1,3-oxazolidin-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303044 (22.0 mg, 55.7 μmol, yield 91.95%) was prepared as a yellow solid by replacing JD-5303028a with JD-5303044c according to the synthesis method of Example 33.

[0600] LC-MS [M+H] + = 395.0.

[0601] 1 1H NMR: (400 MHz, DMSO-d6) 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 = 9.26 Hz, 1H), 4.97 (s, 2H), 6.65 (dd, J = 8.88, 2.88 Hz, 1H), 6.79 (d, J = 8.88 Hz, 1H), 7.13 (s, 1H), 7.34 (d, J = 2.88 Hz, 1H), 7.59 (d, J = 8.38 Hz, 1H), 9.95 - 10.38 (m, 2H).

[0602] Preparation of 3-[(4-{[(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-6-yl)oxy]benzene-1-carboxamide Hydrochloride JD-5303045, Example 50

[0603]

[0604] 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 Methyl Ester JD-5303045-1 (270 mg, 700 μmol, 88.0%) was obtained as a yellow gum by replacing compound JD-5303047a with JD-5303045a according to the synthetic method of Reference Example 52.

[0605] LC-MS [385+Na] + = 408.

[0606] 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]oxazepin-6-yl)oxy]benzoic Acid JD-5303045-2

[0607]

[0608] 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]oxazin-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). NaOH (17.9 mg, 449 μmol, 2.00 eq) was added to the mixture, and the reaction mixture was stirred at 25 °C for 16 h. 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 = 4, and then extracted with ethyl acetate (4.00 mL, 2.00 mL * 2). The solvent was evaporated under reduced pressure to obtain 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]oxazin-6-yl)oxy]benzoic acid JD-5303045-2 (100 mg, 192 μmol, yield 85.5%) as a white solid.

[0609] LC-MS[519-99] + = 420

[0610] Step 2 Preparation of 4-[({6-[(3-formamidophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl}carbonyl)amino]-3,3-difluorotetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303045-3

[0611]

[0612] Dissolve 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]oxazin-6-yl)oxy]benzoic acid JD-5303045 (50.0 mg, 96.2 μmol, 1.00 eq) in dioxane (2.00 mL). Add NH4HCO3 (9.13 mg, 115 μmol, 1.26 eq), Boc2O (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) to the reaction mixture. Stir the reaction mixture at 25 °C for 16 h. Quench the reaction mixture by adding H2O (2.00 mL), and then extract with EtOAc (4.00 mL, 2.00 mL * 2). Concentrate the combined organic layers under reduced pressure to obtain a residue. Purify the residue by preparative high performance liquid chromatography (column: CD04-Welch uultimate C18 150 * 25 * 7 μm; mobile phase: [water (TFA)-ACN]; gradient: 36% - 66% B over 10 minutes) to obtain 2-methylpropan-2-yl 4-[({6-[(3-formamidophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl}carbonyl)amino]-3,3-difluorotetrahydro-1H-pyrrole-1-carboxylate JD-5303045-3 (20.0 mg, 38.5 μmol, yield 40.08%) as a white solid.

[0613] LC-MS[518-99] + = 419

[0614] Step 3 Preparation of 3-[(4-{[(4,4-difluorotetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)oxy]benzene-1-carboxamide hydrochloride JD-5303045

[0615]

[0616] 4-[({6-[(3-Carbamoylphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl}carbonyl)amino]-3,3-difluorotetrahydropyrrole-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303045 (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. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain 3-[(4-{[(4,4-difluorotetrahydro-1H-pyrrol-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazin-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.

[0617] LC-MS [418 + H] + = 419.

[0618] 1 1H NMR: (400 MHz, DMSO-d6) 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, 2.75 Hz, 1H), 6.92 (d, J = 8.76 Hz, 1H), 7.11 (dd, J = 8.07, 2.31 Hz, 1H), 7.35 - 7.44 (m, 3H), 7.45 - 7.54 (m, 2H), 7.58 (d, J = 7.75 Hz, 1H), 7.98 (s, 1H) 9.39 - 9.75 (m, 2H).

[0619] Example 51 Preparation of N-(Hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303046

[0620]

[0621] Step 1 Preparation of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-2

[0622]

[0623] 6-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-1 (0.9 g, 5.0 mmol, 1.0 eq) was dissolved in Dioxane (10.0 mL), and Boc2O (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 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 30 / 1) to obtain 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-2 (1.2 g, yield 85.7%, purity 94%) as a white solid.

[0624] LC-MS([M+H2O] + ) = 298.1.

[0625] 1 1H NMR (300 MHz, CDCl3) δ = 8.79 (s, 1H), 7.88 (dd, J = 9.0, 2.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.33 (t, J = 4.5 Hz, 2H), 3.91 (t, J = 4.8 Hz, 2H), 1.58 (s, 9H).

[0626] Step 2 Preparation of 6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-3

[0627]

[0628] 6-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester 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 h. The mixture was filtered, and the filtrate was concentrated to obtain 6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-3 (1.1 g, crude product) as a white solid.

[0629] LC-MS([M+H] + ) = 251.1.

[0630] 1 1H NMR (400 MHz, DMSO-d6)

[0631] δ = 7.12 (s, 1H), 6.52 (d, J = 8.8, 1H), 6.21 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 4.60 (s, 2H), 4.05 (t, J = 4.4 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 1.48 (s, 9H).

[0632] Step 3 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-4

[0633]

[0634] Dissolve 6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-3 (0.9 g, 3.6 mmol, 1.0 eq) in THF (10.0 mL), add 5-(chloromethyl)-4-methyl-1,3-thiazole JD-5303001c (0.58 g, 4.0 mmol, 1.1 eq) and TEA (0.73 g, 7.2 mmol, 2.0 eq), and react the reaction mixture at 60 °C for 3 hours. Quench the mixture by adding water (20 mL) at room temperature, and then extract with ethyl acetate (40 mL, 20.0 mL * 2). Wash the collected organic phase with water (45 mL, 15.0 mL * 3) and brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a residue. Purify the residue by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-4 (0.75 g, two-step yield 59.2%, purity 92%) as a yellow solid.

[0635] LC-MS ([M+H] + ) = 362.5.

[0636] 11H NMR (400 MHz, CDCl3) δ = 8.61 (s, 1H), 7.36 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.34 (dd, J = 8.8, 2.8 Hz, 1H), 4.40 (s, 2H), 4.17 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.8 Hz, 2H), 2.46 (s, 3H), 1.53 (s, 9H).

[0637] Step 4 Preparation of 6-[5-(4-Methyl-1,3-thiazol-5-yl)-3-oxo-1-phenyl-4-aza-2-oxapent-4-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-5

[0638]

[0639] Dissolve 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-4 (150 mg, 0.42 mmol, 1.0 eq) in THF (3.0 mL). Cool to 0 °C and add NaH (60%) (33 mg, 0.83 mmol, 2.0 eq). After the reaction mixture has reacted at 0 °C for 0.5 h, add CbzCl (127 mg, 0.75 mmol, 1.8 eq). Then warm the mixture to room temperature and stir for 11.5 h. Quench the mixture at room temperature by adding saturated aqueous ammonium chloride solution (10 mL), and then extract with ethyl acetate (30 mL, 10.0 mL * 3). Wash the collected organic phase with brine (10 mL) and dry over anhydrous sodium sulfate, then concentrate under reduced pressure to obtain a residue. Purify the residue by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain 6-[5-(4-Methyl-1,3-thiazol-5-yl)-3-oxo-1-phenyl-4-aza-2-oxapent-4-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-5 (180 mg, yield 87.5%, purity 92%) as a yellow solid.

[0640] LC-MS ([M+H] + ) = 496.5.

[0641] 11H NMR (300 MHz, CDCl3) δ = 8.60 (s, 1H), 7.82–7.62 (m, 1H), 7.29 (s, 5H), 6.77 (d, J = 8.7 Hz, 1H), 6.58 (s, 1H), 5.16 (s, 2H), 4.92 (s, 2H), 4.24 (t, J = 4.2 Hz, 2H), 3.84 (t, J = 4.5 Hz, 2H), 2.17 (s, 3H), 1.49 (s, 9H).

[0642] Step 5 Preparation of Benzyl [(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)[(4-methyl-1,3-thiazol-5-yl)methyl]amino]methanecarboxylate JD-5303046-6

[0643]

[0644] Dissolve 6-[5-(4-methyl-1,3-thiazol-5-yl)-3-oxo-1-phenyl-4-aza-2-oxopent-4-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-5 (180 mg, 0.36 mmol, 1.0 eq) in DCM (3 mL), add Dioxane / HCl (0.91 ml, 3.63 mmol, 10.0 eq) (4N) to the mixture, and the reaction mixture is reacted at room temperature for 12 h. The mixture is concentrated under reduced pressure to obtain a residue. The residue is quenched with sodium hydroxide solution (15%) (3 mL), then extracted with DCM (20 mL, 10 mL * 2). The collected organic phase is washed with brine (10 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain Benzyl [(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)[(4-methyl-1,3-thiazol-5-yl)methyl]amino]methanecarboxylate JD-5303046-6 (125 mg, crude) as a yellow solid.

[0645] LC-MS ([M+H] + ) = 396.6.

[0646] 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]oxazin-6-yl)[(4-methyl-1,3-thiazol-5-yl)methyl]amino]methanecarboxylate JD-5303046-7

[0647]

[0648] Dissolve benzyl [(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)[(4-methyl-1,3-thiazol-5-yl)methyl]amino]methanecarboxylate JD-5303046-6 (125 mg, 0.32 mmol, 1.0 eq) and TEA (96 mg, 0.95 mmol, 3.0 eq) in DCM (1.0 mL), add (COCl2)3 (47 mg, 0.16 mmol, 0.5 eq), and react the reaction mixture at room temperature for 0.5 h. Then dissolve 2-methylpropyl 3-aminopiperidine-1-carboxylate JD-5303002a (76 mg, 0.38 mmol, 1.2 eq) in DCM (0.5 mL), add it to the mixture, and stir at room temperature for 12 h. Quench the reaction system with water (5 mL), extract with DCM (20 mL, 10 mL×2), wash the collected organic phase with brine (10 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain yellow solid of benzyl [(4-{[(1-{[(2-methylpropyl)oxy]carbonyl}piperidin-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)[(4-methyl-1,3-thiazol-5-yl)methyl]amino]methanecarboxylate JD-5303046-7 (300 mg, crude).

[0649] LC-MS([M+H] + ) = 622.4.

[0650] Step 7 Preparation of N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303046

[0651]

[0652] Dissolve benzyl [(4-{[(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)amino]carbonyl}-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)[(4-methyl-1,3-thiazol-5-yl)methyl]amino]methanecarboxylate JD-5303046-7 (300 mg, 0.48 mmol, 1.0 eq) in DCM (3 mL), add TMSI (483 mg, 2.42 mmol, 5.0 eq) to the mixture, and the reaction mixture is reacted at room temperature for 12 h. The mixture is quenched with water (3 mL), and then impurities are extracted with DCM (20 mL, 10 mL * 2). The aqueous phase is adjusted to pH 9 with sodium hydroxide (3 mL, 15%) solution, and then extracted with DCM (20 mL, 10 mL * 2). The collected organic phase is washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue is purified by prep-HPLC (column: Welch Ul C18 150 * 25 mm * 5 mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 15%-25%, 6 min) to obtain the yellow solid of N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303046 (29.9 mg, three-step yield 18.3%, purity 97.9%).

[0653] LC-MS([M - 1.34FA + H] + ) = 388.3.

[0654] 1 H NMR (300 MHz, DMSO-d6) δ = 8.81 (s, 1H), 8.31 (brs, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 6.27 (dd, J = 8.7, 2.4 Hz, 1H), 5.82 (s, 1H), 4.29 (s, 2H), 4.05 (t, J = 4.2 Hz, 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).

[0655] Preparation of 52N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide trifluoroacetate JD-5303047

[0656]

[0657] Step 1 Preparation of 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303047-1

[0658]

[0659] 6-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303001-1 (13.0 g, 60.7 mmol, 1.00 eq) was added to Boc2O (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) in THF (130 mL), and the mixture was 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 (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 0 / 1) to obtain 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303047-1 (15.0 g, 47.7 mmol, 78.6% yield) as a white solid.

[0660] LC-MS [313-55]+ = 258.

[0661] Step 2 Preparation of 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303047-2

[0662]

[0663] To a solution of 6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester 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) was added Cs2CO3 (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 h. The reaction mixture was quenched by adding H2O (10.0 mL), 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 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303047-2 (60.0 mg, 167 μmol, yield 16.8%) as a yellow oil.

[0664] LC-MS[357-55] + = 302.

[0665] Step 3 Preparation of 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303047-3

[0666]

[0667] 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303047-2 (60.0 mg, 167 μmol, 1.00 eq) was added to a solution of TFE (1.00 mL), and TMSCl (36.4 mg, 335 μmol, 42.6 μL, 2.00 eq) was added. The mixture was stirred at 25 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to obtain 6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303047-3 (40.0 mg, crude product) as a colorless oil.

[0668] LC-MS[257+H] + = 258

[0669] Step 4 Preparation of 2-methylpropan-2-yl 3,3-difluoro-4-([(6-((3-methoxyphenyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino)pyrrolidine-1-carboxylate JD-5303047-4

[0670]

[0671] To a solution of 6-((3-methoxyphenyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303047-3 (40.0 mg, 155 μmol, 1.00 eq) and 2-methylpropan-2-yl 4-amino-3,3-difluoropyrrolidine-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), and the mixture was stirred at 65 °C for 12 h. LC-MS showed that the starting materials were completely consumed and a main peak with the required mass was detected. The reaction mixture was quenched by adding 10.0 mL of H2O, then extracted with 20.0 mL of EtOAc, and the organic phase was concentrated under reduced pressure to obtain the crude product. Purification by high performance liquid chromatography (column: CD01 - Phenomenex luna C18 150*25*10um; mobile phase: [water (FA)-ACN]; gradient: 54% - 84% B over 11 min) gave 2-methylpropan-2-yl 3,3-difluoro-4-([(6-((3-methoxyphenyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino)pyrrolidine-1-carboxylate JD-5303047-4 (20.0 mg, 39.5 μmol, yield 25.4%) as a white solid.

[0672] LC-MS [505+Na] + = 528.

[0673] Step 5 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-((3-methoxyphenyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide trifluoroacetate JD-5303047

[0674]

[0675] 3,3-Difluoro-4-[({6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl}carbonyl)amino]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303047 (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 h. N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-methoxyphenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide trifluoroacetate JD-5303047 (14.1 mg, 34.9 μmol, yield 88.2%, purity 99.89%) was obtained as a white solid by high performance liquid chromatography (column: CD01 - Phenomenex luna C18 150*25*10um; mobile phase: [water (TFA)-ACN]; gradient: 21% - 51% B over 10 min).

[0676] LC-MS [405 + H] + = 406.

[0677] 1H NMR: (400 MHz, DMSO-d6) 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 = 8.76 Hz, 1H), 7.23 (t, J = 8.13 Hz, 1H), 7.37 - 7.47 (m, 2H), 9.33 (br s, 2H).

[0678] Example 53 Preparation of N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-[(3-fluorophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303048

[0679]

[0680] Prepared 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 by replacing compound JD-5303047a with JD-5303048a according to the synthetic method of Example 52.

[0681] LCMS[393+H] + = 394.

[0682] 1 H NMR (400 MHz, DMSO-d6) 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, 2.81 Hz, 1H) 6.76 - 6.83 (m, 2H) 6.86 - 6.96 (m, 2H) 7.31 - 7.41 (m, 1H) 7.48 (d, J = 2.88 Hz, 1H) 7.60 (br d, J = 8.25 Hz, 1H) 9.87 (br s, 2H).

[0683] Example 54 Preparation of N-(hexahydropyridin-3-yl)-6-{[1-(4-methyl-1,3-thiazol-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303055

[0684]

[0685] Prepared N-(hexahydropyridin-3-yl)-6-{[1-(4-methyl-1,3-thiazol-5-yl)ethyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303055 (25.2 mg, 56.4 μmol, yield 94.5%, purity 98%, hydrochloride) as a white solid by replacing JD-5303028a with JD-5303039c and replacing JD-5303028b with JD-5303002a according to the synthetic method of Example 33.

[0686] LC-MS[M+H] + = 403.1.

[0687] 11H NMR (400 MHz, methanol-d4) δ 1.59 - 1.65 (m, 1H), 1.66 (d, J = 6.38 Hz, 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, 3.80 Hz, 1H), 3.67 - 3.81 (m, 2H), 3.99 (tt, J = 10.69, 3.94 Hz, 1H), 4.11 - 4.22 (m, 2H), 5.65 (q, J = 6.30 Hz, 1H), 6.60 (ddd, J = 8.94, 2.81, 0.88 Hz, 1H), 6.76 (d, J = 9.01 Hz, 1H), 7.17 - 7.23 (m, 1H), 8.96 (s, 1H).

[0688] Preparation of N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide Hydrochloride JD-5303049, Example 55

[0689]

[0690] 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]oxazin-3-one JD-5303049-2

[0691]

[0692] To a solution of 6-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-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 PdCl2(dppf) (377 mg, 516 μmol, 0.05 eq), and the mixture was stirred at 100 °C under N2 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]oxazin-3-one JD-5303049-2 (3.00 g, crude) as a black solid.

[0693] LC-MS [M] = 289.8.

[0694] Step 2 Preparation of 6-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303049-3

[0695]

[0696] 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one 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 controlled at 0 °C. Then, 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 h. The reaction mixture was quenched by adding Na2CO3(aq., 16.0 mL) at 0 °C, and then extracted with EtOAc (32.0 mL, 16.0 mL * 2). The residue was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 - 2 / 1) to give 6-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303049-3 (650 mg, 3.63 mmol, yield 69.9%) as a white solid.

[0697] LC-MS [M + H]+ = 180.0。

[0698] Step 3 Preparation of 2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303049-4

[0699]

[0700] In DMF (5.00 mL), 6-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303049-3 (500 mg, 2.79 mmol, 1.00 eq) was mixed with K2CO3 (771 mg, 5.58 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazole JD-5303001c (411 mg, 2.79 mmol, 1.00 eq), and stirred at 50 °C for 2 h. The reaction mixture was quenched by adding H2O (6.00 mL), and then 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 - 2 / 1) to give 2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303049-4 (400 mg, 1.38 mmol, yield 49.3%) as a white solid.

[0701] LC-MS [M+H] + = 291.0。

[0702] Step 4 Preparation of 2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303049-5

[0703]

[0704] BH3-Me2S (10 M, 258 μL, 2.50 eq) was added to a solution of 2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-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 the addition of 5.00 mL of MeOH at 0 °C and then concentrated under reduced pressure to give 2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin JD-5303049-5 (300 mg, crude) as a yellow solid.

[0705] LC-MS [M+H] + = 277.0.

[0706] Step 5 Preparation of 2-methylpropyl 3,3-difluoro-4-{[(2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}pyrrolidine-1-carboxylate JD-5303049-5

[0707]

[0708] To a solution of 2-methylpropan-2-yl 4-amino-3,3-difluorotetrahydro-1H-pyrrole-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 h. 2-Methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-one 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 h. After concentration of the reaction mixture, purification was performed by high performance liquid chromatography (column: Welch xextreme C18 150*25 mm*5 μm; mobile phase: [water (TFA)-ACN]; gradient: 40%-70% B over 10 min). The combined product was purified by high performance liquid chromatography to obtain 2-methylpropan-2-yl 3,3-difluoro-4-{[(2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}tetrahydro-1H-pyrrole-1-carboxylate JD-5303049-5 (120 mg, 228 μmol, yield 63.2%) as a white solid.

[0709] LC-MS [M+H] + = 525.1.

[0710] Step 6 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303049

[0711]

[0712] 3,3-Difluoro-4-{[(2-methyl-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303049 (100 mg, 190 μmol, 1.00 eq) was added to a solution of TFE (2.00 mL), and TMSCl (41.4 mg, 381 μmol, 48.3 μL, 2.00 eq) was added. 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-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303049 (35.1 mg, 82.7 μmol, yield 43.3%, purity 98.89%) as a white gum.

[0713] LC-MS [M+H] + = 425.0.

[0714] 1 1H NMR: (400 MHz, DMSO-d6) δ = 1.26 (t, J = 6.13 Hz, 3H), 2.39 (s, 3H), 2.81 (td, J = 11.69, 8.38 Hz, 1H), 2.89 - 3.03 (m, 1H), 3.12 - 3.26 (m, 3H), 3.87 - 4.03 (m, 1H), 4.07 - 4.24 (m, 1H), 4.28 - 4.46 (m, 1H), 5.16 (s, 2H), 6.63 (dd, J = 8.88, 2.88 Hz, 1H), 6.78 (dd, J = 8.82, 2.69 Hz, 1H), 7.09 - 7.20 (m, 1H), 7.30 (dd, J = 6.38, 2.88 Hz, 1H), 8.98 (s, 1H).

[0715] Example 56 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carboxamide hydrochloride JD-5303050

[0716]

[0717] Step 1 Preparation of 1-[(4-bromo-2-nitrophenyl)oxy]cyclopropane-1-carboxylic acid JD-5303050-2

[0718]

[0719] Under 0 °C and N2 atmosphere, NaH (4.90 g, 122 mmol, 60% purity, 2.50 eq) was added 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), and the mixture was stirred at 0 °C for 1 hour. Then 4-bromo-1-fluoro-2-nitrobenzene JD-5303050-1 (5.00 g, 48.9 mmol, 1.00 eq) was added, and the mixture was continuously stirred at 25 °C for 15 hours. The reaction mixture was quenched by adding H2O (300 mL) at 0 °C, extracted with ethyl acetate (150 mL × 3), the aqueous phase was adjusted to pH = 6 by adding 2 M HCl, then extracted with EtAOc (300 mL, 150 mL × 2), the organic layer was collected, 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 obtain 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.

[0720] LC-MS [M] = 301.9.

[0721] Step 2 Preparation of 6-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazocine-2,1'-cyclopropane]-3-one JD-5303050-3

[0722]

[0723] 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), NH4Cl (2.83 g, 52.9 mmol, 4.00 eq) and Fe (2.96 g, 52.9 mmol, 4.00 eq) were added, and the mixture was stirred at 90 °C for 16 h. The filtrate after filtration was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to obtain 6-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazocine-2,1'-cyclopropane]-3-one JD-5303050-3 (2.20 g, 8.66 mmol, yield 65.3%) as a white solid.

[0724] LC-MS[M+2] = 256.1。

[0725] Step 3 Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-one JD-5303050-4

[0726]

[0727] Dissolve 6-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-one JD-5303050-3 (2.20 g, 8.66 mmol, 1.00 eq) in dioxane (25.0 mL), then add 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), and stir at 100 °C under N2 atmosphere for 2 hours. Quench the reaction mixture with H2O (25.0 mL), and then extract with EtOAc (50.0 mL, 25.0 mL * 2). Concentrate under reduced pressure to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-one JD-5303050-4 (3.00 g, crude product) as a black solid.

[0728] LC-MS[M+H] + = 302.1。

[0729] Step 4 Preparation of 6-hydroxy-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-one JD-5303050-5

[0730]

[0731] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-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). The temperature was controlled at about 0 °C, and then 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. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding Na2SO3 (aq., 50.0 mL), and then extracted with ethyl acetate (100 mL, 50.0 mL * 2). The residue was obtained by concentration under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 - 2 / 1) to obtain 6-hydroxy-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-one JD-5303050-5 (1.20 g, 6.28 mmol, yield 72.7%) as a white solid.

[0732] LC-MS [M + H] + = 192.1.

[0733] Step 5 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-one JD-5303050-6

[0734]

[0735] 6-Hydroxy-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropan]-3-one JD-5303050-5 (1.00 g, 5.23 mmol, 1.00 eq) was added to a solution of DMF (10.0 mL). Then, K2CO3 (1.45 g, 10.4 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazolane JD-5303001c (772 mg, 5.23 mmol, 1.00 eq) were added, and the mixture was stirred at 50 °C for 16 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., 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-thiazolan-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropan]-3-one JD-5303050-6 (600 mg, 1.98 mmol, yield 37.9%) as an off-white solid.

[0736] LC-MS [M+H] + = 303.2.

[0737] Step 6 Preparation of 6-{[(4-methyl-1,3-thiazolan-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane] JD-5303050-7

[0738]

[0739] 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3-one JD-5303050-6 (100 mg, 330 μmol, 1.00 eq) was added to THF (2.00 mL), and BH3-Me2S (10 M, 82.6 μL, 2.50 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 6 h. The reaction mixture was quenched with 5.00 mL of methanol at 0 °C and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography (column: CD04-Welch uultimate C18 150*25*7um; mobile phase: [water (TFA)-ACN]; gradient: 25%-45% B over 10 minutes) to obtain 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane] JD-5303050-7 (30.0 mg, 104 μmol, yield 31.4%) as a brown oil.

[0740] LC-MS [M+H] + = 289.0.

[0741] Step 7 Preparation of 2-Methyl-2-propanyl 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylate JD-5303050-8

[0742]

[0743] 4-Amino-3,3-difluorotetrahydropyrrole-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303001d (46.2 mg, 208 μmol, 2.00 eq) and CDI (37.6 mg, 232 μmol, 2.23 eq) were added to a solution of DMF (1.00 mL), and the mixture was stirred at 65 °C for 1 h. Then, 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane] JD-5303050-7 (30.0 mg, 104 μmol, 1.00 eq) was added, and the reaction was carried out at 65 °C for 16 h. The reaction mixture was quenched by adding H2O (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. Purification by high performance liquid chromatography (column: CD04-Welch uultimate C18 150*25*7um; mobile phase: [water (TFA)-ACN]; gradient: 38%-68% B over 10 minutes) gave 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-4-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303050-8 (30.0 mg, 55.9 μmol, 53.7% yield) as a white solid.

[0744] LC-MS [M+H] + = 537.1.

[0745] Step 8 Preparation of N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-4-carboxamide JD-5303050

[0746]

[0747] TMSCl (12.1 mg, 111 μmol, 14.1 μL, 2.00 eq) was added to a solution of 2-methylpropyl 3,3-difluoro-4-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydrospiro[benzo[b][1,4]oxazepine-2,1'-cyclopropane]-4-yl)carbonyl]amino}pyrrolidine-1-carboxylate JD-5303050 (30.0 mg, 55.9 μmol, 1.00 eq) in TFE (3.00 mL), and the mixture was 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-thiazol-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, yield 32.7%, purity 100%) as a yellow gum.

[0748] LC-MS [M+H] + = 437.0.

[0749] 1 H NMR: (400 MHz, DMSO-d6) δ = 0.68 - 0.84 (m, 2H), 0.90 (s, 2H) 2.40 (s, 3H), 3.47 (brs, 1H), 3.68 (br s, 3H), 3.85 (br s, 2H), 4.79 (dt, J = 11.48, 8.58 Hz, 1H), 5.20 (s, 2H), 6.68 (d, J = 2.88 Hz, 1H), 6.72 - 6.79 (m, 1H), 7.36 (d, J = 2.88 Hz, 1H), 7.60 (d, J = 8.38 Hz, 1H), 9.10 (s, 1H), 10.08 - 10.41 (m, 2H)

[0750] Example 57 Preparation of 7-fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303051

[0751]

[0752] Step 1 Preparation of methyl [(5-fluoro-4-methoxy-2-nitrophenyl)oxy]acetate JD-5303051-2

[0753]

[0754] Methyl (5-fluoro-4-methoxy-2-nitrophenoxy)acetate JD-5303051-2 was prepared by adding methyl glycolate JD-5303051a (4.29 g, 47.5 mmol, 3.67 mL, 0.90 eq) to NaH (1.90 g, 47.5 mmol, 60% purity, 0.90 eq) in THF (100 mL). The mixture was stirred at 0 °C for 0.5 h. 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 h. The reaction mixture was quenched with 10.0 mL of NH4Cl at 0 °C, diluted with 30.0 mL of H2O, extracted with 30 mL of ethyl acetate, and 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) to obtain methyl (5-fluoro-4-methoxy-2-nitrophenoxy)acetate JD-5303051-2 (1.80 g, 6.94 mmol, yield 13.1%) as a yellow oil.

[0755] LC-MS [M+Na] = 282.0.

[0756] Step 2 Preparation of 7-fluoro-6-methoxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-3

[0757]

[0758] Iron powder (3.88 g, 69.4 mmol, 10.0 eq) was added to methyl (5-fluoro-4-methoxy-2-nitrophenoxy)acetate JD-5303051-2 (1.80 g, 6.94 mmol, 1.00 eq), and EtOH (20.0 mL) and AcOH (20.0 mL) were added respectively. The mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain 7-fluoro-6-methoxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-3 (1.40 g, crude product) as a brown solid.

[0759] LC-MS [M+H] + = 198.1.

[0760] Step 3 Preparation of 7-fluoro-6-hydroxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-4

[0761]

[0762] To a solution of 7-fluoro-6-methoxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-3 (1.40 g, 7.10 mmol, 1.00 eq) in DCM (15.0 mL) was added BBr3 (8.89 g, 35.5 mmol, 3.42 mL, 5.00 eq). The mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with 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]oxazin-3-one JD-5303051-4 (500 mg, crude) as a brown solid.

[0763] LC-MS [M-H] - = 182.8.

[0764] Step 4 Preparation of 7-fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-5

[0765]

[0766] To a solution of 7-fluoro-6-hydroxy-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-4 (500 mg, 2.73 mmol, 1.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazole JD-5303001c (362 mg, 2.46 mmol, 0.90 eq) in DMF (5.00 mL) was added K2CO3 (754 mg, 5.46 mmol, 2.00 eq). The mixture was stirred at 25 °C for 4 h. 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-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-5 (800 mg, crude) as a brown solid.

[0767] LC-MS [M+H] + = 295.0.

[0768] Preparation of JD-5303051-6 of 7-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one

[0769]

[0770] 7-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one JD-5303051-5 (200 mg, 679 μmol, 1.00 eq) was added to a solution of THF (2.00 mL), and BMS (10 M, 339 μL, 5.00 eq) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with 5.00 mL of MeOH at 0 °C and then concentrated under reduced pressure to obtain JD-5303051-6 (520 mg, crude) of 7-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-3-one as a brown oil.

[0771] LC-MS [M+H] + = 281.0.

[0772] Preparation of JD-5303051-7 of 3-{[(7-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-4-yl)carbonyl]amino}piperidine-1-carboxylic acid 2-methylpropan-2-yl ester

[0773]

[0774] JD-5303051-6 (50.0 mg, 178 μmol, 1.00 eq) of 7-fluoro-6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepine and JD-5303002a (107 mg, 535 μmol, 3.00 eq) of 3-aminohexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester were added to a solution of THF (1.00 mL). 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 H2O (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 3-{[(7-fluoro-6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303051-7 (5.00 mg, 9.87 μmol, yield 5.53%) as a white solid.

[0775] LC-MS [M+H] + = 507.1.

[0776] Step 7 Preparation of 7-fluoro-N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazepine-4-carboxamide hydrochloride JD-5303051

[0777]

[0778] A solution of 2-methylpropyl 3-{[(7-fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303051 (5.00 mg, 9.87 μmol, 1.00 eq) in TFE (1.00 mL) was added with TMSCl (2.14 mg, 19.7 μmol, 2.51 μL, 2.00 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain 7-fluoro-N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[2,1-b][1,4]oxazine-4-carboxamide hydrochloride JD-5303051 (3.66 mg, 8.26 μmol, yield 83.7%, purity 98.52%, HCl) as a yellow solid.

[0779] LC-MS [M+H] + = 407.1.

[0780] 1 1H NMR: (400 MHz, METHANOL-d4) δ ppm 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 = 3.50 Hz, 1H) 3.49 (br dd, J = 11.94, 3.69 Hz, 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 = 11.76 Hz, 1H) 7.39 (d, J = 8.63 Hz, 1H) 8.93 (s, 1H).

[0781] Example 58 Preparation of 2-(piperidin-3-yl)-1-(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethan-1-one JD-5303052

[0782]

[0783] Prepared according to the synthesis method of Example 1 by replacing compound JD-5303001d with JD-5303052-1 to obtain 2-(hexahydropyridin-3-yl)-1-(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethan-1-one JD-5303052 (16 mg, yield 44.7%, purity 99.2%) as a yellow solid.

[0784] LC-MS([M+H] + ) = 388.1.

[0785] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.92 (s, 1H), 7.52 (s, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.76 (dd, J = 8.9, 2.9 Hz, 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).

[0786] Preparation of Example 59 N-(hexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxamide JD-5303053

[0787]

[0788] Step 1 Preparation of 6-bromo-3,4-dihydro-2H-chromene-4-carbonitrile JD-5303053-2

[0789]

[0790] 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). After protecting with nitrogen, the temperature was lowered to 0 °C, and t-BuOK (5.43 g, 48.44 mmol, 2.2 eq) was added. The reaction mixture was reacted at room temperature for 15 h. The mixture was quenched by adding aqueous ammonium chloride solution (40 mL) at room temperature, and then extracted with ethyl acetate (60 mL, 30.0 mL × 2). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1) to obtain 6-bromo-3,4-dihydro-2H-chromene-4-carbonitrile JD-5303053-2 (2.4 g, yield 45.7%) as a white solid.

[0791] 1 H NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.38–4.29 (m, 1H), 4.27–4.20 (m, 1H), 3.99 (t, J = 6.0 Hz, 1H), 2.39–2.28 (m, 2H).

[0792] Step 2 Preparation of methyl 6-bromo-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-3

[0793]

[0794] 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 for 15 h under a nitrogen atmosphere. The mixture was quenched by adding water (10 mL) at room temperature, and then extracted with ethyl acetate (30 mL, 15.0 mL × 2). The combined organic phases were washed with saturated Na2CO3 solution (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and then the collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain methyl 6-bromo-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-3 (550 mg, yield 80.5%) as a colorless oil.

[0795] LC-MS ([M+H]+ ) = 271.0。

[0796] 1 1H NMR (300 MHz, CDCl3) δ = 7.37 (dd, J = 2.4, 0.6 Hz, 1H), 7.24 (dd, J = 8.7, 2.4 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 4.30–4.21 (m, 2H), 3.80–3.70 (m, 4H), 2.38–2.27 (m, 1H), 2.16–2.00 (m, 1H).

[0797] 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

[0798]

[0799] Dissolve methyl 6-bromo-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-3 (550 mg, 2.03 mmol, 1.0 eq) in Dioxane (8.0 mL), add 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). The reaction mixture is reacted at 100 °C for 3 h. The mixture is quenched by adding water (10 mL) at room temperature and then extracted with ethyl acetate (30 mL, 15.0 mL * 2). The collected organic phase is washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 15 / 1) to obtain a yellow oil of 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 product, with BPD residue in NMR).

[0800] LC-MS ([M+H] + ) = 319.0。

[0801] 11H NMR (300 MHz, CDCl3) δ = 7.66 (s, 1H), 7.61 (dd, J = 8.1, 1.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 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).

[0802] Step 4 Preparation of methyl 6-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-5

[0803]

[0804] Dissolve 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) in THF (4.0 mL) and H2O (4.0 mL). Add AcOH (755 mg, 12.57 mmol, 5.0 eq) and H2O2 (2.85 g, 25.14 mmol, 10.0 eq) (30%) at 0 °C. The reaction mixture is stirred at room temperature for 15 h. The mixture is quenched by adding saturated aqueous Na2SO3 solution (10 mL) at 0 °C and then extracted with ethyl acetate (30 mL, 15.0 mL * 2). The collected organic phase is washed with brine (10 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (silica gel, 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.

[0805] LC-MS ([M+H] + ) = 209.0.

[0806] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.87 (s, 1H), 6.63–6.50 (m, 3H), 4.15–4.02 (m, 2H), 3.81 (t, J = 5.6 Hz, 1H), 3.67 (s, 3H), 2.18–2.08 (m, 1H), 2.07–1.95 (m, 1H).

[0807] Step 5 Preparation of methyl 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-6

[0808]

[0809] 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), and 5-(chloromethyl)-4-methyl-1,3-thiazole 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 h. The mixture was quenched by adding 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) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain methyl 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylate JD-5303053-6 (100 g, yield 65.2%) as a yellow oil.

[0810] LC-MS([M+H] + ) = 320.1.

[0811] 1 1H NMR (400 MHz, CDCl3) δ = 8.7(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).

[0812] Step 6 Preparation of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylic acid JD-5303053-7

[0813]

[0814] Methyl 6-{[(4-methyl-1,3-thiazol-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 H2O (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 h. The mixture was adjusted to pH 3 by adding saturated aqueous potassium bisulfate solution at room temperature and diluted with ethyl acetate (5 mL). The mixture was filtered and the cake was collected to obtain white solid of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxylic acid JD-5303053-7 (70 mg, yield 73.1%).

[0815] LC-MS([M+H] + ) = 306.1.

[0816] 1 H NMR (300 MHz, DMSO-d6) 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), 4.20–4.00 (m, 2H), 3.72 (t, J = 5.4 Hz, 1H), 2.39 (s, 3H), 2.22–2.10 (m, 1H), 2.08–1.93 (m, 1H).

[0817] Step 7 Preparation of 2-methylpropan-2-yl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromen-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303053-8

[0818]

[0819] 6-{[(4-Methyl-1,3-thiazol-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 a drop of DMF were added at 0 °C, and the reaction mixture was reacted at room temperature for 0.5 h. The mixture was concentrated to obtain a residue. Then the residue was diluted with DCM (2 mL), and 6 (40 mg, 0.15 mmol, 1.0 eq) and TEA (46 mg, 0.46 mmol, 3.0 eq) were added thereto at room temperature. The reaction mixture was reacted at room temperature for 1 h. The reaction system was quenched with water (15 mL), extracted with dichloromethane (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 obtain a residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 200 / 1 to 100 / 1) to obtain 2-methylpropyl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromen-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303053-8 (70 mg, yield 73.4%) as a yellow oil.

[0820] LC-MS([M+H] + ) = 488.2.

[0821] 1 1H NMR (300 MHz, CDCl3) δ = 8.72 (d, J = 1.5 Hz, 1H), 6.90–6.77 (m, 2H), 6.67 (d, J = 2.1 Hz, 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 = 3.3 Hz, 3H), 2.44–2.32 (m, 1H), 2.27–1.74 (m, 3H), 1.60–1.49 (m, 2H), 1.41 (d, J = 2.1 Hz, 9H).

[0822] Step 8 Preparation of N-(Piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxamide JD-5303053

[0823]

[0824] Dissolve 2-methylpropan-2-yl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromen-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303053 (70 mg, 0.14 mmol, 1.0 eq) in DCM (2.5 mL), add Dioxane / HCl (4 M, 0.7 mL, 2.8 mmol, 20.0 eq) to the mixture, and react the reaction mixture at room temperature for 2 hours. Concentrate the mixture under reduced pressure to obtain a residue. Adjust the pH of the residue to 9 with sodium bicarbonate, then extract with DCM (10 mL * 2). Wash the collected organic phase with brine (8 mL) and dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain a residue. Purify the residue by prep-TLC (dichloromethane / methanol = 8 / 1) to obtain N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-chromene-4-carboxamide JD-5303053 (23 mg, yield 41.0%, purity 94.0%) as a white solid.

[0825] LC-MS([M+H] + ) = 388.2.

[0826] 1 H NMR (300 MHz, CDCl3) δ = 8.70 (d, J = 0.9 Hz, 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).

[0827] Example 60 Preparation of 5-fluoro-N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303054

[0828]

[0829] Step 1 Preparation of 5-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303054-2

[0830]

[0831] To a solution of 6-bromo-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-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) was added KOAc (897 mg, 9.15 mmol, 2.50 eq) and Pd(dppf)Cl2 (535 mg, 731 μmol, 0.20 eq), and the mixture was stirred at 100 °C for 2 h. The reaction mixture was partitioned between H2O (20.0 mL) and EtOAc (20.0 mL), and the organic phase was collected, separated, filtered, and concentrated under reduced pressure to give 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303054-2 (2.90 g, crude) as a black solid.

[0832] LC-MS [M+H] + = 168.1.

[0833] Step 2 Preparation of 5-Fluoro-6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303054-3

[0834]

[0835] To a solution of 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-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 h. 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 give 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]oxazin-3-one JD-5303054-3 (450 mg, 2.46 mmol, yield 24.8%) was obtained as a yellow solid.

[0836] LC-MS [M+H] += 184.0。

[0837] Step 3 Preparation of 5-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303054-4

[0838]

[0839] 5-Fluoro-6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303054-3 (253 mg, 1.72 mmol, 0.90 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazole JD-5303001c (253 mg, 1.72 mmol, 0.9 eq) were added with K2CO3 (528 mg, 3.82 mmol, 2.00 eq) in DMF (3.00 mL). Stirred at 25 °C for 2 h. The reaction mixture was washed with H2O (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 high performance liquid chromatography to obtain 5-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303054-4 (60.0 mg, 203 μmol, yield 10.6%) as a white solid.

[0840] LC-MS [M+H] + = 295.0。

[0841] Step 4 Preparation of 5-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303054-5

[0842]

[0843] BMS (10M, 135 μL, 5.00 eq) was added to a solution of 5-fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one JD-5303054-4 (80.0 mg, 271 μmol, 1.00 eq) in THF (1.00 mL), and the mixture was stirred at 50 °C for 8 h. The reaction mixture was quenched by adding 5 mL of MeOH at 0 °C and then concentrated under reduced pressure to give a residue. The residue was purified by preparative high performance liquid chromatography to afford 5-fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin JD-5303054-5 (10.0 mg, 35.6 μmol, yield 13.12%) as a white solid.

[0844] LC-MS [M+H] + = 281.1.

[0845] Step 5 Preparation of 2-methylpropyl 3-{[(5-fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}piperidine-1-carboxylate JD-5303054-6

[0846]

[0847] 5-Fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-one JD-5303054-5 (5.00 mg, 17.8 μmol, 1.00 eq) and 3-amino-1-(2-methylpropan-2-yl)piperidine-1-carboxylate JD-5303002a (10.7 mg, 53.5 μmol, 3.00 eq) were added to a solution of THF (1.00 mL), and DIEA (4.61 mg, 35.6 μmol, 6.21 μL, 2.00 eq) and BTC (2.12 mg, 7.13 μmol, 0.40 eq) were added respectively. The mixture was stirred at 25 °C for 12 h. 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 3-{[(5-fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-1-(2-methylpropan-2-yl)piperidine-1-carboxylate JD-5303054-6 (15.0 mg, crude product) as a colorless oil.

[0848] LC-MS [M+H] + = 507.2.

[0849] Step 6 Preparation of 5-fluoro-N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303054

[0850]

[0851] To a solution of 3-{[(5-fluoro-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}piperidine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303054 (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 h. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography to give 5-fluoro-N-(piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303054 (9.66 mg, 21.8 μmol, yield 73.6%, purity 99.64% HCl) as a yellow solid.

[0852] LC-MS [M+H] + = 407.2.

[0853] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 1.42 - 1.71 (m, 2H) 1.85 (br d, J = 10.51 Hz, 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 = 4.38 Hz, 2H) 5.25 (s, 2H) 6.64 (dd, J = 9.19, 1.56 Hz, 1H) 6.97 (t, J = 8.94 Hz, 1H) 7.18 (d, J = 7.38 Hz, 1H) 8.54 - 8.80 (m, 2H) 8.99 (s, 1H).

[0854] Preparation of N-(2-methylpyrazol-3-yl)-7-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303072 in Example 61

[0855]

[0856] Using the synthesis method of Reference Example 1, replace compound JD-5303001-1 with JD-5303072-1 and replace compound JD-5303001d with JD-5303014a to obtain N-(2-methylpyrazol-3-yl)-7-{[(4-methyl-1,3-thiazolacyclopent-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303072 (6.8 mg, 27.28 mmol, yield 81.39%). It is a white solid.

[0857] LC-MS [389+H] + = 384.0.

[0858] 1 H NMR: (400 MHz, MeOD) δ 8.75 (s, 1H), 7.39 (s, 1H) 6.94 (d, J = 8.40 Hz, 1H) 6.43 - 6.39 (m, 2H) 6.21 (s, 1H) 4.61 (d, J = 6.00 Hz, 4H) 3.74 (s, 3H) 2.70 - 2.76 (m, 2H) 2.46 (s, 3H) 1.93 - 2.00 (m, 2H).

[0859] Preparation of Example 62 N-[3-(3-hydroxypropyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazolacyclopent-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide formate JD-5303073

[0860]

[0861] Step 1 Preparation of 3-{[(6-{[(4-methyl-1,3-thiazolacyclopent-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}-3-(prop-2-en-1-yl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303073-1

[0862]

[0863] The intermediate 3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-(prop-2-enyl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303017-1 (60 mg, 0.113 mmol, 1.0 eq) of Example 17 was dissolved in THF (2.0 mL), and BH3-DMS (0.17 mL, 0.339 mmol, 3.0 eq) (2N) was added at 0 °C. The mixture was stirred at room temperature for 12 hours. Then the reaction was cooled to 0 °C, and NaOH (1.0 mL) (3N), H2O2 (1.0 mL) and EtOH (1.0 mL) were added. The mixture was stirred at room temperature for 4 hours. The mixture was quenched by adding water (5 mL), 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 obtain 3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}-3-(prop-2-enyl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303073-1 (60 mg, crude product) as a white solid.

[0864] LC-MS([M+H] + ) = 547.5.

[0865] Preparation of N-[3-(3-hydroxypropyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide formate JD-5303073

[0866]

[0867] 3-{[(6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-3-(prop-2-enyl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303073-1 (60 mg, 0.110 mmol, 1.0 eq, crude) was dissolved in DCM (2 mL), and TFA (0.6 mL) was added to the mixture. The reaction mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was treated with sodium hydroxide solution (15%) (5 mL) at room temperature and stirred at room temperature for 1 h, 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 a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150 * 25 mm * 5 mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 25%-35%, 6 min) to give N-[3-(3-hydroxypropyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303073 (11.3 mg, two-step yield 19.6%, purity 98.6%) as a white solid.

[0868] LC-MS([M-FA + H] + ) = 447.3.

[0869] 1 H NMR (400 MHz, MeOD) δ = 8.88 (s, 1H), 8.38 (brs, 1.34H), 7.30–7.25 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.72–6.67 (m, 1H), 5.19 (s, 2H), 4.29–4.14 (m, 3H), 3.95–3.86 (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).

[0870] Example 63 Preparation of 3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxamide JD-5303074

[0871]

[0872] Step 1 Preparation of benzyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2

[0873]

[0874] Dissolve benzyl 3-oxohexahydropyridine-1-carboxylate JD-5303074-1 (3.0 g, 12.86 mmol, 1.0 eq) in MeOH (22.5 mL) and H2O (22.5 mL), add (NH4)2CO3 (2.6 g, 27.0 mmol, 2.1 eq) and TMSCN (2.55 g, 25.72 mmol, 2.0 eq), and react the reaction mixture at 80 °C for 15 hours. Concentrate the mixture under reduced pressure to obtain a residue. Collect the filter cake by filtration from the residue to obtain benzyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (3.4 g, yield 87.1%, purity 92%) as a yellow solid.

[0875] LC-MS ([M+H] + ) = 304.4.

[0876] 1 H NMR (400 MHz, DMSO-d6) δ = 10.71 (s, 1H), 8.52 (d, J = 21.6 Hz, 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, 6.8 Hz, 1H), 1.93–1.76 (m, 1H), 1.76–1.56 (m, 3H).

[0877] Step 2 Preparation of tert-butyl 7-[(benzyloxy)carbonyl]-1-{[(tert-butyl)oxy]carbonyl}-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3

[0878]

[0879] Dissolve benzyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (2.2 g, 7.25 mmol, 1.0 eq) in DME (70.0 mL), add TEA (734 mg, 7.25 mmol, 1.0 eq), (Boc)2O (6.33 g, 29.0 mmol, 4.0 eq) and DMAP (89 mg, 0.725 mmol, 0.1 eq), and react the reaction mixture at room temperature for 15 h. Concentrate the mixture under reduced pressure to obtain a residue. Purify the residue by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain white solid of 2-methylpropyl 7-[(benzyloxy)carbonyl]-1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3 (1.5 g, yield 41.0%, purity 94%).

[0880] LC-MS ([M + H2O] + ) = 521.3.

[0881] 1 1H NMR (400 MHz, CDCl3)

[0882] δ = 7.39–7.27 (m, 5H), 5.18–4.95 (m, 2H), 4.42–4.29 (m, 1H), 4.20 (d, J = 13.6 Hz, 1H), 3.96–3.77 (m, 1H), 2.92–2.59 (m, 2H), 2.41–2.25 (m, 1H), 1.94 (d, J = 13.2 Hz, 1H), 1.74–1.66 (m, 1H), 1.59–1.52 (m, 18H).

[0883] Step 3 Preparation of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4

[0884]

[0885] 7-[(Benzyloxy)carbonyl]-1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-3-carboxylic acid 2-methylpropan-2-yl ester JD-5303074-3 (1.5 g, 2.98 mmol, 1.0 eq) was dissolved in THF (15.0 mL) and H2O (24.0 mL), and LiOH (1.0 g, 23.83 mmol, 8.0 eq) was added. The reaction mixture was reacted 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 * 2). The collected organic phase was washed with brine (100 mL) and dried over anhydrous sodium sulfate, and then 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 obtain a white solid of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude).

[0886] LC-MS([M+H] + ) = 279.3.

[0887] Step 4 Preparation of methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5

[0888]

[0889] 3-Amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude, 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 * 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 white solid of methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5 (400 mg, two-step yield 45.9%, purity 92%).

[0890] LC-MS([M+H] + ) = 293.1.

[0891] Step 5 Preparation of Benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303074-6

[0892] Dissolve 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303001-4 (310 mg, 1.18 mmol, 1.0 eq) and TEA (598 mg, 5.91 mmol, 5.0 eq) in DCM (3.0 mL), add (COCl2)3 (175 mg, 0.59 mmol, 0.5 eq), and react the reaction mixture at room temperature for 0.5 h. Then dissolve methyl 3-amino-1-[(benzyloxy)carbonyl]hexahydropyridine-3-carboxylate JD-5303074-5 (380 mg, 1.30 mmol, 1.1 eq) in DCM (1 mL), add it to the mixture, and stir at room temperature for 48 h. Quench the reaction system with water (10 mL), extract with DCM (20 mL, 10 mL * 2), wash the collected organic phase with brine (10 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a residue. Purify the residue by column chromatography (silica gel, dichloromethane / methanol = 150 / 1 to 100 / 1) to obtain yellow solid of benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303074-6 (350 mg, yield 51.0%, purity 92%).

[0893] LC-MS([M+H] + ) = 581.2.

[0894] Step 6 Preparation of 1-[(Benzyloxy)carbonyl]-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxylic Acid JD-5303074-7

[0895]

[0896] 3-(Methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid benzyl ester JD-5303074-6 (100 mg, 0.17 mmol, 1.0 eq) was dissolved in MeOH (1.0 mL), THF (1 mL) and H2O (1 mL). LiOH (22 mg, 0.52 mmol, 3.0 eq) was added, and the reaction mixture was reacted at room temperature for 15 h. The reaction system was adjusted to pH 3 with saturated KHSO4 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 obtain 1-[(benzyloxy)carbonyl]-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxylic acid JD-5303074-7 (90 mg, crude product) as a yellow solid.

[0897] LC-MS ([M+H] + ) = 567.2.

[0898] Step 7 Preparation of 3-formamido-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid benzyl ester JD-5303074-8

[0899]

[0900] 1-[(Benzyloxy)carbonyl]-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-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 NH4Cl (13 mg, 0.24 mmol, 1.5 eq) were added. The reaction mixture was reacted at room temperature for 3 h. The reaction system was quenched with water (10 mL), 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 obtain a residue. The residue was purified by prep-TLC (methylene chloride / methanol = 15 / 1) to obtain benzyl 3-formamido-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303074-8 (50 mg, two-step yield 51.3%, purity 93%) as a yellow solid.

[0901] LC-MS ([M+H] + ) = 565.9.

[0902] Step 7 Preparation of 3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxamide JD-5303074

[0903]

[0904] 3-Carbamoyl-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid benzyl ester JD-5303074 (45 mg, 0.08 mmol, 1.0 eq) was dissolved in DCM (2 mL), and TMSI (48 mg, 0.24 mmol, 3.0 eq) was added to the mixture. The reaction mixture was reacted at room temperature for 4 h. The mixture was quenched with water (0.5 mL), then PTSA (10 mg) was added and stirred for 5 min. Then the pH was adjusted to 9 with saturated sodium bicarbonate solution, and extracted with DCM (15 mL, 5 mL×2). The collected organic phase was washed with brine (5 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150*25 mm*5 mm; mobile phase: [water (0.1% H3PO4)-acetonitrile]; B%: 25%-45%, 6 min) to obtain a residue, then the pH was adjusted to 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) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxamide JD-5303074 (3.5 mg, yield 10.1%, purity 95.2%) as a white solid.

[0905] LC-MS([M+H] + ) = 432.3.

[0906] 1 1H NMR (400 MHz, MeOD) δ = 8.88 (s, 1H), 7.39 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.68 (dd, J = 8.8, 2.8 Hz, 1H), 5.21 (s, 2H), 4.20 (t, J = 4.0 Hz, 2H), 3.83–3.76 (m, 2H), 3.40 (d, J = 12.4 Hz, 1H), 3.00 (d, J = 12.8 Hz, 1H), 2.82 (q, J = 5.0 Hz, 2H), 2.44 (s, 3H), 2.09–2.02 (m, 1H), 2.00–1.92 (m, 1H), 1.71–1.63 (m, 2H).

[0907] Preparation of 64N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide trifluoroacetate JD-5303075

[0908]

[0909] Referring to the synthesis method of Reference Example 63: Step 1 Preparation of benzyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2

[0910]

[0911] Dissolve benzyl 3-oxohexahydropyridine-1-carboxylate JD-5303074-1 (3.0 g, 12.86 mmol, 1.0 eq) in MeOH (22.5 mL) and H2O (22.5 mL), add (NH4)2CO3 (2.6 g, 27.0 mmol, 2.1 eq) and TMSCN (2.55 g, 25.72 mmol, 2.0 eq), and react the reaction mixture at 80 °C for 15 hours. Concentrate the mixture under reduced pressure to obtain a residue. Collect the filter cake by filtration to obtain yellow solid of benzyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (3.4 g, yield 87.1%, purity 92%).

[0912] LC-MS([M+H] + ) = 304.4.

[0913] 1 H NMR (400 MHz, DMSO-d6) δ = 10.71 (s, 1H), 8.52 (d, J = 21.6 Hz, 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, 6.8 Hz, 1H), 1.93–1.76 (m, 1H), 1.76–1.56 (m, 3H).

[0914] Step 2 Preparation of tert-butyl 7-[(benzyloxy)carbonyl]-1-{[(tert-butyl)oxy]carbonyl}-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3

[0915]

[0916] Dissolve benzyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate JD-5303074-2 (2.2 g, 7.25 mmol, 1.0 eq) in DME (70.0 mL), add TEA (734 mg, 7.25 mmol, 1.0 eq), (Boc)2O (6.33 g, 29.0 mmol, 4.0 eq) and DMAP (89 mg, 0.725 mmol, 0.1 eq), and react the reaction mixture at room temperature for 15 hours. Concentrate the mixture under reduced pressure to obtain a residue. Purify the residue by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain white solid of 2-methylpropan-2-yl 7-[(benzyloxy)carbonyl]-1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-3-carboxylate JD-5303074-3 (1.5 g, yield 41.0%, purity 94%).

[0917] LC-MS([M+H2O] + ) = 521.3.

[0918] 1 H NMR (400 MHz, CDCl3)

[0919] δ = 7.39–7.27 (m, 5H), 5.18–4.95 (m, 2H), 4.42–4.29 (m, 1H), 4.20 (d, J = 13.6 Hz, 1H), 3.96–3.77 (m, 1H), 2.92–2.59 (m, 2H), 2.41–2.25 (m, 1H), 1.94 (d, J = 13.2 Hz, 1H), 1.74–1.66 (m, 1H), 1.59–1.52 (m, 18H).

[0920] Step 3 Preparation of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4

[0921]

[0922] 7-[(Benzyloxy)carbonyl]-1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-3-carboxylic acid 2-methylpropan-2-yl ester JD-5303074-3 (1.5 g, 2.98 mmol, 1.0 eq) was dissolved in THF (15.0 mL) and H2O (24.0 mL), and LiOH (1.0 g, 23.83 mmol, 8.0 eq) was added. The reaction mixture was reacted 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 * 2). The collected organic phase was washed with brine (100 mL) and dried over anhydrous sodium sulfate, and then 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 obtain a white solid of 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude).

[0923] LC-MS([M+H] + ) = 279.3.

[0924] Step 4 Preparation of methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5

[0925]

[0926] 3-Amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid JD-5303074-4 (1.0 g, crude, 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 * 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 white solid of methyl 3-amino-1-[(benzyloxy)carbonyl]piperidine-3-carboxylate JD-5303074-5 (400 mg, two-step yield 45.9%, purity 92%).

[0927] LC-MS([M+H] + ) = 293.1.

[0928] Synthesis method of Reference Example 1: Step 5 Preparation of 5-(chloromethyl)-4-methyl-1,3-thiazole JD-5303001c

[0929]

[0930] Dissolve (4-methyl-1,3-thiazol-5-yl)methanol JD-5303001b (400 mg, 3.10 mmol, 1.00 eq) and SOCl2 in THF (25.0 mL), and stir the reaction mixture at 25 °C for 1 hour. Quench the reaction mixture with H2O (30.0 mL) and extract with EtOAC (30.0 mL). Collect the organic phase, separate, filter, and concentrate under reduced pressure to obtain 5-(chloromethyl)-4-methyl-1,3-thiazole JD-5303001c (500 mg, crude product) as a colorless oil.

[0931] Step 6 Preparation of JD-5303001-4 of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazocine

[0932]

[0933] Dissolve 3,4-dihydro-2H-benzo[b][1,4]oxazocin-6-ol JD-5303001-3 (0.20 g, 1.32 mmol, 1.00 eq) in DMF (2 mL), add K2CO3 (365 mg, 2.65 mmol, 2.00 eq) and 5-(chloromethyl)-4-methyl-1,3-thiazole JD-5303001c (292 mg, 1.98 mmol, 1.50 eq). Stir the reaction mixture at 80 °C for 16 hours. Wash the reaction mixture with H2O (10 mL) and ethyl acetate (10 mL, 5 mL * 2). Collect the organic phase, separate and concentrate under reduced pressure to obtain a residue. Purify the residue by preparative chromatography (SiO2, petroleum ether / ethyl acetate = 1:1) to obtain JD-5303001-4 of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazocine (0.12 g, 457 μmol, yield 34.5%) as a colorless oil.

[0934] LC-MS [M+H] + = 263.1.

[0935] Step 7 Preparation of benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazocin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303074-6

[0936]

[0937] 6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-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 (COCl2)3 (175 mg, 0.59 mmol, 0.5 eq) was added. The reaction mixture was reacted at room temperature for 0.5 h. Then, methyl 3-amino-1-[(benzyloxy)carbonyl]hexahydropyridine-3-carboxylate JD-5303074-5 (380 mg, 1.30 mmol, 1.1 eq) was dissolved in DCM (1 mL) and added to the mixture, and the mixture was stirred at room temperature for 48 h. The reaction system was quenched with water (10 mL), 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 obtain a residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 150 / 1 to 100 / 1) to obtain benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303074-6 (350 mg, yield 51.0%, purity 92%) as a yellow solid.

[0938] LC-MS([M+H] + ) = 581.2.

[0939] Step 8 Preparation of methyl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxylate JD-5303075-1

[0940]

[0941] Dissolve benzyl 3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303074-6 (150 mg, 0.258 mmol, 1.2 eq) in DCM (2 mL), add TMSI (155 mg, 0.774 mmol, 3.0 eq), and stir the mixture at room temperature for 3 h. Quench the mixture by adding water (5 mL). Then extract with DCM (10 mL, 5 mL * 2), adjust the pH of the aqueous phase to 9 with saturated sodium bicarbonate solution, and then extract with DCM / MeOH = 8 / 1 (27 mL, 9 mL * 3). Wash the collected organic phase with brine (10 mL) and dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain methyl 3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxylate JD-5303075-1 (70 mg, yield 60.8%, purity 90%) as a yellow solid.

[0942] LC-MS([M+H] + ) = 447.4.

[0943] Preparation of N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303075

[0944]

[0945] Methyl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-3-carboxylate JD-5303075 (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, and the reaction mixture was reacted at 0 °C for 1 h. The mixture was quenched by dropwise addition of NaOH solution (15%) (0.1 mL) at 0 °C and dried over Na2SO4. The mixture was filtered to collect the filtrate and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150*25 mm*5 mm; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 25%-45%, 6 min) to obtain N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide trifluoroacetate JD-5303075 (20.7 mg, yield 31.5%, purity 95.7%) as a pink solid.

[0946] LC-MS([M-TFA+H] + ) = 419.2.

[0947] 1 H NMR (300 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 2.7, Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 6.62 (dd, J = 9.0, 3.0 Hz, 1H), 6.24 (d, J = 5.1 Hz, 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), 3.05–2.89 (m, 1H), 2.76–2.52 (m, 2H), 2.39 (s, 3H), 2.17–2.08 (m, 1H), 1.66–1.37 (m, 3H).

[0948] Chiral resolution of JD-5303075: JD-5303075 was resolved into JD-5303075A and JD-5303075B by the following resolution method.

[0949] Resolution method of JD-5303075

[0950] 2.1 Instruments: Shimadzu High Performance Liquid Chromatograph (HPLC-Z)

[0951] Column: Chiralpak IC 50 * 4.6 mm 3 µm

[0952] Mobile phase: A is hexane (0.1% diethanolamine), B is isopropanol / methylnaphthalene chloride = 2 / 1

[0953] Gradient: B 60%

[0954] Flow rate: 1 mL / min

[0955] Back pressure: 100 bar

[0956] Column temperature: 35 °C

[0957] Wavelength: 220 nM

[0958] Cycle time: about 7 minutes

[0959] 2.2 Sample preparation: Dissolve the compound in ~150 ml of ethanol / hydroxyethyl cellulose, injection method: 12 ml per injection.

[0960] Post-treatment: After separation, dry at 40 °C using a rotary evaporator to obtain the target isomers JD-5303075A and JD-5303075B.

[0961] MS and NMR of isomer JD-5303075A:

[0962] LC-MS ([M-TFA + H] + ) = 419.2.

[0963] 1 H NMR (300 MHz, DMSO-d6) δ = 8.97 (s, 1H), 7.31 (d, J = 3.0 Hz, 1H), 6.80 (d, J = 9.0, Hz, 1H), 6.38 (d, J = 3.0 Hz, 1H), 6.35 (dd, J = 9.0, 3.0 Hz, 1H), 6.24 (d, J = 5.1 Hz, 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), 3.67–3.31 (m, 1H), 2.96–2.75 (m, 2H), 2.50 (s, 3H), 2.51–2.39 (m, 1H), 1.42–1.29 (m, 3H).

[0964] MS and NMR of Isomer JD-5303075:

[0965] LC-MS([M-TFA+H]+) = 419.2.

[0966] 1H NMR(300MHz, DMSO-d6) δ = 8.97(s, 1H), 7.31(d, J = 2.1Hz, 1H), 6.79(d, J = 6.9,Hz, 1H), 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), 3.67–3.31(m, 1H), 2.94–2.75(m, 2H), 2.50(s, 3H), 2.44–2.38(m, 1H), 1.40–1.29(m, 3H).

[0967] Preparation of N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-[(4-methyl-1,3-thiazol-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide Hydrochloride JD-5303076 in Example 65

[0968]

[0969] Referring to the synthesis method of Example 52, replacing compound JD-5303047a with JD-5303076a, N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-[(4-methyl-1,3-thiazol-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide Hydrochloride JD-5303076 (14.6 mg, 36.9 μmol, yield 45.8%, purity 96.49%) was obtained as an off-white solid.

[0970] LC-MS[396+1]+ = 397.

[0971] 11H NMR: (400 MHz, DMSO-d6) δ = 9.59 - 10.24 (m, 2H), 8.68 (s, 1H), 7.45 - 7.68 (m, 2H), 6.87 (d, J = 8.88 Hz, 1H), 6.68 (dd, J = 8.88, 3.00 Hz, 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).

[0972] Example 66 Preparation of 6-[(3-cyclopropylphenyl)oxy]-N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303077

[0973]

[0974] Refer to the synthetic method of Example 52, replace compound JD-5303047a 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]oxazin-4-carboxamide hydrochloride JD-5303077 (3.84 mg, 9.24 μmol, yield 47.7%, purity 100.00%) as an off-white solid.

[0975] LC-MS [415 + H] + = 416.

[0976] 1 1H NMR: (400 MHz, DMSO-d6) δ = 0.64 (dd, J = 4.94, 2.06 Hz, 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, 3.19 Hz, 1H), 4.13 - 4.27 (m, 2H), 4.67 - 4.81 (m, 1H), 6.62 - 6.71 (m, 3H), 6.76 (d, J = 7.75 Hz, 1H), 6.88 (d, J = 8.88 Hz, 1H), 7.19 (t, J = 7.82 Hz, 1H), 7.42 (d, J = 2.75 Hz, 1H), 7.53 (d, J = 8.25 Hz, 1H), 9.68 (br d, J = 2.00 Hz, 2H).

[0977] Preparation of 67N-(Piperidin-3-yl)-6-{methyl-[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide formate JD-5303079

[0978]

[0979] Step 1 Preparation of 6-{methyl-[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303079-1

[0980]

[0981] Dissolve 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303046-4 (350 mg, 0.97 mmol, 1.0 eq) in DMF (4.0 mL), add NaH (60%) (232 mg, 5.8 mmol, 6.0 eq) at 0 °C and stir for 0.5 h. Then add Mel (824 mg, 5.8 mmol, 6.0 eq) to the mixture and stir at room temperature for 2.5 h. Quench the mixture by adding saturated NH4Cl solution (10 mL) at 0 °C. Then extract with ethyl acetate (30 mL, 10 mL * 3), wash the collected organic phase with water (30 mL, 10 mL * 3), brine (10 mL) and dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 6-{methyl-[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxylic acid 2-methylpropan-2-yl ester JD-5303079-1 (350 mg, crude) as a yellow solid.

[0982] LC-MS([M + H] + ) = 376.2.

[0983] Step 2 Preparation of 6-{methyl-[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303079-2

[0984]

[0985] 6-{Methyl[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxylic acid 2-methylpropan-2-yl ester 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) (4N) was added at room temperature. The mixture was concentrated under reduced pressure to give 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). 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-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine JD-5303079-2 (200 mg, crude) as a yellow solid.

[0986] LC-MS([M+H] + ) = 276.1.

[0987] Step 3 Preparation of 3-{[(6-{methyl[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303079-3

[0988]

[0989] 6-{Methyl[(4-methyl-1,3-thiazepan-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepine 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 (COCl2)3 (108 mg, 0.36 mmol, 0.5 eq) were added. After 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, and the reaction was continued at room temperature for 11.5 h. The mixture was quenched by adding water (5 mL) at room temperature, and then extracted with dichloromethane (20 mL, 10.0 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 a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain 3-{[(6-{methyl[(4-methyl-1,3-thiazepan-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303079-3 (80 mg, yield 16.5% in three steps, purity 93%) as a yellow solid.

[0990] LC-MS([M+H] + ) = 502.4

[0991] 1 H NMR (300 MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.03 (d, J = 3.0 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 6.62–6.55 (m, 1H), 6.53 (dd, J = 9.0, 2.7 Hz, 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).

[0992] Step 4 Preparation of N-(Hexahydropyridin-3-yl)-6-{methyl[(4-methyl-1,3-thiazepan-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide formate JD-5303079

[0993]

[0994] 3-{[(6-{Methyl[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}piperidine-1-carboxylic acid 2-methylpropan-2-yl ester JD-5303079-3 (80 mg, 0.16 mmol, 1.0 eq) was dissolved in DCM (3 mL), and Dioxane / HCl (0.4 mL, 1.6 mmol, 10.0 eq, 4N) was added to the mixture. 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 10 with sodium hydroxide solution (3 mL, 15%), then extracted with DCM (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 a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150 * 25 mm * 5 mm; mobile phase: [water (0.1% FA)-acetonitrile]; B%: 15%-25%, 6 min) to obtain N-(piperidin-3-yl)-6-{methyl[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303079 (25.4 mg, yield 34.4%, purity 98.4%) as a yellow solid.

[0995] LC-MS([M - 1.3FA + H] + ) = 402.4.

[0996] 1 1H NMR (300 MHz, DMSO-d6) δ = 8.80 (s, 1H), 8.30 (brs, 1H), 7.07 (d, J = 2.7 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.52 (dd, J = 8.7, 2.7 Hz, 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).

[0997] Preparation of N-[(1S,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303080

[0998]

[0999] Using the synthesis method of Reference Example 1, replacing compound JD-5303001d with JD-5303080a, N-[(1S,3S)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303080 (111 mg, 254 μmol, yield 51.2%, purity 99.92% HCl) was obtained as an off-white solid.

[1000] LC-MS [415+H] + = 403.2.

[1001] 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 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 = 4.63 Hz, 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 = 8.76 Hz, 1H) 7.31 (d, J = 2.50 Hz, 1H) 8.97 (s, 1H).

[1002] Preparation of N-[(1R,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303081

[1003]

[1004] Using the synthesis method of Reference Example 1, replace compound JD-5303001d with JD-5303081a to prepare N-[(1R,3R)-3-aminocyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303081 (111 mg, 254 μmol, yield 51.2%, purity 98.43% HCl), which is an off-white solid.

[1005] LC-MS [415+H] + = 403.2.

[1006] 1 H NMR (400 MHz, DMSO-d6) δ ppm 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 = 4.63 Hz, 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 = 8.76 Hz, 1H) 7.31 (d, J = 2.50 Hz, 1H) 8.97 (s, 1H).

[1007] Example 70 Preparation of 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303091

[1008]

[1009] Using the synthesis method of Reference Example 64, replace compound JD-5303001c with JD-5303028a to prepare 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide formate JD-5303091 (30 mg, 18.7%), which is a white solid.

[1010] LCMS: 416.2 ([M-FA+H] + )

[1011] 11H NMR (300 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.53 (td, J = 7.5, 1.8 Hz, 1H), 7.47–7.33 (m, 2H), 7.28–7.20 (m, 2H), 6.78 (d, J = 9.0 Hz, 1H), 6.62 (dd, J = 9.0, 3.0 Hz, 1H), 6.23 (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 = 12.6 Hz, 1H), 1.82–1.15 (m, 3H).

[1012] Example 71 Preparation of N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-6-{[(2-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303109

[1013]

[1014] Prepared by replacing compound JD-5303001c with JD-5303109a according to the synthetic method of Reference Example 64, N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-6-{[(2-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303109 (31.7 mg, yield 26.8%, purity 98.0%) was a white solid.

[1015] LC-MS ([M+H] + ) = 419.1.

[1016] 1 1H NMR (300 MHz, DMSO-d6) δ = 7.66 (s, 1H), 7.29 (d, J = 3.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 6.61 (dd, J = 9.0, 3.0 Hz, 1H), 6.11 (s, 1H), 5.26–5.10 (m, 2H), 4.78 (brs, 1H), 4.13 (t, J = 4.5 Hz, 2H), 3.80–

[1017] 3.60 (m, 3H), 3.50–3.37 (m, 2H), 3.03 (d, J = 12.0 Hz, 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).

[1018] Preparation of N-[3-(Hydroxymethyl)hexahydropyridin-3-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide 2,2,2-trifluoroacetate JD-5303110, Example 72

[1019]

[1020] Prepared by replacing compound JD-5303001c with JD-5303031b according to the synthesis method of Reference Example 64, N-[3-(Hydroxymethyl)hexahydropyridin-3-yl]-6-({[2-(trifluoromethyl)pyridin-3-yl]methyl}oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide 2,2,2-trifluoroacetate JD-5303110 (21.7 mg, yield 12.3%, purity 98.2%) is a white solid.

[1021] LC-MS ([M-TFA + H] + ) = 467.2.

[1022] 1 1H NMR (300 MHz, DMSO-d6) δ = 8.85 (d, J = 11.7 Hz, 1H), 8.72 (d, J = 4.5 Hz, 1H), 8.28–8.09 (m, 2H), 7.78 (dd, J = 8.1, 4.8 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.63 (dd, J = 9.0, 3.0 Hz, 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 = 10.8 Hz, 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).

[1023] Example 73 Preparation of 6-{[(2,3-difluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303107

[1024]

[1025] Prepared 6-{[(2,3-difluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303107 (35 mg, yield 24.8%, purity 95.1%) as a white solid by replacing compound JD-5303001c with JD-5303036b according to the synthesis method of Reference Example 64.

[1026] LC-MS([M+H] + ) = 434.2.

[1027] 1 1H NMR: (300 MHz, DMSO-d6) δ = 7.46–7.31 (m, 3H), 7.28–7.20 (m, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.64 (dd, J = 9.0, 3.0 Hz, 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 = 10.8 Hz, 1H), 2.97 (d, J = 12.3 Hz, 1H), 2.85–2.74 (m, 1H), 2.49–2.40 (m, 2H), 2.13 (d, J = 12.9 Hz, 1H), 1.53–1.23 (m, 3H).

[1028] Example 74 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2-methylthiophen-3-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide 2,2,2-trifluoroacetate JD-5303101

[1029]

[1030] Using the synthetic method of Reference Example 52, replace the 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]oxazin-4-carboxamide 2,2,2-trifluoroacetate JD-5303101 (6 mg, yield 26.5%, purity 99.8%) is a white solid.

[1031] LC-MS([M-TFA+H] + ) = 396.1.

[1032] 1 H NMR (300 MHz, DMSO-d6) δ = 9.48 (brs, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.32–7.22 (m, 2H), 6.3 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 5.4 Hz, 1H), 6.55 (dd, J = 9.0, 3.0 Hz, 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).

[1033] Example 75 Preparation of 6-[(cyclohexylmethyl)oxy]-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303103

[1034]

[1035] Using the synthetic method of Reference Example 64, replace the compound JD-5303001c with JD-5303103a to obtain 6-[(cyclohexylmethyl)oxy]-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303103 (30 mg, 45.7%) as a yellow solid.

[1036] LCMS: 404.4 ([M+H] + )

[1037] 11H NMR (300 MHz, DMSO-d6): δ 7.22 (d, J = 2.9 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.52 (dd, J = 8.9, 2.9 Hz, 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).

[1038] Example 76 Preparation of 7-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303099

[1039]

[1040] Prepared by replacing compound JD-5303001-1 with JD-5303072-1 according to the synthetic method of Reference Example 70, 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%) was a white solid.

[1041] LCMS: 414.2 ([M+H] + )

[1042] 1 1H NMR (300 MHz, DMSO-d6): δ 8.53–8.00 (m, 1H), 7.58–7.49 (m, 1H), 7.47–7.38 (m, 1H), 7.31–7.19 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.7 Hz, 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 = 6.3 Hz, 2H), 2.13–2.00 (m, 1H), 1.92–1.33 (m, 6H).

[1043] 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

[1044]

[1045] Prepared according to the synthetic method of Reference Example 52 by replacing compound JD-5303047a with JD-5303083a to obtain 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), which is an off-white solid.

[1046] LCMS[389+H] + = 390.

[1047] 1 H NMR (400 MHz, 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, 2.81 Hz, 1H) 6.70 - 6.78 (m, 2H) 6.84 - 6.91 (m, 2H) 7.20 (t, J = 7.82 Hz, 1H) 7.42 (d, J = 2.88 Hz, 1H) 7.50 (d, J = 8.38 Hz, 1H) 9.48 - 9.76 (m, 2H).

[1048] Preparation of N-(4,4-Difluorotetrahydro-1H-pyrrol-3-yl)-6-(1,3-thiazol-5-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide Trifluoroacetate JD-5303088

[1049]

[1050] Prepared according to the synthetic method of Reference Example 52 by replacing compound JD-5303047a with JD-5303088a to obtain N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-(1,3-thiazol-5-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide trifluoroacetate JD-5303088 (19.7 mg, 39.7 μmol, yield 19.1%, FA), which is an off-white solid.

[1051] LCMS[382 + H] + = 383。

[1052] 1 H NMR: (400 MHz, DMSO-d6) δ = ppm 3.38 (dd, J = 11.69, 9.69 Hz, 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, 2.88 Hz, 1H) 6.91 (d, J = 9.01 Hz, 1H) 7.41 - 7.68 (m, 3H) 8.68 (d, J = 0.88 Hz, 1H) 9.41 - 9.90 (m, 2H)。

[1053] Preparation of Example 79 N-[(1S,3R)-3-aminocyclohexyl]-6-[(4-methyl-1,3-thiazol-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303089

[1054]

[1055] Using the synthesis method of Reference Example 65, replacing compound JD-5303001d with JD-5303022a, N-[(1S,3R)-3-aminocyclohexyl]-6-[(4-methyl-1,3-thiazol-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303089 (16.1 mg, 25.3%) was obtained as a white solid.

[1056] LCMS: 389.2 ([M + H] + )。

[1057] 1 H NMR (300 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.18–7.57 (m, 2H), 7.48 (d, J = 3.0 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 6.63 (dd, J = 8.7, 2.7 Hz, 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)。

[1058] Example 80 Preparation of N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2-fluorophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303092

[1059]

[1060] Prepared N-(4,4-difluorotetrahydro-1H-pyrrol-3-yl)-6-[(2-fluorophenyl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide hydrochloride JD-5303092 (19.2 mg, 44.2 μmol, yield 14.5%, purity 99.1%, HCl) as a white solid by replacing compound JD-5303047a with JD-5303092a according to the synthetic method of Reference Example 52.

[1061] LCMS [393 + H] + = 394.

[1062] 1 H NMR (400 MHz, DMSO-d6) 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, 2.88 Hz, 1H) 6.88 (d, J = 8.88 Hz, 1H) 7.03 - 7.10 (m, 1H) 7.11 - 7.21 (m, 2H) 7.30 - 7.38 (m, 1H) 7.44 (d, J = 2.88 Hz, 1H) 7.57 (br d, J = 8.13 Hz, 1H) 9.57 - 10.03 (m, 2H).

[1063] 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]oxazin-4-carboxamide hydrochloride JD-5303097

[1064]

[1065] Using the synthetic method of Reference Example 52, replace the compound JD-5303047a 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]oxazine-4-carboxamide hydrochloride JD-5303097 (70.0 mg, 145 μmol, 99.0%, HCl) as a white solid.

[1066] LC-MS [444 + H] + = 445.

[1067] 1 H NMR: (400 MHz, DMSO-d6) δ = 3.39 (br t, J = 9.69 Hz, 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, 2.88 Hz, 1H), 6.95 (d, J = 8.76 Hz, 1H), 7.45 - 7.58 (m, 2H), 7.61 - 7.77 (m, 2H), 8.42 (d, J = 4.25 Hz, 1H), 9.77 - 10.31 (m, 2H).

[1068] 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]oxazine-4-carboxamide JD-5303098

[1069]

[1070] Using the synthetic method of Reference Example 52, replace the compound JD-5303047a 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]oxazine-4-carboxamide JD-5303098 (9.3 mg, 29.3%) as a white solid.

[1071] LCMS: 410.1 ([M + H] + )

[1072] 11H NMR (400 MHz, DMSO-d6): δ 7.23 (d, J = 3.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.52 (dd, J = 8.8, 2.8 Hz, 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).

[1073] Example 83 Preparation of N-[3-(Hydroxymethyl)hexahydropyridin-3-yl]-6-[(4-methyl-1,3-thiazol-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303090

[1074]

[1075] Prepared according to the synthetic method of Reference Example 65 by replacing compound JD-5303001d with JD-5303074-6, N-[3-(Hydroxymethyl)hexahydropyridin-3-yl]-6-[(4-methyl-1,3-thiazol-5-yl)oxy]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303090 (20 mg, 42.8%) was a white solid.

[1076] LCMS: 405.1 ([M+H] + )

[1077] 1 1H NMR (300 MHz, DMSO-d6): δ 8.65 (s, 1H), 7.47 (d, J = 3.0 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.65 (dd, J = 9.0, 3.0 Hz, 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).

[1078] Preparation of Example 84 N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303104

[1079]

[1080] Step 1 Preparation of ({1-[(benzyloxy)carbonyl]-4-hydroxyhexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester JD-5303104-2

[1081]

[1082] Dissolve benzyl hexahydrooxazolo[2,3-c]pyridine-3-carboxylate JD-5303104-1 (7.0 g, 30.01 mmol, 1.0 eq) in EtOH (35.0 mL), add NH3·H2O (35.0 mL), and react the mixture in an autoclave at 70 °C for 15 hours. The mixture was directly concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM (70.0 mL), add TEA (4.0 g, 39.01 mmol, 1.3 eq) and Boc2O (7.2 g, 33.01 mmol, 1.1 eq), and react the mixture 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 obtain ({1-[(benzyloxy)carbonyl]-4-hydroxyhexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester JD-5303104-2 (3.2 g, yield 30.4%, purity 92%) as a transparent oil.

[1083] LC-MS ([M-56+H] + ) = 295.1.

[1084] 1 H NMR: (300 MHz, CDCl3) 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).

[1085] Step 2 Preparation of ({'1-[(benzyloxy)carbonyl]-4-oxohexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester JD-5303104-3

[1086]

[1087] Dissolve (2-methylpropan-2-yl {1-[(benzyloxy)carbonyl]-4-hydroxyhexahydropyridin-3-yl}carbamate) JD-5303104-2 (3.2 g, 9.13 mmol, 1.0 eq) in DCM (35.0 mL), add DMP (5.8 g, 13.70 mmol, 1.5 eq), and react the reaction mixture at room temperature for 15 h. Quench the reaction mixture by adding NaHCO3 (40 mL) and Na2S2O3 (10 mL), and then extract with DCM (150 mL, 50 mL * 3). Wash the collected organic phase with brine (50 mL) and dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain a residue. Purify the residue by column chromatography (silica gel, petroleum ether / ethyl acetate = 8 / 1) to obtain (2-methylpropan-2-yl {1-[(benzyloxy)carbonyl]-4-oxohexahydropyridin-3-yl}carbamate) JD-5303104-3 (2.7 g, yield 84.9%, purity 90%) as a yellow oil.

[1088] LC-MS ([M - 56 + H] + ) = 293.1.

[1089] 1 H NMR: (400 MHz, CDCl3) 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 = 11.6 Hz, 1H), 2.67–2.45 (m, 2H), 1.45 (s, 9H).

[1090] Step 3 Preparation of bis[(2-methylpropan-2-yl {1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}carbamate)] JD-5303104-4

[1091]

[1092] Dissolve ({1-[(benzyloxy)carbonyl]-4-oxohexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester JD-5303104-3 (300 mg, 0.86 mmol, 1.0 eq) in DCM (5.0 mL), and slowly add DAST (1.4 g, 8.61 mmol, 10.0 eq) at 0 °C under nitrogen protection. The reaction mixture was reacted at 30 °C for 72 hours. The reaction mixture was quenched by adding saturated aqueous NaHCO3 solution (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) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1) to obtain bis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester] JD-5303104-4 (150 mg, yield 47.0%, purity 89%) as a yellow oil.

[1093] LC-MS([M - 56 + H] + ) = 315.1.

[1094] 1 H NMR: (300 MHz, CDCl3) 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).

[1095] Step 4 Preparation of bis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester] JD-5303104-5

[1096]

[1097] Dissolve bis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester] JD-5303104-4 (150 mg, 0.41 mmol, 1.0 eq) in DCM (3.0 mL), add Dioxane / HCl (1.01 mL, 4.05 mmol, 10.0 eq), and react the reaction mixture at room temperature for 15 h. The mixture was directly concentrated under reduced pressure to obtain bis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester] JD-5303104-5 (150 mg, crude) as a yellow solid.

[1098] LC-MS([M-HCl+H] + ) = 271.1.

[1099] Step 5 Preparation of benzyl 4,4-difluoro-3-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303104-6

[1100]

[1101] Dissolve bis[({1-[(benzyloxy)carbonyl]-4,4-difluorohexahydropyridin-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester] JD-5303104-5 (40 mg, 0.14 mmol, 1.0 eq) in DCM (4.0 mL), add TEA (137 mg, 1.35 mmol, 10.0 eq) and (COCl2)3 (20 mg, 0.07 mmol, 0.5 eq), stir the reaction mixture at 30 °C for 0.5 h, dissolve 70-5 (50 mg crude, 0.14 mmol, 1.0 eq) in DCM (1.0 mL) and add it to the reaction system and stir at 30 °C for 14.5 h. The mixture was quenched by adding 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) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, 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]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303104-6 (40 mg, total yield of two steps 53.3%, purity 85%) as a white solid.

[1102] LC-MS([M+H] + ) = 556.2。

[1103] Step 6 Preparation of N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303104

[1104]

[1105] Dissolve benzyl 4,4-difluoro-3-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303104-6 (40 mg, 0.07 mmol, 1.0 eq) in DCM (3.0 mL), add TMSI (72 mg, 0.36 mmol, 5.0 eq), and stir the mixture at room temperature for 3 hours. Quench the mixture by adding water (5 mL). Then extract with DCM (20 mL, 10 mL * 2). Adjust the pH of the aqueous phase to 10 with saturated sodium bicarbonate solution, and then extract with DCM (20 mL, 10 mL * 2). Wash the collected organic phase with brine (10 mL) and dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain a residue. Purify the residue by prep-TLC (DCM / MeOH = 15 / 1) to obtain N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303104 (6.6 mg, yield 21.8%, purity 95.2%) as a white solid.

[1106] LC-MS([M+H] + ) = 422.1。

[1107] 1 H NMR: (300 MHz, CD3OD) δ = 7.56–7.43 (m, 1H), 7.42–7.29 (m, 1H), 7.23–7.04 (m, 3H), 6.81 (d, J = 9.0 Hz, 1H), 6.68 (dd, J = 9.0, 3.0 Hz, 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).

[1108] Preparation of Example 85 N-[3-(Formylamino)cyclohexyl]-6-{[(4-Methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303100

[1109]

[1110]

[1111] Compound 1 (100 mg, 0.25 mmol, 1.0 eq) was added to DCM (2.0 mL), 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). The mixture was stirred at room temperature for 15 h, diluted with K2CO3 solution (5 mL), and extracted with DCM (10 mL * 2). The collected organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a residue, which was purified by thin layer chromatography (DCM / MeOH = 8 / 1) to give JD-5303100 (70 mg, 65.4%) as a yellow solid.

[1112] LCMS: 431.2 ([M+H] + )。

[1113] 1 H NMR (300 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.97–7.91 (m, 1H), 7.32 (d, J = 3.0 Hz, 1H), 6.79–6.68 (m, 2H), 6.58 (dd, J = 8.7, 2.7 Hz, 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).

[1114] Preparation of Example 86 (2S)-2-{[(6-{[(2-Fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-3-hydroxypropanamide JD-5303084

[1115]

[1116] Prepared according to the synthetic method of Reference Example 33 by replacing compound JD-5303028b with JD-5303084a to obtain (2S)-2-{[(6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-3-hydroxypropanamide JD-5303084 (82 mg, 65.2%) as a white solid.

[1117] LCMS: 390.1 ([M+H] + )。

[1118] 1 H NMR (400 MHz, DMSO-d6): δ 7.60–7.35 (m, 4H), 7.30–7.19 (m, 2H), 7.13 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.64 (dd, J = 9.2, 3.2 Hz, 1H), 5.10–5.00 (m, 2H), 4.94 (t, J = 5.6 Hz, 1H), 4.25–4.08 (m, 3H), 3.85–3.61 (m, 4H).

[1119] Preparation of N-[(1S,3R)-3-aminocyclohexyl]-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303086 in Example 87

[1120]

[1121] Prepared according to the synthetic method of Reference Example 33 by replacing compound JD-5303028b with JD-5303022a to obtain N-[(1S,3R)-3-aminocyclohexyl]-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303086 (43.7 mg, 55.0%) as a white solid.

[1122] LCMS: 400.3 ([M+H] + )。

[1123] 11H NMR (400 MHz, DMSO-d6): δ 7.62–7.32 (m, 5H), 7.27–7.20 (m, 2H), 6.97 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.8, 2.8 Hz, 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 = 11.6 Hz, 1H), 1.92–1.71 (m, 3H), 1.39–1.08 (m, 4H).

[1124] 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

[1125]

[1126] Prepared by replacing JD-5303001d with JD-5303035a according to the synthetic method of Reference Example 22, 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%) was a white solid.

[1127] LCMS: 418.3 ([M+H] + )

[1128] 1 1H NMR (300 MHz, DMSO-d6): δ 7.58–7.46 (m, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.17 (t, J = 7.8 Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.59 (dd, J = 8.7, 2.7 Hz, 1H), 4.99 (s, 2H), 4.11 (t, J = 4.5 Hz, 2H), 3.70–3.63 (m, 2H), 3.61–3.41 (m, 3H), 2.86–2.72 (m, 1H), 2.00 (d, J = 12.0 Hz, 1H), 1.83–1.64 (m, 3H), 1.34–1.06 (m, 4H).

[1129] Preparation of N-[3-(hydroxymethyl)-2-oxohexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303095, Example 89

[1130]

[1131] Step 1 Preparation of ethyl 3-azido-2-oxohexahydropyridine-3-carboxylate JD-5303095-2

[1132]

[1133] Ethyl 2-oxohexahydropyridine-3-carboxylate JD-5303095-1 (3.0 g, 17.52 mmol, 1.0 eq) was added to a solution of DBU (2.94 g, 19.28 mmol, 1.1 eq) and TsN3 (3.80 g, 19.28 mmol, 1.1 eq) in DCM (30 mL). The mixture was stirred at room temperature for 72 h, diluted with water (15 ml), and extracted with DCM (15 ml × 2). The collected organic phase was washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Purification by silica gel column chromatography (DCM) gave ethyl 3-azido-2-oxohexahydropyridine-3-carboxylate JD-5303095-2 (3.0 g, 80.6%) as a yellow solid.

[1134] LCMS: 213.1 ([M+H] + ).

[1135] 1 H NMR (400 MHz, CDCl3): δ 6.36 (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 = 7.2 Hz, 3H).

[1136] Step 2 Preparation of ethyl 3-amino-2-oxohexahydropyridine-3-carboxylate JD-5303095-3

[1137]

[1138] To a solution of ethyl 3-azido-2-oxohexahydropyridine-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 h, 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 give ethyl 3-amino-2-oxohexahydropyridine-3-carboxylate JD-5303095-3 (160 mg, crude) as a yellow oil.

[1139] LCMS: 187.1 ([M+H] + ).

[1140] Step 3 Preparation of ethyl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-2-oxohexahydropyridine-3-carboxylate JD-5303095-4

[1141]

[1142] JD-5303001-4 (120 mg, 0.46 mmol, 1.0 eq) of 6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one 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 reacted at room temperature for 0.5 h. Then, JD-5303095-3 (127 mg, 0.69 mmol, 1.4 eq) of ethyl 3-amino-2-oxohexahydropyridine-3-carboxylate was dissolved in DCM (0.5 mL) and added to the mixture, and the mixture was stirred at 40 °C for 15 h. The reaction system was quenched with water (10 mL), 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 obtain a residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 50 / 1) to obtain ethyl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-2-oxohexahydropyridine-3-carboxylate JD-5303095-4 (120 mg, yield 55.3%, purity 90%) as a white solid.

[1143] LCMS: 475.2 ([M+H] + ).

[1144] 1 H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.14 (s, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.68 (dd, J = 9.0, 3.0 Hz, 1H), 6.04 (d, J = 3.0 Hz, 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 = 7.2 Hz, 3H).

[1145] Preparation of N-[3-(Hydroxymethyl)-2-oxohexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303095

[1146]

[1147] Ethyl 3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}-2-oxohexahydropyridine-3-carboxylate JD-5303095-4 (120 mg, 0.25 mmol, 1.0 eq) was stirred in THF (3 mL), and LiAlH4 (1.0 M in 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 give a residue. The residue was purified by preparative TLC (DCM / MeOH = 8:1) to give JD-5303095 (15 mg, 13.7%) as a white solid.

[1148] LCMS: 433.1 ([M+H] + )。

[1149] 1 1H NMR (300 MHz, DMSO-d6): δ 8.98 (s, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.70–6.58 (m, 2H), 5.27–5.04 (m, 3H), 4.11 (t, J = 4.2 Hz, 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).

[1150] Example 90 Preparation of 6-{[(2-Fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)-2-oxohexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303102

[1151]

[1152] Using the synthesis method of Reference Example 89, replace the compound JD-5303001-4 with JD-5303028-3 to prepare 6-{[(2-fluorophenyl)methyl]oxy}-N-[3-(hydroxymethyl)-2-oxohexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303102 (40 mg, 46.3%) as a white solid.

[1153] LCMS: 430.2 ([M+H] + )。

[1154] 1 H NMR (300 MHz, DMSO-d6): δ 7.59–7.48 (m, 2H), 7.48–7.38 (m, 1H), 7.34 (d, J = 3.0 Hz, 1H), 7.30–7.17 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 6.69–6.58 (m, 2H), 5.14 (t, J = 6.3 Hz, 1H), 5.04 (s, 2H), 4.11 (t, J = 4.5 Hz, 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).

[1155] Preparation of N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-7-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303094 in Example 91

[1156]

[1157] Using the synthesis method of Reference Example 76, replace the compound JD-5303028a with JD-5303001d to prepare N-[3-(hydroxymethyl)hexahydropyridin-3-yl]-7-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxamide JD-5303094 (7.5 mg, 5.0%) as a white solid.

[1158] LCMS: 417.2 ([M+H] + )。

[1159] 11H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.0, 2.4 Hz, 1H), 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 = 10.8 Hz, 1H), 3.06–2.97 (m, 1H), 2.78–2.72 (m, 1H), 2.72–2.66 (m, 1H), 2.64 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 2.12–2.05 (m, 1H), 1.85–1.77 (m, 2H), 1.73–1.37 (m, 4H).

[1160] Example 92 Preparation of N-[3-(methoxymethyl)hexahydropyridin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303093

[1161]

[1162] Step 1 Methyl 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridine-3-carboxylate JD-5303093-2

[1163]

[1164] The compound methyl 1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylate JD-530309-1 (500 mg, 2.055 mmol, 1.0 eq) was added to LDA (2.0 M in THF) (1.13 mL, 2.26 mmol, 1.1 eq) in THF (8 mL), and stirred under a nitrogen atmosphere at -65 °C. The mixture was stirred at -65 °C for 0.5 h, then MOMBr (308 mg, 2.46 mmol, 1.2 eq) was added, and 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 × 2). The combined organic phases were washed with brine (15 mL) and dried over Na2SO4. The residue was obtained by filtration and concentration under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give methyl 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylate JD-5303093-2 (500 mg, 84.6%) as a yellow oil.

[1165] LCMS: 232.1 ([M-56+H] + ).

[1166] 1 H NMR (300 MHz, CDCl3): δ 3.80–3.65 (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).

[1167] Step 2 Preparation of 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid JD-5303093-3

[1168]

[1169] 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) was added to LiOH·H2O (219 mg, 5.22 mmol, 3.0 eq) in THF (3 ml) and H2O (3 ml). The mixture was stirred at room temperature for 15 h. It was diluted with water (10 mL) and extracted with ethyl acetate (8 mL * 2). The aqueous phase was adjusted to pH 3 with KHSO4 solution and extracted with ethyl acetate (8 mL * 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the compound 3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidine-3-carboxylic acid JD-5303093-3 (420 mg, crude) as a colorless oil.

[1170] LCMS: 218.3 ([M - 56 + H] + ).

[1171] Preparation of benzyl {[3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidin-3-yl]amino}methanecarboxylate JD-5303093-4

[1172]

[1173] To a solution of the compound 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). Then the mixture was stirred at 90 °C for 15 h. The mixture was diluted with water (8 ml) and extracted with ethyl acetate (8 ml * 2). The collected organic phase was washed with brine (8 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to give the compound benzyl {[3-(methoxymethyl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidin-3-yl]amino}methanecarboxylate JD-5303093-4 (650 mg, crude) as a colorless oil.

[1174] LCMS: 323.1 ([M - 56 + H] + ).

[1175] Step 4 Preparation of 2-methylpropan-2-yl 3-amino-3-(methoxymethyl)piperidine-1-carboxylate JD-5303093-5

[1176] To a solution of 2-methylpropan-2-yl 3-amino-3-(methoxymethyl)piperidine-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%). Then the mixture was stirred under hydrogen at room temperature for 15 h. The mixture was filtered and the filtrate was concentrated to give 480 mg of crude oil. The crude oil 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×2). The aqueous phase was adjusted to pH 8 with Na2CO3 solution and extracted with DCM (5 mL×3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-methylpropan-2-yl 3-amino-3-(methoxymethyl)piperidine-1-carboxylate JD-5303093-5 (220 mg, 51.7%, three steps) as a colorless oil.

[1177] LCMS: 245.2 ([M+H] + ).

[1178] Using the synthetic method of Reference Example 1, the compound JD-3503001d was replaced with JD-5303093-5 to prepare N-[3-(methoxymethyl)piperidin-3-yl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamide JD-5303093 (53 mg, 65.4%) as a yellow solid.

[1179] LCMS: 433.2 ([M+H] + )

[1180] 11H NMR (300 MHz, DMSO-d6): δ 8.98 (s, 1H), 7.32 (d, J = 3.0 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 6.63 (dd, J = 9.0, 3.0 Hz, 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 = 9.0 Hz, 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).

[1181] Example 93 Preparation of 6-{[(2-Fluorophenyl)methyl]oxy}-N-[3-(methoxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303096

[1182]

[1183] Prepared by replacing compound JD-3503001c with JD-5303028a according to the synthetic method of Reference Example 92, 6-{[(2-Fluorophenyl)methyl]oxy}-N-[3-(methoxymethyl)hexahydropyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303096 (51 mg, 39.4%) was a white solid.

[1184] LCMS: 430.2 ([M+H] + )

[1185] 11H NMR (300 MHz, DMSO-d6): δ 8.28 (brs, 1H), 7.53 (td, J = 7.2, 1.5 Hz, 1H), 7.46–7.37 (m, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.29–7.16 (m, 2H), 6.78 (d, J = 9.0 Hz, 1H), 6.63 (dd, J = 9.0, 3.0 Hz, 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 = 9.3 Hz, 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).

[1186] Preparation of Example 94 N-[3-Amino-1-(hydroxymethyl)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303108

[1187]

[1188] Step 1 Preparation of Benzyl [(2,4-dioxo-1,3-diazaspiro[4.5]dec-7-yl)amino]carbamate JD-5303108-2

[1189]

[1190] Dissolve benzyl [(3-oxocyclohexyl)amino]carbamate JD-5303108-1 (5.0 g, 20.22 mmol, 1.0 eq) in MeOH (30 mL) and H2O (30 mL), add (NH4)2CO3 (5.8 g, 60.66 mmol, 3.0 eq) and TMSCN (4.0 g, 40.44 mmol, 2.0 eq), and react the reaction mixture at 80 °C for 15 h. Concentrate the mixture under reduced pressure to obtain a residue. Collect the filter cake by filtration of the residue to obtain benzyl [(2,4-dioxo-1,3-diazaspiro[4.5]dec-7-yl)amino]carbamate JD-5303108-2 (5.5 g, crude) as a yellow solid. LC-MS ([M+H] + ) = 318.1.

[1191] Step 2 Preparation of 2-methylpropan-2-yl 7-(7,7-dimethyl-3,5-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-4-yl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-carboxylate JD-5303108-3

[1192]

[1193] Dissolve benzyl [(2,4-dioxo-1,3-diazaspiro[4.5]dec-7-yl)amino]methanecarboxylate JD-5303108-2 (5.5 g, 17.33 mmol, 1.0 eq) in Dioxane (60 mL), add TEA (10.5 g, 103.99 mmol, 6.0 eq), (Boc)2O (18.9 g, 86.66 mmol, 5.0 eq) and DMAP (212 mg, 1.73 mmol, 0.1 eq). The reaction mixture is reacted at 70 °C for 15 h. The mixture is concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1) to obtain 2-methylpropan-2-yl 7-(7,7-dimethyl-3,5-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-4-yl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-carboxylate JD-5303108-3 (6.2 g, two-step yield 49.6%, purity 94%) as a yellow oil.

[1194] LC-MS ([M+H2O] + ) = 635.3.

[1195] 1 1H NMR: (300 MHz, CDCl3) δ = 7.45 - 7.28 (m, 5H), 5.35 - 5.24 (m, 2H), 4.49 - 4.44 (m, 1H), 2.71 (t, J = 6.3 Hz, 1H), 2.61 - 2.50 (m, 1H), 2.14 (d, J = 10.8 Hz, 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).

[1196] Step 3 Preparation of 1-amino-3-(7,7-dimethyl-3,5-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-4-yl)cyclohexane-1-carboxylic acid JD-5303108-4

[1197]

[1198] 7-(7,7-Dimethyl-3,5-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-4-yl)-1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,4-dioxo-1,3-diazaspiro[4.5]decane-3-carboxylic acid 2-methylpropan-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), and 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-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-4-yl)cyclohexane-1-carboxylic acid JD-5303108-4 (7.0 g, crude) as a white solid.

[1199] LC-MS ([M-H] - ) = 391.2.

[1200] Step 4 Preparation of 1-amino-3-{[(benzyloxy)carbonyl]amino}cyclohexane-1-carboxylic acid JD-5303108-5

[1201]

[1202] 1-Amino-3-(7,7-dimethyl-3,5-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-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), and HCl / Dioxane (4.0 M) (75.3 mL, 301.2 mmol, 30.0 eq) was added. 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-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-4-yl)cyclohexane-1-carboxylic acid JD-5303108-5 (8.0 g, crude) as a white solid.

[1203] LC-MS ([M+H] + ) = 293.1.

[1204] Step 5 Preparation of methyl 1-amino-3-{[(benzyloxy)carbonyl]amino}cyclohexane-1-carboxylate JD-5303108-6

[1205]

[1206] 1-Amino-3-(7,7-dimethyl-3,5-dioxo-1-phenyl-4-aza-2,6-dioxaoctan-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 mixture was adjusted to pH 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 * 3). The mixture was filtered to collect the filtrate and concentrated under reduced pressure to obtain a filter residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 80 / 1) to obtain methyl 1-amino-3-{[(benzyloxy)carbonyl]amino}cyclohexane-1-carboxylate JD-5303108-6 (170 mg, three-step yield 11.1%, purity 90%) as a yellow oil.

[1207] LC-MS([M+H] + ) = 307.1.

[1208] 1 H NMR: (300 MHz, CDCl3) δ = 7.38 - 7.31 (m, 5H), 5.07 (s, 2H), 4.63 (d, J = 6.3 Hz, 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).

[1209] Preparation of benzyl {[3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}cyclohexyl]amino}methanecarboxylate JD-5303108-7

[1210]

[1211] 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. Then Int-1 (100 mg, 0.38 mmol, 1.0 eq) was dissolved in DCM (1 mL) and added to the mixture, and the mixture was stirred at 40 °C for 15 h. The reaction system was quenched with water (5 mL), extracted with DCM (10 mL, 5 mL * 2), and the collected organic phase was washed with brine (5 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 gel, petroleum ether / ethyl acetate = 1 / 1) to obtain benzyl {[3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}cyclohexyl]amino}methanecarboxylate JD-5303108-7 (150 mg, yield 66.1%, purity 90%) as a yellow solid.

[1212] LC-MS ([M+H] + ) = 595.2.

[1213] Step 7 Preparation of methyl 3-amino-1-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carbonyl]amino}cyclohexane-1-carboxylate JD-5303108-8

[1214]

[1215] Benzyl {[3-(methoxycarbonyl)-3-{[(6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-yl)carbonyl]amino}cyclohexyl]amino}methanecarboxylate JD-5303108-7 (150 mg, 0.25 mmol, 1.0 eq) was dissolved in DCM (5 mL), and TMSI (151 mg, 0.75 mmol, 3.0 eq) was added. The mixture was stirred at room temperature for 4 h. The mixture was quenched by adding water (5 mL). Then it was 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 a residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to give methyl 3-amino-1-{[(6-{[(4-methyl-1,3-thiazepan-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, yield 51.7%, purity 90%) as a yellow solid.

[1216] LC-MS([M+H] + ) = 461.2.

[1217] Preparation of N-[3-amino-1-(hydroxymethyl)cyclohexyl]-6-{[(4-methyl-1,3-thiazepan-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-carboxamide JD-5303108

[1218]

[1219] 53 - 8 (60 mg, 0.13 mmol, 1.0 eq) was dissolved in THF (5 mL). The temperature was lowered to 0 °C, and LiAlH4 (1.0 M in THF) (0.26 mL, 0.26 mmol, 2.0 eq) was added to the mixture. The reaction mixture was reacted at 0 °C for 1 hour. The mixture was quenched by dropwise addition of NaOH solution (15%) (0.1 mL) at 0 °C and dried with Na2SO4. The mixture was filtered to collect the filtrate and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Ul C18 150*25mm*5mm; mobile phase: [water (0.1% TFA) - acetonitrile]; B%: 25% - 45%, 6 min) to obtain the product. The product was dissolved in water (5 mL), the pH was adjusted to 9 with saturated aqueous sodium hydroxide solution, and then extracted with DCM (5 mL * 2). The collected organic phase was washed with brine (5 mL) and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain JD01-LHNY-53 (4.5 mg, yield 8.0%, purity 95.3%) as a white solid.

[1220] LC-MS ([M + H] + ) = 433.3.

[1221] 1 1H NMR: (300 MHz, DeOD) δ = 8.89 (s, 1H), 7.17 (d, J = 3.0 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.69 (dd, J = 9.0, 3.0 Hz, 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 = 13.2 Hz, 1H), 1.93 (d, J = 11.7 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.60 - 1.45 (m, 1H), 1.26 - 1.09 (m, 3H).

[1222] Example 95 Preparation of N-[3-Amino-1-(hydroxymethyl)cyclohexyl]-6-{[(2-fluorophenyl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepin-4-carboxamide JD-5303111

[1223]

[1224] Using the synthesis method of Reference Example 94, replace the compound JD-5303001-4 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%), which is a white solid.

[1225] LC-MS([M+H] + ) = 430.3.

[1226] 1 H NMR: (300 MHz, DMSO-d6) δ = 7.53 (td, J = 7.5, 1.5 Hz, 1H), 7.48 - 7.34 (m, 1H), 7.30 - 7.14 (m, 3H), 6.77 (d, J = 9.0 Hz, 1H), 6.61 (dd, J = 8.7, 2.7 Hz, 1H), 6.28 - 5.80 (m, 2H), 5.02 (s, 2H), 4.23 - 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).

[1227] Example 96 Preparation of Benzyl 4,4-difluoro-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303105

[1228]

[1229] Using the synthesis method of Reference Example 84, in step 5, replace the compound JD-5303104-5 with JD-5303001-4 to prepare benzyl 4,4-difluoro-3-{[(6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-4-yl)carbonyl]amino}hexahydropyridine-1-carboxylate JD-5303105 (95 mg, yield 69.4%, purity 99%), which is a white solid.

[1230] LC-MS([M+H] + ) = 559.2.

[1231] 1 1H NMR: (300 MHz, DMSO-d6) δ = 8.87 (s, 1H), 7.42–7.23 (m, 5H), 7.17 (d, J = 3.0 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.66 (dd, J = 9.0, 2.7 Hz, 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).

[1232] Example 97 Preparation of N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303106

[1233]

[1234] Prepared by the synthetic method of Reference Example 84 by replacing compound JD-5303104-5 with JD-5303001-4, N-(4,4-difluorohexahydropyridin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303106 (10 mg, yield 18.8%, purity 99%) was a white solid.

[1235] LC-MS ([M+H] + ) = 425.2.

[1236] 1 1H NMR: (300 MHz, DMSO-d6) δ = 8.98 (s, 1H), 7.27 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 6.62 (dd, J = 9.0, 3.0 Hz, 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).

[1237] Preparation of N-methyl-N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303082

[1238]

[1239] Step 1 Preparation of N-methyl-N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303082

[1240]

[1241] Dissolve N-(3-aminocyclohexyl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303008 (100 mg, 0.25 mmol, 1.0 eq) in MeOH (2 mL), add (HCHO) n (11 mg, 0.37 mmol, 1.5 eq) to the mixture. The reaction mixture is reacted at room temperature for 0.5 h, then NaBH3CN (31 mg, 0.5 mmol, 2.0 eq) is added to the mixture and stirred at 50 °C for 11.5 h. After concentrating the mixture, the crude product is obtained, diluted with water (8 mL), then extracted with dichloromethane (20 mL, 10 mL * 2). The collected organic phase is washed with brine (8 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (silica gel, dichloromethane / methanol = 30 / 1 to 10 / 1) to obtain N-methyl-N-[3-(methylamino)cyclohexyl]-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-carboxamide JD-5303082 (12.9 mg, yield 12.1%, purity 97%) as a yellow solid.

[1242] LC-MS([M+H] + ) = 431.2.

[1243] 11H NMR (300 MHz, DMSO-d6) δ = 10.43 (brs, 1H), 8.97 (s, 1H), 7.34 (d, J = 3.0 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 5.7 Hz, 1H), 6.60 (dd, J = 9.0, 3.0 Hz, 1H), 5.17 (s, 2H), 4.18–4.00 (m, 3H), 3.79–

[1244] 3.60 (m, 2H), 2.73–2.56 (m, 6H), 2.39 (s, 3H), 2.10–1.41 (m, 8H).

[1245] Comparative Example 1 Preparation of N-(Piperidin-3-yl)-7-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazepine-1-carboxamide trifluoroacetate JD-5303065

[1246]

[1247] According to the synthesis method of Example 1, replacing compound JD-5303001-1 with JD-5303065-1, N-(Piperidin-3-yl)-7-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazepine-1-carboxamide trifluoroacetate JD-5303065 (1.42 mg, 3.57 μmol, yield 34.9%, purity 98%) was obtained as a yellow gum.

[1248] LCMS [389+H] + = 390.

[1249] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 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 = 11.51 Hz, 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 = 7.13 Hz, 1H) 7.62 (d, J = 2.63 Hz, 1H) 7.94 (d, J = 2.75 Hz, 1H) 8.55 (br s, 2H) 9.00 (s, 1H).

[1250] Preparation of Comparative Example 2 N-(Piperidin-3-yl)-6-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-4-carboxamide JD-5303066

[1251]

[1252] Prepared N-(Piperidin-3-yl)-7-{[(4-methyl-1,3-thiazol-5-yl)methyl]oxy}-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide trifluoroacetate JD-5303066 (22.4 mg, purity 98.83%) as a yellow gum by replacing compound JD-5303001-1 with JD-5303066-1 according to the synthesis method of Reference Example 1.

[1253] LC-MS [389+H] + = 390.

[1254] 1 H NMR: (400 MHz, METHANOL-d4) δ = 1.55 (qd, J = 11.63, 3.38 Hz, 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 = 11.13 Hz, 2H), 3.19 (br d, J = 12.01 Hz, 1H), 3.42 (br d, J = 10.26 Hz, 1H), 3.89 (br dd, J = 6.44, 3.06 Hz, 1H), 3.95 - 4.04 (m, 2H), 4.12 - 4.23 (m, 2H), 5.41 (d, J = 3.38 Hz, 2H), 6.53 (d, J = 8.63 Hz, 1H), 7.39 (d, J = 8.63 Hz, 1H), 8.54 - 8.83 (m, 2H), 9.01 (s, 1H), 9.26 (d, J = 6.75 Hz, 1H).

[1255] Biological Test Example

[1256] 1. hTRPM3 Calcium Flux Assay

[1257] This test uses The Calcium 5 Assay Kit was used to screen small molecules. HeLa cells transfected with human TRPM3 protein for about 24 hours were seeded in a 96-well plate in advance and cultured adherently. When they grew to an appropriate density, the culture medium was discarded. At the same time, a cell-permeable calcium ion concentration indicator (FLIPR Calcium 5 Assay kit) prepared with extracellular buffer was added and co-incubated with the cells at 37 °C and 5% CO2 for 50 minutes. Then, small molecule solutions at different concentrations and a positive inhibitor were added to the 96-well plate, and a blank control was set and incubated for another 15 minutes. The small molecules were prepared as a 10 mM stock solution with DMSO and then diluted to the required concentration with a drug preparation solvent (10% DMSO + 90% HBSS). The blank control was extracellular buffer containing the corresponding concentration of the co-solvent DMSO. The whole process was placed in the dark. After incubation, the 96-well plate was placed on a FlexStation3 multi-functional microplate reader. The sample plate of the specific agonist pregnenolone sulfate (PregS) of TRPM3 was loaded into the sampler of the microplate reader in advance, with the concentration set at 60 μM (the final concentration in the well was 15 μM). The test program was set, the cell fluorescence was excited at 485 nM, and the fluorescence emitted at 525 nM was detected. The test time for each well was 90 s, and the data acquisition interval was 1.52 s. After recording for 25 s, the positive agonist PregS (final concentration 15 μM) was added by the liquid addition arm of the instrument, and the remaining data points were continuously collected. After all the well plates were tested, the fluorescence increment before and after adding the agonist for all wells was calculated according to the quantified fluorescence intensity change curve output by the machine, and was normalized with the fluorescence increment of the corresponding blank control wells to obtain the inhibition rate of the fluorescence intensity under the action of small molecules at different concentrations. The inhibition curve of the logarithm of the concentration against the inhibition rate was obtained by curve fitting (Y = 100 / (1 + 10^((LogIC50 - X)*HillSlope))) in GraphPad. All the charts were generated using GraphPad Prism 8.0 version.

[1258] Table 1 Test results of hTRPM3 calcium flux assay

[1259]

[1260]

[1261] “A”: IC 50 ≤1 μΜ; “B”: 1 μΜ < IC 50 ≤10 μΜ; “C” > 10 μM.

[1262] The test results show that the compounds of the present invention exhibit good inhibitory effects on hTRPM3, and some of the compounds can achieve an hTRPM3 inhibition effect of 1 μΜ.

Claims

1. A compound I, its stereoisomers or its pharmaceutically acceptable salts, wherein, X is N or CH; Y is O or -CH2-; L 1 For -L a -L b -L c -L d -; L a 、 L b 、 L c and L d are each independently a linking key, O, S or and L a 、 L b 、 L c and L d are not simultaneously linking keys; Among L a 、 L b 、 L c and L d the number of O, S and is 1 or 2; R 6 、R 6a and R 6b and R 6-1 are each independently H, a C1-C6 alkyl group, or a C1-C6 alkyl group substituted by one or more R R 6-1 each independently is a hydroxyl group, a halogen, an amino group, -NHC1-C6 alkyl or -N(C1-C6 alkyl)2; U is a 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered cycloalkyl, or a C6-C 9-1 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered cycloalkyl substituted with one or more R 10 groups; 9-2 a 5- to 10-membered heteroaryl substituted with one or more R 9-a groups, or a 3- to 8-membered cycloalkyl substituted with one or more R R 9-1 、R 9-2 and R 9-a each independently represents a halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, oxo, -O-(3-8 membered cycloalkyl) or a C1-C6 alkyl substituted with one or more R 9-4 substituents; R 9-3 each independently is H, a C1-C6 alkyl group or a 3-8 membered cycloalkyl group; R 9-4 each independently is a hydroxyl group, a halogen, or a C1-C6 alkoxy group; R 1 、R 2 and R 3 are each independently H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkyl substituted by one or more halogens; R 4 、R 4a 、R 5a and R 5 each independently represents H, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered cycloalkyl group, or a C1-C6 alkyl group substituted by one or more halogens; Alternatively, R 4 and R 4a together with the adjacent carbon atom form a 3- to 8-membered cycloalkyl group; W is L 2 R 7 ; L 2 is a linking group, -CH2-, -NH- or -N(C1-C6 alkyl)-; R 7 is a 3- to 8-membered cycloalkyl, 3- to 12-membered heteroalkyl, 5- to 10-membered heteroaryl, 3- to 12-membered heteroalkyl substituted with one or more R 7-1 groups, 5- to 10-membered heteroaryl substituted with one or more R 7-2 groups, C1-C6 alkyl substituted with one or more R 7-3 groups or 3- to 8-membered cycloalkyl substituted with one or more R 7-4 groups; R 7-1 、R 7-2 and R 7-4 each independently represents a halogen, a hydroxyl group, an oxo group, an amino group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, -O-(3-8 membered cycloalkyl), C1-C6 alkyl substituted with one or more R 7-1-1 or C1-C6 alkoxy substituted with one or more R 7-1-2 ; R 7-1-1 and R 7-1-2 each independently represents a halogen atom, a hydroxyl group, an amino group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, R 7-3 each independently is halogen, hydroxy, amino, C1-C6 alkoxy, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, R 7-2-1 each independently is H, a C1-C6 alkyl group, a 3- to 8-membered cycloalkyl group, or a C1-C6 alkyl group substituted by one or more C6-C 10 aryl groups; The heteroatoms in the 3- to 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- to 10-membered heteroaryl group are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3.

2. The compound I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, characterized in that, L 1 For wherein the a end is connected to U; U is a 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, a C6-C 9-1 aryl substituted with one or more R 10 or a 5- to 10-membered heteroaryl substituted with one or more R 9-2 ; R 9-1 and R 9-2 each independently is halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, oxo, -O-(3-8 membered cycloalkyl) or C1-C6 alkyl substituted with one or more R 9-4 substituents; R 7-1 、R 7-2 and R 7-4 each independently represents a halogen, a hydroxyl group, an oxo group, an amino group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, -O-(3-8 membered cycloalkyl), C1-C6 alkyl substituted by one or more R 7-1-1 or C1-C6 alkoxy substituted by one or more R 7-1-2 ; R 7-1-1 and R 7-1-2 each independently represents a halogen, a hydroxyl group, an amino group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, R 7-2-1 Each independently is H, a C1-C6 alkyl group or a 3-8 membered cycloalkyl group.

3. The compound I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or 2, characterized in that, The compound I satisfies one or more of the following conditions: (1) Each C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (2) Each C2-C6 alkenyl group is independently vinyl, propenyl, allyl, butenyl or pentenyl, preferably vinyl; (3) Each C2-C6 alkynyl group is independently ethynyl, propynyl, propargyl, butynyl or pentynyl; (4) Each C1-C6 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 heteroatoms in each 3- to 12-membered heterocycloalkyl group are independently N; the number of heteroatoms can independently be 1 or 2; (7) Each 3- to 12-membered heterocycloalkyl group is independently a 4- to 10-membered heterocycloalkyl group; (8) Each 3- to 12-membered heterocyclic group is independently monocyclic or bicyclic, and the bicyclic group can be a bridged ring or a spiro ring; (9) Each C6-C 10 aryl is independently phenyl or naphthyl, preferably phenyl; (10) Each 5- to 10-membered heteroaryl group is independently a 5- to 6-membered heteroaryl group; (11) The heteroatoms in each 5- to 10-membered heteroaryl group are independently N, S or O; the number of heteroatoms can independently be 1 or 2; (12) Each 5- to 10-membered heteroaryl group is independently monocyclic or bicyclic; (13) Each 3- to 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.

4. The compound I, its stereoisomers or pharmaceutically acceptable salts 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 the a end is connected to U; (4)R 6 、R 6a and R 6b each independently is H or C1-C6 alkyl, preferably H; (5)U is C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 9-1 aryl substituted by one or more R 10 or 5- to 10-membered heteroaryl substituted by one or more R 9-2 ; (6)R 9-1 and R 9-2 each independently represents a halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered cycloalkyl group, or a C1-C6 alkyl group substituted with one or more R 9-4 substituents; (7)R 9-3 Each independently is H or a C1-C6 alkyl group, preferably H; (8)R 9-4 is a 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 is H; (12)R 4 is H or a C1-C6 alkyl group, preferably H; (13)L 2 is a linking bond, -CH2- or -NH-, preferably -NH-; (14)R 7 is a 3- to 12-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocycloalkyl group substituted with one or more R 7-1 a 5- to 10-membered heteroaryl group substituted with one or more R 7-2 or a 3- to 8-membered cycloalkyl group substituted with one or more R 7-4 ; Preferably, R 7 is a 3- to 12-membered heterocycloalkyl group or a 3- to 12-membered heterocycloalkyl group substituted with one or more R 7-1 substituents; More preferably, R 7 is piperidinyl, pyrrolidinyl, pyrrolidinyl substituted with one or more halogens, or piperidinyl substituted with one or more halogens; More preferably, R 7 is a piperidinyl group substituted with one or two Fs or a pyrrolidinyl group substituted with one or two Fs; (15)R 7-1 、R 7-2 and R 7-4 each independently represents a halogen, an amino group, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkyl substituted by one or more R 7-1-1 or C1-C6 alkoxy substituted by one or more R 7-1-2 ​ (16)R 7-1-1 and R 7-1-2 each independently is halogen, hydroxy, C2-C6 alkenyl, (17)R 7-2-1 each independently is H or a C1-C6 alkyl group; and (18) When L 2 is a linking group, R 7 is a 3- to 12-membered heterocycloalkyl group or a 3- to 12-membered heterocycloalkyl group substituted by one or more R 7-1 ; the 3- to 12-membered heterocycloalkyl group is preferably a spiro ring; preferably, the heteroatom of the 3- to 12-membered heterocycloalkyl group can be N, and the number of heteroatoms can be 1 or 2; more preferably, the N atom in the 3- to 12-membered heterocycloalkyl group is connected to L 2 .

5. The compound I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or 2, characterized in that, The compound I satisfies one or more of the following conditions: (1)L 1 For wherein the a end is connected to U; (2)U is and (3)W is 6. The compound I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or 2, characterized in that, X is N or CH; Y is O or -CH2-; L 1 is wherein the a end is connected to U; R 6 、R 6a and R 6b each independently represents H or a C1-C6 alkyl group; U is C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 9-1 aryl substituted with one or more R 10 or 5- to 10-membered heteroaryl substituted with one or more R 9-2 ; R 9-1 and R 9-2 each independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, or C1-C6 alkyl substituted by one or more halogen; R 9-3 each independently is H or a C1-C6 alkyl group R 1 、R 2 and R 3 each independently is H, a halogen or a C1-C6 alkyl group; R 4 and R 4a each independently is H or a C1-C6 alkyl group; Alternatively, R 4 and R 4a together with the adjacent carbon atom form a 3- to 8-membered cycloalkyl group; W is L 2 R 7 ; L 2 is a linking key, -CH2-, or -NH-; R 7 is a 3- to 12-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocycloalkyl group substituted with one or more R 7-1 groups, a 5- to 10-membered heteroaryl group substituted with one or more R 7-2 groups or a 3- to 8-membered cycloalkyl group substituted with one or more R 7-4 groups; R 7-1 、R 7-2 and R 7-4 Each is independently halogen, amino, -NHC1-C6 alkyl, C1-C6 alkyl, -N(C1-C6 alkyl)2, By one or more R 7-1-1 Substituted C1-C6 alkyl or one or more R 7-1-2 Substituted C1-C6 alkoxy; R 7-1-1 and R 7-1-2 each independently represents a halogen, a hydroxyl group, a C2-C6 alkenyl group, R 7-2-1 each independently is H or a C1-C6 alkyl group; The heteroatoms in the 3- to 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- to 10-membered heteroaryl group are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3.

7. The compound I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or 2, characterized in that, The compound I satisfies one or more of the following conditions: (1)L a 、L b 、L c and L d The number of O, S and in it is 1; (2) U is a 3- to 8-membered cycloalkyl group; (3)R 9-a independently a halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 8-membered cycloalkyl group, or a C1-C6 alkyl group substituted with one or more R 9-4 groups; (4)L 2 is a linking key, -NH-, or -N(CH3)-; (5)R 7 is C1-C6 alkyl substituted by one or more R 7-3 groups; (6)R 7-3 is a hydroxyl group or (7)R 7-1 、R 7-2 and R 7-4 Each independently (8)R 7-1-1 and R 7-1-2 each independently represents a C1-C6 alkoxy group; and (9)R 7-2-1 Each independently is a 3- to 8-membered cycloalkyl or a C1-C6 alkyl substituted by one or more C6-C 10 aryl groups.

8. The compound I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or 2, characterized in that, The compound I satisfies one or two of the following conditions: (1)U is, and (2) W is 9. The compound I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or 2, characterized in that, The compound I satisfies any one of the following schemes: Scheme one: X is N or CH; Y is O or -CH2-; L 1 For where the a end is connected to U; R 6 、R 6a and R 6b each independently represents H or a C1-C6 alkyl group; U is C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered cycloalkyl, C6-C 9-1 aryl substituted with one or more R 10 or 5- to 10-membered heteroaryl substituted with one or more R 9-2 ; R 9-1 and R 9-2 each independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, or C1-C6 alkyl substituted with one or more halogens; R 9-3 each independently is H or a C1-C6 alkyl group R 1 、R 2 and R 3 each independently represents H, a halogen, or a C1-C6 alkyl group; R 4 and R 4a each independently is H or a C1-C6 alkyl group; Alternatively, R 4 and R 4a together with the adjacent carbon atom form a 3- to 8-membered cycloalkyl group; R 5 and R 5a is H; W is L 2 R 7 ; L 2 is a linking key, -CH2- or -NH-; R 7 is a 3- to 12-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocycloalkyl group substituted with one or more R 7-1 a 5- to 10-membered heteroaryl group substituted with one or more R 7-2 a C1-C6 alkyl group substituted with one or more R 7-3 or a 3- to 8-membered cycloalkyl group substituted with one or more R 7-4 ; R 7-1 、R 7-2 and R 7-4 Each is independently halogen, amino, -NHC1-C6 alkyl, C1-C6 alkyl, -N(C1-C6 alkyl)2, By one or more R 7-1-1 Substituted C1-C6 alkyl or one or more R 7-1-2 Substituted C1-C6 alkoxy; R 7-1-1 and R 7-1-2 each independently represents a halogen, a hydroxyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, R 7-3 each independently is a hydroxyl group or R 7-2-1 each independently is H, a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more C6-C 10 aryl groups; The heteroatom in the 3- to 12-membered heterocycloalkyl is selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3; The heteroatom in the 5- to 10-membered heteroaryl is selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3; Scheme 2: The compound I is compound I-1, I-2, or I-3, 10. The compound I, its stereoisomers or its pharmaceutically acceptable salts 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 the compound I is selected from any one of the following compounds:

11. A compound II, Among them, R 1 、R 2 、R 3 、R 4 、R 4a 、R 5 、R 5a 、L 1 and the definitions of U are as described in any one of claims 1-10.

12. A pharmaceutical composition comprising the compound I, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1-10, and at least one pharmaceutical excipient.

13. Use of the compound I, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1-10, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating pain; the pain is preferably inflammatory pain.

14. Use of the compound I, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1-10, or the 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.

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