1H-Benzo[b]azepin-2(3H)-one compounds, compositions, and methods for treating cancer - Patents.com

Abstract

The present disclosure includes, inter alia, compounds, pharmaceutical compositions, and methods of making and using same that treat or lessen the severity of cancer.

Description

[Background technology]

[0001] background Cancer is the term used to describe diseases in which abnormal cells divide uncontrollably and can invade other tissues. Cancer cells can also spread to other parts of the body through the blood and lymphatic systems.

[0002] There are over 100 different types of cancer, and most cancers are named after the organ or type of cell they begin in. For example, cancer that begins in the colon may be called colon cancer, and cancer that begins in the basal cells of the skin may be called basal cell carcinoma. Common types of cancer include breast cancer and lung cancer.

[0003] Cancer types are sometimes divided into broader categories. The major categories of cancer include carcinoma (cancer that begins in the skin or tissues that line or cover the internal organs), sarcoma (cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supporting tissues), leukemia (cancer that begins in blood-forming tissues such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood), lymphoma and myeloma (cancer that begins in cells of the immune system), and central nervous system cancer (cancer that begins in tissues of the brain and spinal cord).

[0004] In the art, there are several techniques known for treating cancer. These techniques include chemotherapy, radiotherapy, surgery, and transplantation. However, each of these techniques has undesirable side effects and different success rates. Therefore, there is a need to develop new methods for treating cancer and / or cell proliferation-related diseases. Summary of the Invention

[0005] overview The present disclosure provides a compound of formula (I): or a pharma- ceutically acceptable salt thereof. Additionally, the disclosure includes, inter alia, pharmaceutical compositions, methods of using and methods of making the compounds of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Detailed Description In some embodiments, the present disclosure provides a compound of formula (I): TIFF2024542204000002.tif52128, or a pharma- ceutically acceptable salt thereof; During the ceremony, X is O= or S=; Ring A is selected from the group consisting of optionally substituted phenyl, optionally substituted 5-membered heteroaryl, and optionally substituted 6-membered heteroaryl; L is selected from the group consisting of a bond, optionally substituted C1-C3 alkylene, -CH(D)-, -C(D)2-, -C(O)-, -C(O)O-, -C(O)NH-, and -S(O)2-; The group C is selected from the group consisting of C1-C6 aliphatic, -C≡CR3, optionally substituted phenyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, optionally substituted 6-membered carbocyclyl, and optionally substituted 6-membered heterocyclyl; Each R A is halogen, -CN, -C≡CR 3 , optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, optionally substituted 3- to 7-membered heterocyclyl, -OR 1 , -SR 1 , -N(R 1 )2, -C(O)OR 1 , C(O)N(R 1 )2, -N(H)C(O)R 1 , and -N(H)C(O)N(R 1 or R B is a halogen, -C≡CR 3, optionally substituted 5-6 membered heteroaryl, optionally substituted C1-C3 aliphatic, and optionally substituted C1-C3 alkoxy, and optionally substituted 3-6 membered carbocyclyl; Each R C is halogen, -CN, an optionally substituted C1-C6 aliphatic group, an optionally substituted phenyl, an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 3- to 7-membered carbocyclyl, an optionally substituted 3- to 7-membered heterocyclyl, -OR 3 , -SR 3 , -N(R 3 )2, -C(O)OR 3 , -C(O)N(R 3 )2, -N(H)C(O)R 3 , and -N(H)C(O)N(R 3 ) 2 independently selected from the group consisting of Here, optionally, R C two examples of which, taken together with the atom to which they are attached, form an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl; R D is an optionally substituted 5-membered heteroaryl, -C(O)OR 3 , C(O)N(R 3 ) 2、 -(CH2) 1~3 N(R 2 )2, -(CH2) 1~3 OR 2 , -(CH2) 1~3 O(CH2) 1~3 R 2 -CHO, Each R 1 is hydrogen, -C(O)R 3 , -(CH2) 1~3 OR 3 , optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl; Each R 2are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl; Here, optionally, R 2 two examples of the formula (I) taken together form an optionally substituted 3- to 7-membered heterocyclyl ring; Each R 3 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5.

[0007] In some embodiments, the present disclosure provides a compound represented by formula (Ia), (Ib), or (Ic): TIFF2024542204000003.tif109128, or a pharma- ceutically acceptable salt thereof, wherein the groups C, R A , R C , R D , m, and p are defined above and described in classes and subclasses herein.

[0008] In some embodiments, the present disclosure provides a compound represented by formula (I-a1), (I-b1), or (I-c1): TIFF2024542204000004.tif124128, or a pharma- ceutically acceptable salt thereof, wherein R A , R D , and m are defined above and described in classes and subclasses herein.

[0009] In some embodiments, the present disclosure provides a compound of formula (I-b2): TIFF2024542204000005.tif62128, or a pharma- ceutically acceptable salt thereof, wherein R A and m are defined above and described in classes and subclasses herein.

[0010] In some embodiments, the present disclosure provides a compound represented by formula (I-c2), (I-c3), or (I-c4): TIFF2024542204000006.tif126128, or a pharma- ceutically acceptable salt thereof, wherein R A and m are defined above and described in classes and subclasses herein.

[0011] X In some embodiments, X is O= or S=. In some embodiments, X is O=. In some embodiments, X is S=.

[0012] Ring A In some embodiments, ring A is selected from the group consisting of optionally substituted phenyl, optionally substituted 5-membered heteroaryl, and optionally substituted 6-membered heteroaryl. In some embodiments, ring A is an optionally substituted phenyl. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrazine, pyridazine, and pyrimidine. In some embodiments, ring A is an optionally substituted pyridine.

[0013] In some embodiments, ring A is TIFF2024542204000007.tif57163.

[0014] In some embodiments, ring A is The file is TIFF2024542204000008.tif16128.

[0015] base C In some embodiments, the group C is selected from the group consisting of C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, optionally substituted 6-membered carbocyclyl, and optionally substituted 6-membered heterocyclyl. In some embodiments, the group C is selected from the group consisting of optionally substituted phenyl and optionally substituted 6-membered heteroaryl. In some embodiments, the group C is an optionally substituted phenyl. In some embodiments, the group C is an optionally substituted heteroaryl. In some embodiments, the group C is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrazine, pyridazine, and pyrimidine. In some embodiments, the group C is an optionally substituted pyridine. In some embodiments, the group C is an optionally substituted phenyl or an optionally substituted pyridine. In some embodiments, the group C is an optionally substituted phenyl.

[0016] L In some embodiments, L is selected from the group consisting of a bond, an optionally substituted C1-C3 alkylene, -C(O)-, -C(O)O-, -C(O)NH-, and -S(O)2-. In some embodiments, L is selected from the group consisting of a bond, an optionally substituted C1-C3 alkylene, and -C(O)-. In some embodiments, L is a bond. In some embodiments, L is an optionally substituted C1-C3 alkylene chain. In some embodiments, L is an optionally substituted C1 alkylene chain. In some embodiments, L is an optionally substituted C2 alkylene chain. In some embodiments, L is an optionally substituted C3 alkylene chain. In some embodiments, L is an unsubstituted C1-C3 alkylene chain. In some embodiments, L is -CH2-. In some embodiments, L is -C(H)(Me)-. In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is -C(O)-. In some embodiments, L is -S(O)-.

[0017] In some embodiments, L and group C together are Form TIFF2024542204000009.tif12128.

[0018] R A In some embodiments, each R A is halogen, -CN, an optionally substituted C1-C6 aliphatic group, an optionally substituted phenyl, an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 3- to 7-membered carbocyclyl, an optionally substituted 3- to 7-membered heterocyclyl, -OR 1 , -SR 1 , -N(R 1 )2, -C(O)OR 1 , C(O)N(R 1 )2, -N(H)C(O)R 1 , and -N(H)C(O)N(R1 In some embodiments, each R A is halogen, -CN, optionally substituted C1-C6 aliphatic group, -OR 1 , -SR 1 , -N(R 1 )2, -C(O)OR 1 , C(O)N(R 1 )2, -N(H)C(O)R 1 , and -N(H)C(O)N(R 1 In some embodiments, R A is halogen, -CN, and -OR 1 In some embodiments, R A is selected from the group consisting of F, Cl, Br, CN, -OH, -OMe, OEt, -OCH2CH2OMe, -OAc, and -OCH2CH2(N-morpholine).

[0019] R B In some embodiments, R B is selected from the group consisting of halogen, optionally substituted 5-6 membered heteroaryl, optionally substituted C1-C3 aliphatic, and optionally substituted C1-C3 alkoxy. B is halogen. In some embodiments, R B is fluoro. In some embodiments, R B is chloro. In some embodiments, R B is bromo. In some embodiments, R B is C1-C3 alkoxy. In some embodiments, R B is methoxy.

[0020] R C In some embodiments, each R Cis halogen, -CN, an optionally substituted C1-C6 aliphatic group, an optionally substituted phenyl, an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 3- to 7-membered carbocyclyl, an optionally substituted 3- to 7-membered heterocyclyl, -OR 3 , -SR 3 , -S(O)2R 3 , -N(R 3 )2, -C(O)OR 3 , C(O)N(R 3 )2, -N(H)C(O)R 3 , and -N(H)C(O)N(R 3 In some embodiments, each R C is halogen, -CN, an optionally substituted C1-C6 aliphatic group, an optionally substituted phenyl group, -OR 3 , -S(O)2R 3 , and -C(O)OR 3 In some embodiments, each R C are independently selected from the group consisting of halogen and optionally substituted C1 to C6 aliphatic groups.

[0021] In some embodiments, R C One example is a halogen, and one example is an optionally substituted C1-C6 aliphatic group.

[0022] In some embodiments, R C is halogen. In some embodiments, R C is fluorine. In some embodiments, R C is chlorine. In some embodiments, R C is bromine. In some embodiments, R C is iodine.

[0023] In some embodiments, R C In some embodiments, R C is -S(O)Me.

[0024] In some embodiments, each R C is independently an optionally substituted C1-C6 aliphatic. C is independently an optionally substituted C1-C4 aliphatic. C is independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, optionally substituted iso-propyl, optionally substituted n-propyl, optionally substituted n-butyl, and optionally substituted tert-butyl. C is independently selected from the group consisting of -CF3 and -CHF2.

[0025] In some embodiments, R C -OR 3 In some embodiments, each R C is independently selected from the group consisting of -OMe, -OCF3, and -OCHF2.

[0026] In some embodiments, R C Two instances of R taken together with the atom to which they are attached form an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl. In some embodiments, R C Two instances of are taken together with the group C to form an optionally substituted naphthyl or an optionally substituted 10-membered heteroaryl. In some embodiments, R C Two examples of R taken together with the group C form an optionally substituted naphthyl, an optionally substituted quinolinyl, or an isoquinolinyl. C Two examples of R taken together with the group C form an optionally substituted naphthyl or an optionally substituted quinolinyl. C Two instances of together with the group C form an optionally substituted naphthyl. In some embodiments, R CThe two examples of the following together with the group C form an optionally substituted quinolinyl:

[0027] In some embodiments, R C One example is C 1~3 is alkyl, R C One example of is halogen. In some embodiments, R C One example of is methyl, R C One example is fluoro.

[0028] R D In some embodiments, R D is an optionally substituted 5-membered heteroaryl, -C(O)OR 3 , C(O)N(R 3 ) 2、 -(CH2) 1~3 N(R 2 )2, -(CH2) 1~3 OR 2 , -(CH2) 1~3 O(CH2) 1~3 R 2 In some embodiments, R D is an optionally substituted 5-membered heteroaryl. In some embodiments, R D is -(CH2) 1~3 OR 2 In some embodiments, R D is -CHO.

[0029] In some embodiments, R D teeth, TIFF2024542204000010.tif61160.

[0030] R 1 In some embodiments, each R 1is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl. 1 is independently an optionally substituted C1-C6 aliphatic. In some embodiments, R 1 is optionally substituted methyl.

[0031] R 2 In some embodiments, each R 2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl. 2 is independently an optionally substituted C1-C6 aliphatic. In some embodiments, R 2 is optionally substituted methyl.

[0032] R 3 In some embodiments, each R 3 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl. 3 is independently an optionally substituted C1-C6 aliphatic. 3 is independently selected from the group consisting of hydrogen, optionally substituted methyl, -CF3, and -CHF2.

[0033] In some embodiments, the disclosure includes a compound set forth in Table 1.

[0034]

Table 1

[0035] Definition The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation; or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation but is not aromatic and has one point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrid groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0036] The term "haloaliphatic" refers to an aliphatic group that is substituted with one or more halogen atoms.

[0037] The term "alkyl" refers to a straight-chain or branched-chain alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0038] The term "haloalkyl" refers to a straight or branched chain alkyl group substituted with one or more halogen atoms.

[0039] The term "halogen" means F, Cl, Br, or I.

[0040] The term "aryl" used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, where at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As the term "aryl" is used herein, its scope also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0041] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety, e.g., "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions are optionally substituted independently.

[0042] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1-4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl portions are optionally independently substituted.

[0043] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0044] As described herein, the compounds of the present disclosure may include "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise stated, an "optionally substituted" group may have a suitable substituent at each of the substitutable positions of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for the production, detection, and in certain embodiments, recovery, purification, and use of the compound for one or more of the purposes disclosed herein.

[0045] The present disclosure includes tautomers of the structures of the compounds presented herein.

[0046] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH) 0~4 R ○ , -(CH2) 0~4 OR ○ , -O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ , -(CH2) 0~4 CH(OR ○ )2, -(CH2) 0~4 S.R. ○ , -(CH2) 0~4 Ph(R○ (optionally substituted with), -(CH2) 0~4 O(CH2) 0~1 Ph(R ○ -CH=CHPh(R ○ (optionally substituted with), -(CH2) 0~4 O(CH2) 0~1 -Pyridyl (R ○ -(CH2) 0~4 N(R ○ )2, -(CH2) 0~4 N(R ○ )C(O)R ○ , -N(R ○ )C(S)R ○ , -(CH2) 0~4 N(R ○ )C(O)NR ○ 2, -N(R ○ )C(S)NR ○ 2, -(CH2) 0~4 N(R ○ )C(O)OR ○ , -N(R ○ )N(R ○ )C(O)R ○ , -N(R ○ )N(R ○ )C(O)NR ○ 2, -N(R ○ )N(R ○ )C(O)OR ○ , -(CH2) 0~4 C(O)R ○ , -C(S)R ○ , -(CH2) 0~4 C(O)OR ○ , -(CH2) 0~4 C(O)SR ○ , -(CH2) 0~4 C(O)OSiR ○ 3. -(CH2) 0~4 O.C.(O)R ○ , -OC(O)(CH2) 0~4 S.R. ○ , SC(S)SR ○ , -(CH2) 0~4 SC(O)R ○ , -(CH2) 0~4 C(O)NR○ 2. -C(S)NR ○ 2. -C(S)SR ○ , -SC(S)SR ○ , -(CH2) 0~4 OC(O)NR ○ 2. -C(O)N(OR ○ )R ○ , -C(O)C(O)R ○ , -C(O)CH2C(O)R ○ , -C(NOR ○ )R ○ , -(CH2) 0~4 SSR ○ , -(CH2) 0~4 S(O)2R ○ , -(CH2) 0~4 S(O)2OR ○ , -(CH2) 0~4 OS(O)2R ○ , -S(O)NR ○ 2, -(CH2) 0~4 S(O)R ○ , -N(R ○ )S(O)NR ○ 2, -N(R ○ )S(O)2R ○ , -N(OR ○ )R ○ , -C(NH)NR ○ 2. -P(O)2R ○ , -P(O)R ○ 2. -OP(O)R ○ 2. -OP(O)(OR ○ )2, SiR ○ 3. -(C 1~4 Linear or branched alkylene)ON(R ○ )2, or -(C 1~4 Linear or branched alkylene)C(O)ON(R ○ )2, where each R ○ are optionally substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, regardless of the above definitions, R ○ two independent occurrences of together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted as defined below.

[0047] R ○ (or R ○ Preferred monovalent substituents on the ring formed by two independent occurrences of -(CH) together with their intervening atoms are independently halogen, -(CH) 0~2 R ● , -(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 S.R. ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ●is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens; and C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 R is independently selected from Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0048] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-, where R * Each independent occurrence of is hydrogen, optionally substituted as defined below, C 1~6 The group is selected from an aliphatic, unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to the substitutable vicinal carbon of the "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of is hydrogen, optionally substituted as defined below, C 1~6 It is selected from an aliphatic, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ●), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and, independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, regardless of the above definitions, R † two independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] R †Suitable substituents on the aliphatic groups are, independently, halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and, independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Salts include, but are not limited to, glyceryl stearate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0053] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0054] Combinations of substituents and variables envisioned by this disclosure are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and to maintain the integrity of the compound for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0055] The recitation of a list of chemical groups in a definition of a variable herein includes definitions of that variable as a single group or combination of listed groups. The recitation of an embodiment of a variable herein includes that embodiment as a single embodiment or in combination with any other embodiment or portion thereof.

[0056] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, biological specimen storage, and biological assays.

[0057] As used herein, a "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that induces a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered as part of a dosing regimen to a subject suffering from or susceptible to the disease, disorder, and / or condition. As will be appreciated by those skilled in the art, the effective amount of a substance may vary depending on factors such as the desired biological endpoint, the substance delivered, the target cell or tissue, etc. For example, an effective amount of a provided compound in a formulation for treating a disease, disorder, and / or condition is an amount that results in the alleviation, amelioration, mitigation, inhibition, prevention, delay in onset, reduction in severity, and / or reduction in incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition.

[0058] As used herein, the terms "treatment", "treat" and "treating" refer to partial or complete alleviation, suppression, delay in onset, prevention, amelioration and / or alleviation of a disorder or condition described herein or one or more symptoms of a disorder or condition. In some embodiments, treatment may be administered after one or more symptoms have occurred. In some embodiments, the term "treating" includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of symptoms and / or taking into account genetic or other susceptibility factors). Treatment may be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing relapse or recurrence of a disease or disorder.

[0059] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0060] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound(s) with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the compounds disclosed herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0061] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that, upon administration to a recipient, is capable of directly or indirectly yielding a compound of the present disclosure, or an inhibitory active metabolite or residue thereof.

[0062] The expression "dosage unit form" used herein refers to a physically separate pharmaceutical unit suitable for the patient to be treated. However, it is to be understood that the total daily use amount of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for a specific patient or organism will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the administration time, administration route and excretion rate of the specific compound used; the duration of treatment; the drugs used in combination or simultaneously with the specific compound used, and similar factors well known in the medical field.

[0063] Alternative Embodiments In alternative embodiments, the compounds described herein may contain one or more isotopic substitutions. For example, hydrogen can be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and the oxygen may be, for example, 18 O, where the nitrogen can be, for example, 15 In other embodiments, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site on the compound.

[0064] Pharmaceutical Compositions In some embodiments, the present disclosure provides a composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of the compound in the compositions contemplated herein is an amount effective to measurably treat a disease or disorder in a biological sample or a patient. In certain embodiments, the amount of the compound in the compositions of the present disclosure is an amount effective to measurably treat a disease or disorder in a biological sample or a patient. In certain embodiments, the compositions contemplated by the present disclosure are formulated for administration to a patient in need of such a composition. In some embodiments, the compositions contemplated by the present disclosure are formulated for oral administration to a patient.

[0065] In some embodiments, the compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, enterally, nasally, bucally, vaginally, or via an implanted reservoir. In some preferred embodiments, the compositions are administered orally, intraperitoneally, or intravenously. In some embodiments, the sterile injectable form of the composition comprising one or more compounds of formula (I) may be an aqueous or oily suspension. In some embodiments, the suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In some embodiments, among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In some embodiments, additional examples include, but are not limited to, sterile, non-volatile oils conventionally used as solvents or suspending media.

[0066] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0067] Pharmaceutically acceptable compositions containing one or more compounds of formula (I) can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In some embodiments, carriers used include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. In some embodiments, useful diluents include lactose and dried corn starch. In some embodiments, when aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. In some embodiments, certain sweetening, flavoring, or coloring agents may be added.

[0068] Alternatively, the pharma- ceutically acceptable composition containing the compound of formula (I) may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0069] The pharma- ceutically acceptable composition comprising the compound of formula (I) may be administered topically, especially when the target of treatment comprises an area or organ easily accessible by topical application, such as diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs. In some embodiments, the pharma- ceutically acceptable composition may be formulated into a suitable ointment comprising the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharma- ceutically acceptable composition provided may be formulated into a suitable lotion or cream comprising the active ingredient suspended or dissolved in one or more pharma- cetically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0070] Pharmaceutically acceptable compositions containing compounds of formula (I) may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0071] In some embodiments, the amount of the compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0072] Methods of Use of the Disclosed Compounds In some embodiments, the present disclosure provides a method of treating or lessening the severity of a disease or condition associated with cell proliferation in a patient, comprising administering to the patient a composition according to the present disclosure.

[0073] The term "cell proliferation-related disease or condition" as used herein refers to any disease or other harmful condition that is known to involve cell proliferation.Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases that are known to involve cell proliferation.In some embodiments, the cell proliferation-related disease or condition is cancer.

[0074] In some embodiments, administration of a compound of the present disclosure results in mitotic arrest or changes in DNA content.

[0075] In some embodiments, administration of a compound of the present disclosure results in mitotic arrest. In some embodiments, mitotic arrest is defined as a 10-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 20-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 30-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 40-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 50-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 60-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 70-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as an 80-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 90-100% reduction in mitosis. In some embodiments, mitotic arrest is defined as a 100% reduction in mitosis.

[0076] In some embodiments, administration of a compound of the present disclosure results in a change in DNA content. In some embodiments, the change in DNA content is an induction of ploidy.

[0077] In some embodiments, the compounds and compositions of the disclosed methods may be administered using any amount and any route of administration effective for treating or reducing the severity of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, etc. The compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.

[0078] In some embodiments, the cancer is selected from the group consisting of lung cancer and breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is lung adenocarcinoma. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is mammary cancer. In some embodiments, the breast cancer is breast adenocarcinoma.

[0079] In some embodiments, pharma- ceutically acceptable compositions comprising compounds of the present disclosure may be administered to humans and other animals orally, enterally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), buccally, as oral or nasal sprays, etc., depending on the severity of the infection being treated. In certain embodiments, compounds of the present disclosure may be administered orally or parenterally, one or more times per day, at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject weight per day, to obtain the desired therapeutic effect.

[0080] In some embodiments, one or more additional therapeutic agents may also be administered in combination with the compound of the present disclosure. In some embodiments, the compound of the present disclosure and one or more additional therapeutic agents may be administered as part of a multiple dose regimen. In some embodiments, the compound of the present disclosure and one or more additional therapeutic agents may be administered simultaneously, sequentially, or within a period of time. In some embodiments, the compound of the present disclosure and one or more additional therapeutic agents may be administered within 5 hours of each other. In some embodiments, the compound of the present disclosure and one or more additional therapeutic agents may be administered within 24 hours of each other. In some embodiments, the compound of the present disclosure and one or more additional therapeutic agents may be administered within one week of each other.

[0081] In some embodiments, a compound of the disclosure and one or more additional therapeutic agents may be formulated into a single dosage form. EXAMPLES

[0082] 1.Chemistry 1.1 General Methodology Unless otherwise stated, all chemicals required for synthesis were purchased from commercially available sources and used without further purification. 1 H NMR spectra were determined at 400 MHz using a Bruker Avance III-400. LC-MS analysis was performed on an Agilent LC-MS 1260-6110 or Agilent LC-MS 1260-6120 equipped platform using a Waters X Bridge C18: 50 mm × 4.6 mm × 3.5 um column. Flash column chromatography was performed using silica gel (200-300 mesh, Qingdao Haiyang Chemical Co. Ltd., China). Analytical and preparative TLC analysis was performed on GF254 silica gel plates (Yantai Jiangyou Inc., China). Unless otherwise stated, reagents and all solvents were of analytically pure grade and were commercially obtained from suppliers such as Chron Chemical or Energy-Chemical.

[0083] Abbreviations: TLC: thin layer chromatography, EA: ethyl acetate, PE: petroleum ether, DMF: N,N-dimethylformamide, THF: tetrahydrofuran, DCM: dichloromethane, DIPEA: N,N-diisopropylethylamine, DMAP: 4-dimethylaminopyridine, NaH: sodium hydride

[0084] 2. Compound synthesis and analytical data Scheme 1: Substitution at the A-ring of 1-(3-fluoro-4-methylbenzyl)-5-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (formula 8) and schematic route for the synthesis of compounds of formula 10 TIFF2024542204000025.tif130165

[0085] Scheme 2: Schematic route for the synthesis of five-membered heterocyclic analogues from formula 7 TIFF2024542204000026.tif104165

[0086] Scheme 3: Schematic route for the synthesis of various analogues from compound 7-1 TIFF2024542204000027.tif94165

[0087] Scheme 4: Schematic route for the synthesis of various analogues from compound 29 TIFF2024542204000028.tif78165

[0088] Scheme 5: Schematic route for the synthesis of various analogues from compound 7-2 TIFF2024542204000029.tif99165

[0089] Example 1: Representative synthesis of compounds of formula 3: TIFF2024542204000030.tif37165Methyl 2-(3-methoxy-3-oxopropanamido)benzoate(3-1) To a solution of methyl 2-aminobenzoate 1-1 (1.95 mL, 15 mmol, 1 equiv) in DCM (45 mL) was added DIEA (2.73 mL, 16.5 mmol, 1.3 equiv) and DMAP (30 mg, 0.075 mmol, 0.5% equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride 2 (2.5 mL, 19.5 mmol, 1.1 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound 1-1. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with H2O (2 x 50 mL) and brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column (silica gel column height and diameter are 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 8, flow rate: 20 mL / min, the collection at elution time of 11-14 min contained the target compound) to obtain 4.8 g (purity=98%) of a pale yellow oily compound in 98% yield. TLC R f = 0.5 (PE:EA=2:1); LCMS (m / z) = 266.2 (M+H); 1 H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.24 (dd, J = 8.4, 1.2 Hz, 1H), 7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.58 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.16 (ddd, J = 8.3, 7.4, 1.2 Hz, 1H), 3.85 (s, 3H), 3.60 (s, 3H), 2.69 (ddd, J = 6.7, 5.4, 1.6 Hz, 2H), 2.62 (ddd, J = 7.8, 5.5, 1.7Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ 172.65, 170.04, 167.62, 139.65, 133.92, 130.48, 123.05, 120.96, 117.47, 52.37, 51.41, 31.61, 28.44

[0090] TIFF2024542204000031.tif48165Methyl 4-bromo-2-(4-methoxy-4-oxobutanamido)benzoate(3-2) To a solution of methyl 2-amino-4-bromobenzoate 1-2 (10 g, 43.5 mmol, 1 equiv) in DCM (130 mL) was added DIEA (11.34 mL, 65.2 mmol, 1.5 equiv) and DMAP (265 mg, 2.17 mmol, 0.05 equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride 2 (6.89 mL, 56.52 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound 1-2. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with H2O (2 x 50 mL) and brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column (silica gel column height and diameter are 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 4, flow rate: 20 mL / min, the collection at elution time of 11-14 min contained the target compound) to obtain 12 g of pale yellow oily compound (purity=95%) in 80% yield. TLC R f = 0.3 (PE:EA=2:1); LCMS (m / z) = 346.20 (M+H)

[0091] TIFF2024542204000032.tif48165Methyl 4-methoxy-2-(4-methoxy-4-oxobutanamido)benzoate(3-3) To a solution of methyl 2-amino-4-methoxybenzoate 1-3 (5000 mg, 27 mmol, 1 equiv) in DCM (80 mL) was added DIEA (5100 mg, 30 mmol, 1.3 equiv) and DMAP (50 mg, 0.135 mmol, 0.05 equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride 2 (4280 μL, 39 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound 1-3. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with H2O (2 x 50 mL) and brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column (silica gel column height and diameter are 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 2, flow rate: 50 mL / min, the collection at elution time of 11-14 min contained the target compound) to obtain 7 g of pale yellow oily compound (purity=98%) in 87% yield. TLC R f = 0.6 (PE:EA=2:1); LCMS (m / z) = 296.50 (M+H)

[0092] TIFF2024542204000033.tif42165 Methyl 2-(4-methoxy-4-oxobutanamido)-4-methylbenzoate (3-4) To a solution of methyl 2-amino-4-methylbenzoate 1-4 (5000 mg, 30 mmol, 1 equiv) in DCM (90 mL) was added DIEA (5460 mg, 39 mmol, 1.3 equiv) and DMAP (60 mg, 0.15 mmol, 0.05 equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride 2 (5000 μL, 39 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound 1-4. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with H2O (2 x 50 mL) and brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column (silica gel column height and diameter are 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 2, flow rate: 50 mL / min, the collection at elution time of 11-14 min contained the target compound) to obtain 6.7 g (purity=97%) of a pale yellow oily compound in 80% yield. TLC R f = 0.6 (PE:EA=2:1); LCMS (m / z) = 280.0 (M+H)

[0093] TIFF2024542204000034.tif58165Methyl 4-fluoro-2-(4-methoxy-4-oxobutanamido)benzoate (3-5) To a solution of methyl 2-amino-4-fluorobenzoate (10.14 g, 60 mmol, 1 equiv) in DCM (180 mL) was added DIEA (15 mL, 90 mmol, 1.5 equiv) and DMAP (366 mg, 3 mmol, 0.05 equiv) under nitrogen. To this solution was added methyl 4-chloro-4-oxobutanoate (10.51 mL, 78 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound 1-5. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with HO (2×50 mL) and brine (1×100 mL), dried over anhydrous NaSO, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 11.5 g of a yellow solid compound (purity=99%) in a yield of 68%. TLC R f = 0.5 (PE:EA=4:1); LCMS (m / z) = 284.30 (M+H)

[0094] TIFF2024542204000035.tif53165Methyl 4-chloro-2-(4-methoxy-4-oxobutanamido)benzoate(3-6) To a solution of methyl 2-amino-4-chlorobenzoate 1-6 (11.1 g, 60 mmol, 1 equiv) in DCM (180 mL) was added DIEA (15.7 mL, 90 mmol, 1.5 equiv) and DMAP (367 mg, 3 mmol, 0.05 equiv) under N2. To this solution was added 3-(carbomethoxy)propionyl chloride 2 (3.6 mL, 29.8 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound 1-6. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3 x 50 mL). The organic solutions were combined, washed with HO (2×50 mL) and brine (1×100 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 9.3 g (purity=95%) of a pale yellow oily compound in 52% yield. TLC R f = 0.4 (PE:EA=4:1); LCMS (m / z) = 300.10 (M+H)

[0095] Example 2: Representative synthesis of compounds of formula 3: TIFF2024542204000036.tif42165Methyl 2-(4-methoxy-4-oxobutanamido)-4-(trifluoromethyl)benzoate (3-7) To a solution of methyl 2-amino-4-(trifluoromethyl)benzoate (10 g, 45.6 mmol, 1 equiv) in DCM (137 mL) was added DIEA (11.4 mL, 68.5 mmol, 1.5 equiv) and DMAP (281 mg, 2.3 mmol, 5% equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride (9.23 mL, 68.4 mmol, 1.5 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with EA (3×50 mL). The organic solutions were combined, washed with HO (2×50 mL) and brine (1×100 mL), dried over anhydrous NaSO, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 14.2 g (purity=99%) of a pale yellow oily compound in a yield of 93.5%. TLC R f = 0.6 (PE:EA=2:1); LCMS (m / z) = 334.30 (M+H)

[0096] TIFF2024542204000037.tif37165Methyl 3-fluoro-2-(4-methoxy-4-oxobutanamido)benzoate (3-8) To a solution of methyl 2-amino-3-fluorobenzoate (4.8 g, 28.37 mmol, 1 equiv) in 1,4-dioxane (27.89 mL) was added pyridine (2.8 mL, 34 mmol, 1.2 equiv) and DMAP (173 mg, 1.42 mmol, 0.05 equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride (4.51 mL, 36.88 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at 80° C. for 4 h. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with HO (2×50 mL) and brine (1×100 mL), dried over anhydrous NaSO, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 3.958 g of a pale yellow solid compound (purity=91.46%) in a yield of 49.25%. TLC R f = 0.4 (PE:EA=2:1) LCMS (m / z) = 284.00 (M+H)

[0097] TIFF2024542204000038.tif42165Methyl 2-fluoro-6-(4-methoxy-4-oxobutanamido)benzoate (3-9) To a solution of methyl 2-amino-6-fluorobenzoate (5 g, 29.56 mmol, 1 equiv) in DCM (89 mL) was added DIEA (7.5 mL, 44.34 mmol, 1.5 equiv) and DMAP (181 mg, 1.48 mmol, 0.05 equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride 2 (4.7 mL, 38.42 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with HO (2×50 mL) and brine (1×100 mL), dried over anhydrous NaSO, filtered and concentrated by rotary evaporation to give the crude compound. The concentrate obtained was then purified on a silica column to give 8 g of a pale yellow oily compound in 95% yield. Purity=98%. TLC R f = 0.4 (EA:PE=1:2) LCMS (m / z) = 284.00 (M+H + )

[0098] TIFF2024542204000039.tif37165Methyl 5-fluoro-2-(4-methoxy-4-oxobutanamido)benzoate (3-10) To a solution of methyl 2-amino-5-fluorobenzoate (5 g, 29.56 mmol, 1 equiv) in DCM (89 mL) was added DIEA (7.5 mL, 44.3 mmol, 1.5 equiv) and DMAP (181 mg, 1.48 mmol, 0.05 equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride 2 (4.7 mL, 38.4 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at room temperature for 4 h. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (3×50 mL). The organic solutions were combined, washed with HO (2×50 mL) and brine (1×100 mL), dried over anhydrous NaSO, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 8.4 g of a pale yellow oily compound in 99% yield. Purity=99%. TLC R f = 0.45 (EA:PE=1:4) LCMS (m / z) = 284.10 (M+H + )

[0099] TIFF2024542204000040.tif42165Methyl 2-(4-methoxy-4-oxobutanamido)-3-methylbenzoate (3-11) To a solution of methyl 2-amino-3-methylbenzoate (5 g, 30.3 mmol, 1 equiv) in 1,4-dioxane (30 mL) was added pyridine (2.94 mL, 36.4 mmol, 1.2 equiv) and DMAP (184.8 mg, 1.5 mmol, 0.05 equiv) under nitrogen. To this solution was added 3-(carbomethoxy)propionyl chloride (4.82 mL, 39.4 mmol, 1.3 equiv) dropwise over 10 min and the reaction mixture was allowed to stir at 80° C. for 4 h. To this reaction mixture was then added HO (40 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with EA (3×50 mL). The organic solutions were combined, washed with HO (2×50 mL) and brine (1×100 mL), dried over anhydrous NaSO, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 6.94 g (purity=99%) of a pale yellow oily compound in a yield of 82%. TLC R f = 0.40 (EA:PE=1:4) LCMS (m / z) = 280.0 (M+H)

[0100] Example 3: Representative synthesis of compounds of formula 4: TIFF2024542204000041.tif37165Methyl 5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-1) To a 5° C. solution of methyl 2-(3-methoxy-3-oxopropanamido)benzoate 3-1 (4.8 g, 18.7 mmol, 1 equiv.) in THF (74 mL), 1 M t-BuOK / THF solution (55 mL, 56 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5° C. After 6 h, 20 mL of H2O was added followed by 80 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×100 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The obtained concentrate was then purified on a silica column (the height and diameter of the silica gel column were 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 4, flow rate: 20 mL / min, the target compound was collected at 8-9 min of elution time) to obtain 2.8 g of white solid compound with a yield of 87% and purity of 95%. TLC R f = 0.3 (PE:EA=2:1); LCMS (m / z) = 234.3 (M+H) 1 H NMR (400 MHz, DMSO) δ 12.46 (s, 1H), 10.35 (s, 1H), 7.79 (dd, J = 8.0, 1.5 Hz, 1H), 7.53 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 7.32 - 7.21 (m, 1H), 7.18 (dd, J = 8.2, 0.8 Hz, 1H), 3.83 (s, 3H), 2.92 (s, 2H). 13 C NMR (100 MHz, DMSO) δ 171.99, 170.80, 166.22, 137.92, 131.91, 128.15, 124.75, 123.47, 121.61, 95.82, 52.49, 30.70

[0101] TIFF2024542204000042.tif48165Methyl 9-bromo-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-2) To a 5° C. solution of methyl 4-bromo-2-(4-methoxy-4-oxobutanamido)benzoate 3-2 (12 g, 34.88 mmol, 1 equiv.) in THF (138 mL), 1 M t-BuOK / THF solution (103 mL, 105 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5° C. After 6 h, 20 mL of H2O was added followed by 120 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×120 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The obtained concentrate was then purified on a silica column (the height and diameter of the silica gel column were 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 4, flow rate: 20 mL / min, the target compound was collected at 8-9 min of elution time) to obtain 6.4 g of a white solid compound with a yield of 59%. Purity=99%. TLC R f = 0.3 (PE:EA=2:1); LCMS (m / z) = 313.83 (M+H)

[0102] TIFF2024542204000043.tif42165Methyl 5-hydroxy-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate(4-3) To a solution of 3-3 (7000 mg, 23.77 mmol, 1 equiv) in THF (90 mL) at 5° C., 1 M t-BuOK / THF solution (71 mL, 71 mmol, 3 equiv) was added dropwise over 10 min while maintaining the temperature at 5° C. After 6 h, 114 mL of H2O was added followed by 114 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×50 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The obtained concentrate was then purified on a silica column (the height and diameter of the silica gel column were 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 2, flow rate: 50 mL / min, the target compound was collected at 1 hour of elution time) to obtain 5500 mg of a white solid with a yield of 88%. Purity=91%. TLC R f = 0.3 (PE:EA=2:1); LCMS (m / z) = 296.30 (M+H)

[0103] TIFF2024542204000044.tif48165Methyl 5-hydroxy-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate(4-4) To a solution of 3-4 (6700 mg, 24 mmol, 1 equiv) in THF (96 mL) at 5° C., 1 M t-BuOK / THF solution (72 mL, 72 mmol, 3 equiv) was added dropwise over 10 min while maintaining the temperature at 5° C. After 6 h, 114 mL of H2O was added followed by 114 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×50 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The obtained concentrate was then purified on a silica column (the height and diameter of the silica gel column were 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 2, flow rate: 50 mL / min, the target compound was contained in the collection at 1 hour of elution time) to obtain 4900 mg of a white solid with a yield of 83%. Purity=93%. TLC R f = 0.3 (PE:EA=2:1); LCMS (m / z) = 248.1 (M+H)

[0104] TIFF2024542204000045.tif48165Methyl 8-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 4-5 To a 5° C. solution of methyl 4-fluoro-2-(4-methoxy-4-oxobutanamido)benzoate 3-5 (11.5 g, 40.6 mmol, 1 equiv.) in THF (160 mL), 1 M t-BuOK / THF solution (120 mL, 122 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5° C. After 6 h, 20 mL of H2O was added followed by 80 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×100 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 9.2 g (purity=99%) of a white solid compound in 90.2% yield. TLC R f= 0.5 (PE:EA=2:1); LCMS (m / z) = 252.0 (M+H)

[0105] TIFF2024542204000046.tif53165Methyl 8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-6) To a 5° C. solution of methyl 4-chloro-2-(4-methoxy-4-oxobutanamido)benzoate (3-6) (9.3 g, 31.0 mol, 1 equiv.) in THF (119 mL), 1 M t-BuOK / THF solution (89 mL, 93.1 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5° C. After 3 h, 20 mL of H2O was added followed by 70 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×120 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 6.5 g of white solid compound in 79% yield. Purity=99%. TLC R f = 0.5 (PE:EA=2:1); LCMS (m / z) = 267.93 (M+H)

[0106] Example 4: Representative synthesis of compounds of formula 4: TIFF2024542204000047.tif42165Methyl 5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-7) To a 5°C solution of methyl 2-(4-methoxy-4-oxobutanamido)-4-(trifluoromethyl)benzoate (14.2 g, 43 mmol, 1 equiv.) in THF (170 mL), 1M t-BuOK / THF solution (157 mL, 128 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5°C. After 6 h, 20 mL of H2O was added followed by 80 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×100 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 11.6 g of white solid compound in 86% yield. Purity=99%. TLC R f = 0.7 (PE:EA=2:1); LCMS (m / z) = 270.20 (M+H)

[0107] TIFF2024542204000048.tif37165Methyl 9-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-8) To a 5° C. solution of methyl 3-fluoro-2-(4-methoxy-4-oxobutanamido)benzoate (3.958 g, 13.97 mmol, 1 equiv.) in THF (55 mL), 1 M t-BuOK / THF solution (51 mL, 41.92 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5° C. After 6 h, 20 mL of H2O was added followed by 80 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×100 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 2.422 g of white solid compound in 69% yield. Purity=86.46%. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 220.00 (M+H)

[0108] TIFF2024542204000049.tif52165Methyl 8-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-9) To a 5°C solution of methyl 2-fluoro-6-(4-methoxy-4-oxobutanamido)benzoate (8 g, 28.27 mol, 1 equiv.) in THF (113 mL), 1M t-BuOK / THF solution (85 mL, 84.81 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5°C. After 3 h, 20 mL of H2O was added followed by 70 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×120 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 6.5 g of white solid compound in 80% yield. Purity=97%. TLC R f = 0.2 (EA:PE=1:2) LCMS (m / z) = 251.90 (M+H + )

[0109] TIFF2024542204000050.tif52165Methyl-7-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-10) To a 5°C solution of methyl 5-fluoro-2-(4-methoxy-4-oxobutanamido)benzoate (8.4 g, 29.6 mol, 1 equiv.) in THF (118 mL), 1M t-BuOK / THF solution (88.7 mL, 84.8 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5°C. After 3 h, 20 mL of H2O was added followed by 70 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×120 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 6.732 g of white solid compound in 90% yield. Purity=96%. TLC R f = 0.2 (EA:PE=1:2) LCMS (m / z) = 251.93 (M+H + )

[0110] TIFF2024542204000051.tif42165Methyl-5-hydroxy-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-11) To a 5° C. solution of methyl 2-(4-methoxy-4-oxobutanamido)-3-methylbenzoate (7.63 g, 27.3 mmol, 1 equiv.) in THF (108 mL), 1 M t-BuOK / THF solution (101 mL, 82 mmol, 3 equiv.) was added dropwise over 10 min while maintaining the temperature at 5° C. After 6 h, 20 mL of H2O was added followed by 80 mL of 1N HCl to bring the solution to pH=4. The resulting mixture was allowed to stir at room temperature for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (3×100 mL). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 5.088 g of white solid compound in 75% yield. Purity=90%. TLC R f = 0.4 (PE:EA=2:1); LCMS (m / z) = 216.00 (M+H)

[0111] Example 5: Methods A and B for the synthesis of compounds of formula 6: Method A: TIFF2024542204000052.tif421651-(3-Fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-1) To a solution of methyl 5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 4-1 (23 mg, 0.1 mmol, 1 equiv.) in DMF (0.7 mL) was added a 60% dispersion of NaH in mineral oil (20 mg, 0.3 mmol, 3 equiv.). To this solution was added 4-(bromomethyl)-2-fluoro-1-methylbenzene (0.12 mmol, 1.2 equiv.) and the reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC until the complete disappearance of 4-1. The resulting solution was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (1×40 mL), dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The resulting concentrate was then purified on a silica column to give 39 mg of a white solid compound in 90% yield and purity=90%. TLC R f = 0.5 (PE:EA=2:1) LCMS (m / z) = 356.2 (M+H) 1 H NMR (400 MHz, DMSO) δ 12.28 (s, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 7.60 - 7.43 (m, 2H), 7.36 - 7.24 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.84 - 6.61 (m, 2H), 5.20 (d, J = 16.1 Hz, 1H), 4.94 (d, J = 16.1 Hz, 1H), 3.85 (s, 3H), 3.49 (d, J = 13.9 Hz, 1H), 2.66 (d, J = 13.9 Hz, 1H), 2.13 (s, 3H). 13C NMR (100 MHz, DMSO) δ 170.45, 170.22, 165.59, 161.71, 159.29, 140.55, 137.59, 137.52, 131.84, 131.57, 131.52, 128.14, 127.76, 125.14, 123.09, 122.71, 122.54, 122.31, 122.28, 113.22, 112.99, 97.72, 52.54, 49.30, 31.06, 13.71, 13.68

[0112] To a DMSO solution (6.33 mL) of the resulting compound methyl 1-(3-fluoro-4-methylbenzyl)-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 5-1 (800 mg, 2.254 mmol, 1 equiv.), HO (0.18 mL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 hours. The reaction mixture was cooled to room temperature, ice (11.30 mL) was added, and the mixture was allowed to stir for 12 hours. 1N HCl (11.30 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 hours. The resulting precipitate was filtered. The crude product was then purified on a silica column (the height and diameter of the silica gel column were 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 2, flow rate: 50 mL / min, the target compound was collected at elution time of 11-14 min) to obtain 580 mg of a pale yellow oily compound (purity=80%) in a yield of 74%. TLC R f = 0.4 (PE:EA=1:1); LCMS (m / z) = 298.60 (M+H) 1H NMR (400 MHz, DMSO) δ 7.54 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 7.40 (dd, J = 7.8, 1.7 Hz, 2H), 7.27 (td, J = 7.6, 1.0 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.84 (dd, J = 13.8, 6.1 Hz, 2H), 5.03 (s, 2H), 2.99 (dd, J = 7.1, 5.7 Hz, 2H), 2.81 - 2.73 (m, 2H), 2.13 (d, J = 1.2 Hz, 3H). 13 C NMR (100 MHz, DMSO) δ 203.00, 171.72, 161.68, 159.26, 140.37, 137.51, 137.44, 133.86, 132.99, 131.58, 131.53, 128.95, 126.09, 123.29, 122.81, 122.78, 122.66, 113.69, 113.46, 48.93, 41.04, 30.65, 13.75, 13.72

[0113] TIFF2024542204000053.tif481658-Bromo-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-2) To a solution of methyl 9-bromo-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (4-2) (6.4 g, 20.51 mmol, 1 equiv.) in DMF (120 mL) was added a 60% dispersion of NaH in mineral oil (2462 mg, 30.77 mmol, 3 equiv.). To this solution was added 4-(bromomethyl)-2-fluoro-1-methylbenzene (3.72 mL, 26.66 mmol, 1.3 equiv.) and the reaction mixture was allowed to stir at room temperature for 4 h. The resulting solution was poured into water (120 mL) and extracted with ethyl acetate (3×120 mL). The combined organic layers were washed with brine (1×120 mL), dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The resulting concentrate was then purified on a silica column to give 5.5 g of a white solid compound in 62% yield and 99% purity. TLC R f = 0.75 (PE:EA=2:1) LCMS (m / z) = 436.20 (M+H)

[0114] To a DMSO solution (29 mL) of the obtained compound 5-2 (5.5 g, 12.67 mmol, 1 equiv.), HO (1 mL) was added under nitrogen, and the reaction mixture was stirred at 150° C. for 5 h. The reaction mixture was cooled to room temperature, ice (45 mL) was added, and the mixture was stirred for 12 h. 1N HCl (45 mL) was added to the flask at 0° C., and the mixture was stirred for 3 h. The resulting precipitate was filtered. The crude product was then purified on a silica column (height and diameter of the silica gel column were 10 cm and 2 cm, respectively; silica gel: 200-300 mesh, eluent: EA / PE=1 / 2, flow rate: 50 mL / min, the target compound was contained in the collection at elution time of 11-14 min) to obtain 2.6 g (purity=95%) of a pale yellow oily compound in 55% yield. TLC R f = 0.4 (PE:EA=1:1) LCMS (m / z) = 377.90 (M+H)

[0115] Method B: TIFF2024542204000054.tif481651-(3-Fluoro-4-methylbenzyl)-8-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-3) A mixture of methyl 5-hydroxy-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 4-3 (5.5 g, 0.02 mol) in DMSO (58 mL) and HO (2 mL) was heated at 150° C. for 4 h. The reaction mixture was cooled to room temperature, ice (0.5 L) was added, and the mixture was allowed to stir for 12 h. 1N HCl (0.5 L) was added to the flask at 0° C., and the mixture was allowed to stir for 3 h. The resulting precipitate was filtered and dried under reduced pressure to give 3.1 g (purity=99%) of the product as a pale yellow solid compound in 72% yield. TLC R f = 0.3 (PE:EA=1:1) LCMS (m / z) = 205.70 (M+H)

[0116] To a solution of the obtained compound i-1 (205 mg, 1 mmol, 1 equiv.), tetrabutylammonium bromide (33 mg, 0.1 mmol, 0.1 equiv.) and KOH (79 mg, 1.4 mmol, 1.4 equiv.) in THF (4 mL) was added 4-(bromomethyl)-2-fluoro-1-methylbenzene (244 mg, 1.2 mmol, 1.2 equiv.) at ambient temperature. The reaction mixture was then stirred at room temperature for 3 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain the crude compound. The obtained concentrate was then purified on a silica column to obtain 219 mg (purity=99%) of a pale yellow solid compound in 67% yield. TLC R f = 0.5 (EA:PE=1:1) LCMS (m / z) = 328.50 (M+H)

[0117] TIFF2024542204000055.tif531651-(3-Fluoro-4-methylbenzyl)-8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-4) A mixture of methyl 5-hydroxy-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 4-4 (4.9 g, 0.019 mol) in DMSO (55 mL) and H2O (2 mL) was heated at 150° C. for 4 h. The reaction mixture was cooled to room temperature, ice (0.5 L) was added, and the mixture was allowed to stir for 12 h. 1N HCl (0.5 L) was added to the flask at 0° C., and the mixture was allowed to stir for 3 h. The resulting precipitate was filtered and dried under reduced pressure to give the product 2 g (purity=97%) as a pale yellow solid compound in 80% yield. TLC R f = 0.3 (PE:EA=1:1) LCMS (m / z) = 189.80 (M+H)

[0118] To a solution of the obtained compound i-2 (189 mg, 1 mmol, 1 equiv.), tetrabutylammonium bromide (32 mg, 0.1 mmol, 0.1 equiv.) and KOH (67 mg, 1.4 mmol, 1.4 equiv.) in THF (4 mL) was added 4-(bromomethyl)-2-fluoro-1-methylbenzene (153 mg, 1.1 mmol, 1.2 equiv.) at ambient temperature. The reaction mixture was then stirred at room temperature for 3 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain the crude compound. The obtained concentrate was then purified on a silica column to obtain 170 mg (purity=99%) of a pale yellow solid compound in 54% yield. TLC R f = 0.5 (PE:EA=1:1) LCMS (m / z) = 312.40 (M+H)

[0119] TIFF2024542204000056.tif421658-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-5) To a solution of methyl 8-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 4-5 (23 mg, 0.1 mmol, 1 equiv.) in DMF (0.7 mL), a 60% dispersion of NaH in mineral oil (20 mg, 0.3 mmol, 3.6 equiv.) was added and stirred for 1 h. To this solution, 4-(bromomethyl)-2-fluoro-1-methylbenzene (0.12 mmol, 1.2 equiv.) was added and the reaction mixture was allowed to stir at room temperature for 4 h. The resulting solution was poured into water (30 mL) and extracted with EA (3×30 mL). The combined organic layers were washed with brine (1×40 mL), dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The resulting concentrate was then purified on a silica column to give 39 mg of a straw-colored solid compound (3.573 g) in 69.85% yield. TLC R f= 0.7 (PE:EA=2:1) LCMS (m / z) = 374.10 (M+H)

[0120] To a solution of 5-3 (3.573 g, 9.57 mmol, 1 equiv) in DMSO (26.91 mL) was added HO (2 mL) under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound 5-3. The reaction mixture was cooled to room temperature, ice (11.30 mL) was added, and the mixture was allowed to stir for 12 h. 1N HCl (11.30 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 h. The resulting precipitate was filtered. The crude product was then purified on a silica column to give 2.767 g (purity=96.52%) of pinkish solid compound in 91.69% yield. TLC R f = 0.4 (PE:EA=2:1) LCMS (m / z) = 316.10 (M+H)

[0121] TIFF2024542204000057.tif481658-Chloro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(6-6) To a stirred solution of 4-6 (4.54 g, 17 mmol, 1 equiv) in DMF (500 mL) was added a 60% dispersion of NaH in mineral oil (2.45 g, 61.2 mmol, 3.6 equiv) and stirred for 1 h, after which the mixture was added with 4-(bromomethyl)-2-fluoro-1-methylbenzene (2.85 mL, 20.4 mmol, 1.2 equiv) and stirred at room temperature for 3 h. The solution was quenched with H2O (10 mL), acidified to PH=5 with 1M H2SO4 solution and extracted with EA (3×10 mL). The organic solutions were combined, washed with brine (1×20 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 5.39 g (purity=96%) of a white solid compound in 81% yield. TLC R f = 0.75 (EA:PE=1:2) LCMS (FA) m / z = 390.10 (M+H)

[0122] To a DMSO solution (21 mL) of the resulting compound methyl 8-chloro-1-(3-fluoro-4-methylbenzyl)-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 5-4 (5.39 g, 13.83 mmol, 1 equiv.), H2O (1 mL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 h. The reaction mixture was cooled to room temperature, ice (70 mL) was added, and the mixture was allowed to stir for 12 h. A 1N H2SO4 solution (35 mL) at 0° C. was added to the flask and the mixture was allowed to stir for 3 h. The resulting precipitate was filtered. The crude product was then purified on a silica column to give 3.51 g (purity=95%) of a pale yellow oily compound in 77% yield. TLC R f = 0.7 (PE:EA=2:1); LCMS (m / z) = 332.40 (M+H)

[0123] Example 6: Methods A and B for the synthesis of compounds of formula 6: TIFF2024542204000058.tif631651-(3-Fluoro-4-methylbenzyl)-8-(trifluoromethyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-7) To a solution of methyl 5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (5.12 g, 17 mmol, 1 equiv.) in DMF (120 mL) was added a 60% dispersion of NaH in mineral oil (2.45 g, 61.2 mmol, 3.6 equiv.). To this solution was added 4-(bromomethyl)-2-fluoro-1-methylbenzene (2.84 ml, 20.4 mmol, 1.2 equiv.) and the reaction mixture was allowed to stir at room temperature for 4 hours. The resulting solution was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The resulting concentrate was then purified on a silica column to give 5.35 g of a white solid compound in 74% yield and purity=97%. TLC R f = 0.5 (PE:EA=4:1) LCMS (m / z) = 424.30 (M+H)

[0124] To a solution (36 mL) of the obtained compound methyl 1-(3-fluoro-4-methylbenzyl)-5-hydroxy-2-oxo-8-(trifluoromethyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (5.35 g, 12.64 mmol, 1 equiv.), H2O (1 mL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 hours. The reaction mixture was cooled to room temperature, ice (60 mL) was added, and the mixture was allowed to stir for 12 hours. 1N H2SO4 (30 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 hours. The resulting precipitate was filtered. The crude product was then purified on a silica column to obtain 3.89 g (purity=99%) of a pale yellow oily compound in 84% yield. TLC R f = 0.7 (PE:EA=2:1); LCMS (m / z) = 366.40 (M+H)

[0125] TIFF2024542204000059.tif581659-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-8) To a solution of methyl 9-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (2.322 g, 9.24 mmol, 1 equiv.) in DMF (75 mL) was added a 60% dispersion of NaH in mineral oil (1.331 g, 33.27 mmol, 3.6 equiv.). To this solution was added 4-(bromomethyl)-2-fluoro-1-methylbenzene (11.09 mmol, 1.2 equiv.) and the reaction mixture was allowed to stir at room temperature for 4 h. The resulting solution was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The resulting concentrate was then purified on a silica column to give 2.469 g of a yellow oily compound in 71.56% yield and purity=96.88%. TLC R f = 0.7 (PE:EA=2:1) LCMS (m / z) = 374.70 (M+H)

[0126] To a DMSO solution (18.59 mL) of the resulting compound 9-fluoro-1-(3-fluoro-4-methylbenzyl)-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (2.469 g, 6.613 mmol, 1 eq.), HO (1.38 mL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 hours. The reaction mixture was cooled to room temperature, ice (11.30 mL) was added, and the mixture was allowed to stir for 12 hours. 1N HCl (11.3 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 hours. The resulting precipitate was filtered. The crude product was then purified on a silica column to obtain 1.602 g (purity=97.46%) of a pink oily compound in 76% yield. TLC R f = 0.4 (PE:EA=2:1) LCMS (m / z) = 316.60 (M+H)

[0127] TIFF2024542204000060.tif621656-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-9) To a stirred solution of methyl 6-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (5.924 g, 23.58 mmol, 1 equiv) in DMSO (94 mL) was added a 60% dispersion of NaH in mineral oil (3.396 g, 84.89 mmol, 3.6 equiv) at room temperature. After 0.5 h, the mixture was added with 4-(bromomethyl)-2-fluoro-1-methylbenzene (3.945 mL, 28.3 mmol, 1.2 equiv) over 3 h at ambient temperature. The solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with 1M H2SO4 (2×10 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 7g of a white solid compound in 79% yield. Purity=90%. TLC R f = 0.4 (EA:PE=1:2) LCMS (m / z) = 374.10 (M+H)

[0128] To a solution of methyl 6-fluoro-1-(3-fluoro-4-methylbenzyl)-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (7 g, 18.75 mmol, 1 equiv.) in DMSO (29 mL), HO (1 mL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 h. The reaction mixture was cooled to room temperature, ice (45 mL) was added, and the mixture was allowed to stir for 12 h. 1N HCl (45 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 h. The resulting precipitate was filtered. The crude product was then purified on a silica column to give 5.685 g of a pale yellow oily compound in 96% yield. Purity=89%. TLC R f = 0.3 (EA:PE=1:2) LCMS (m / z) = 316.00 (M+H)

[0129] TIFF2024542204000061.tif521657-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-10) To a stirred solution of methyl 7-fluoro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (6.732 g, 26.80 mmol, 1 equiv) in DMSO (107 mL) was added a 60% dispersion of NaH in mineral oil (3.859 g, 96.47 mmol, 3.6 equiv) at room temperature. After 0.5 h, the mixture was added with 4-(bromomethyl)-2-fluoro-1-methylbenzene (4.48 mL, 32.16 mmol, 1.2 equiv) over 3 h at ambient temperature. The solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with 1M H2SO4 (2×10 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 7.747 g of a white solid compound in 77% yield. Purity=89%. TLC R f = 0.5 (EA:PE=1:2) LCMS (FA) m / z = 374.10 (M+H)

[0130] To a solution of methyl 7-fluoro-1-(3-fluoro-4-methylbenzyl)-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (7.747 g, 20.75 mmol, 1 equiv.) in DMSO (32 mL), HO (1 mL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 h. The reaction mixture was cooled to room temperature, ice (50 mL) was added, and the mixture was allowed to stir for 12 h. 1N HCl (50 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 h. The resulting precipitate was filtered. The crude product was then purified on a silica column to give 4.538 g of a pale yellow oily compound in 69% yield. Purity=97%. TLC R f= 0.35 (EA:PE=1:2) LCMS (FA) m / z = 316.00 (M+H)

[0131] TIFF2024542204000062.tif631651-(3-Fluoro-4-methylbenzyl)-9-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-11) To a solution of methyl 5-hydroxy-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (2.6 g, 10.5 mmol, 1 equiv.) in DMF (74 mL) was added a 60% dispersion of NaH in mineral oil (907 mg, 37.8 mmol, 3 equiv.). To this solution was added 4-(bromomethyl)-2-fluoro-1-methylbenzene (12.6 mmol, 1.2 equiv.) and the reaction mixture was allowed to stir at room temperature for 4 h. The resulting solution was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The resulting concentrate was then purified on a silica column to give 1.08 g of a white solid compound in 28% yield and purity=97%. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 370.10 (M+H)

[0132] To a solution (8.2 mL) of the obtained compound methyl 1-(3-fluoro-4-methylbenzyl)-5-hydroxy-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (1.08 g, 2.92 mmol, 1 equiv.), H2O (233 uL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 hours. The reaction mixture was cooled to room temperature, ice (11.3 mL) was added, and the mixture was allowed to stir for 12 hours. 1N HCl (11.3 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 hours. The resulting precipitate was filtered. The crude product was then purified on a silica column to obtain 800 mg (purity=98%) of a pale yellow oily compound in 88% yield. TLC R f= 0.4 (PE:EA=2:1); LCMS (m / z) = 312.10 (M+H)

[0133] TIFF2024542204000063.tif671651-(4-Methoxybenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (6-12) To a stirred solution of methyl 5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (19 g, 81.47 mmol, 1 equiv) in DMSO (244 mL) was added a 60% dispersion of NaH in mineral oil (11.7 g, 293.28 mmol, 3.6 equiv) at room temperature. After 0.5 h, the mixture was added with 1-(bromomethyl)-4-methoxybenzene (11.9 mL, 97.76 mmol, 1.2 equiv) over 3 h at ambient temperature. The solution was quenched with saturated ammonium chloride and extracted with EA (3×100 mL). The organic solutions were combined, washed with 1M H2SO4 (2×100 mL) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 14 g of a white solid compound in 49% yield. Purity=73%. TLC R f = 0.6 (EA:PE=1:2) LCMS (m / z) = 354.20 (M+H)

[0134] To a solution of methyl 5-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (20 g, 56.6 mmol, 1 equiv.) in DMSO (88 mL), HO (3 mL) was added under nitrogen and the reaction mixture was allowed to stir at 150° C. for 5 h. The reaction mixture was cooled to room temperature, ice (150 mL) was added, and the mixture was allowed to stir for 12 h. 1N HCl (150 mL) was added to the flask at 0° C. and the mixture was allowed to stir for 3 h. The resulting precipitate was filtered. The crude product was then purified on a silica column to give 12.9 g of a pale yellow oily compound in 77% yield. Purity=91%. TLC R f= 0.5 (EA:PE=1:1) LCMS (m / z) = 296.100 (M+H)

[0135] Example 7: Representative synthesis of compounds of formula 7: TIFF2024542204000064.tif531655-Chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-1) Phosphorus oxychloride (61 μL, 0.65 mmol) was added to a flask containing N,N-dimethylformamide (0.5 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-1 (148 mg, 0.5 mmol) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water, neutralized with 20% sodium acetate solution, and extracted with EA (3 × 10-20 mL). The combined organic extracts were washed with 50 mL of saturated aqueous sodium bicarbonate and 50 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 144 mg (purity=99%) of a yellow solid compound in 84% yield. TLC R f = 0.5 (PE:EA=2:1) LCMS (m / z) = 344.20 (M+H)

[0136] TIFF2024542204000065.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-2) Phosphorus tribromide (271.6 μL, 2.86 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (22 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-1 (653.4 mg, 2.2 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water, neutralized with 20% sodium acetate solution, and extracted with EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 608 mg of a yellow solid compound (purity=99%) in a yield of 71%. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 390.04 (M+2H) 1 H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 7.89 - 7.78 (m, 1H), 7.65 - 7.50 (m, 2H), 7.36 (ddd, J = 8.2, 6.2, 2.3 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 9.3 Hz, 2H), 5.33 (d, J = 16.0 Hz, 1H), 4.89 (d, J = 16.0 Hz, 1H), 3.73 (d, J = 12.9 Hz, 1H), 2.63 (d, J = 12.9 Hz, 1H), 2.12 (s, 3H). 13C NMR (100 MHz, DMSO) δ 190.39, 169.23, 162.22, 159.80, 140.38, 137.70, 137.63, 136.09, 134.20, 132.78, 132.52, 132.03, 131.98, 130.70, 126.15, 123.93, 123.30, 123.13, 123.01, 122.98, 113.83, 113.60, 49.69, 33.66, 14.24, 14.21

[0137] TIFF2024542204000066.tif581655,8-Dibromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-3) Phosphorus tribromide (185 μL, 1.95 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (15 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 8-Bromo-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-2 (564 mg, 1.5 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine 50 mL, and water (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 700.5 mg (purity=98%) of a yellow solid compound in a yield of 71%. TLC R f = 0.6 (PE:EA=4:1) LCMS (m / z) = 467.90 (M+H)

[0138] TIFF2024542204000067.tif531655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-formyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-8-carbonitrile (7-4) To a solution of 8-bromo-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-2 (1 g, 2.66 mmol, 1 equiv.) in 1,4-dioxane (9.4 mL) was added potassium acetate (32.3 mg, 0.33 mmol, 0.25 equiv.), potassium ferricyanide(II) trihydrate (437.6 mg, 1.33 mmol, 0.5 equiv.), t-BuXPhos palladium(I) phenethylamine chloride (89 mg, 0.13 mmol, 0.05 equiv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (55 mg, 0.13 mmol, 0.05 equiv.), and water (9.4 mL). After heating at 110° C. for 1 h with stirring, the reaction mixture was diluted with EA. After removing the catalyst by filtration, the filtrate was washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuum. The resulting concentrate was then purified on a silica column to give 815 mg (purity=99%) of a yellow solid compound in 95% yield. TLC R f = 0.3 (PE:EA=2:1) LCMS (m / z) = 323.40 (M+H)

[0139] Phosphorus oxychloride (61 μL, 0.65 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (0.5 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10–15 min. 1-(3-Fluoro-4-methylbenzyl)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carbonitrile (Intermediate 1) (161 mg, 0.5 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 4 h. The orange solution was diluted with ice water, neutralized with 20% sodium acetate solution and extracted with EA (3 × 10–20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 140 mg (purity=99%) of a yellow solid compound in 76% yield. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 369.50 (M+H)

[0140] TIFF2024542204000068.tif581655-Chloro-1-(3-fluoro-4-methylbenzyl)-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-5) Phosphorus oxychloride (0.12 mL, 1.19 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (1 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methylbenzyl)-8-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-3 (300 mg, 0.917 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water, neutralized with 20% sodium acetate solution, and extracted with EA (3 × 10-20 mL). The combined organic extracts were washed with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of brine, and water (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 343 mg (purity=99%) of a yellow solid compound in 99% yield. TLC R f = 0.6 (EA:PE=1:2) LCMS (m / z) = 374.60 (M+H)

[0141] TIFF2024542204000069.tif481655-Bromo-1-(3-fluoro-4-methylbenzyl)-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-6) Phosphorus tribromide (112 μL, 1.19 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (20 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-3 (300 mg, 0.917 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine 50 mL, and water (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 248 mg (purity=98%) of a yellow solid compound in 65% yield. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 418.40 (M+H)

[0142] TIFF2024542204000070.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-7) Phosphorus tribromide (126 μL, 1.326 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (11 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methylbenzyl)-8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-4 (316.8 mg, 1.02 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 320 mg (purity=98%) of a yellow solid compound in 78% yield. TLC R f = 0.8 (PE:EA=2:1) LCMS (m / z) = 402.30 (M+H)

[0143] TIFF2024542204000071.tif581655-Bromo-8-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-8) Phosphorus tribromide (274.1 uL, 2.88 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (22.33 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 8-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-6 (700 mg, 2.22 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine 50 mL, and water (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 704 mg of an orange solid compound (purity=99%) in a yield of 78.06%. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 406.0 (M+H)

[0144] TIFF2024542204000072.tif631655-Bromo-8-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-9) Phosphorus tribromide (0.75 ml, 7.84 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (66 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 8-Chloro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione 6-6 (2 g, 6 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 1.97 g (purity=97%) of a yellow solid compound in 78% yield. TLC R f = 0.6 (PE:EA=2:1); LCMS (m / z) = 423.70(M+H)

[0145] Example 8: Representative synthesis of compounds of formula 7: TIFF2024542204000073.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-(trifluoromethyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-10) Phosphorus tribromide (889 μL, 9.36 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (72 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methylbenzyl)-8-(trifluoromethyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (2.6 g, 7.2 mmol, 1.0 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 1 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and diethyl ether (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 2.889 g (purity=91%) of a yellow oily compound in 88% yield. TLC R f = 0.85 (PE:EA = 1:1); LCMS (m / z) = 459.00 (M+H)

[0146] TIFF2024542204000074.tif631655-Bromo-9-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-11) Tribromophosphane (627.3 μL, 6.60 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (51.09 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 9-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (1.602 g, 5.08 mmol, 1.0 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water, neutralized with 20% sodium acetate solution, and extracted with EA (3 × 10-20 mL). The combined organic extracts were washed with 50 mL of saturated aqueous sodium bicarbonate and 50 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 1.3 g of an orange solid compound (purity=99%) in a yield of 63.52%. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 406.70 (M+H)

[0147] TIFF2024542204000075.tif631655-Bromo-6-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-12) Phosphorus tribromide (2.23 mL, 23.46 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (180 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 6-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (5.685 g, 18.02 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 3.95 g of a yellow solid compound in 54% yield. Purity=87%. TLC R f = 0.5 (EA:PE=1:2) LCMS (m / z) = 407.60 (M+H)

[0148] TIFF2024542204000076.tif631655-Bromo-7-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-13) Phosphorus tribromide (1.76 mL, 18.73 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (144 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 7-Fluoro-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (4.538 g, 14.4 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 4 g of yellow solid compound in 68% yield. Purity=98%. TLC R f = 0.6 (EA:PE=1:2) LCMS (m / z) = 407.70 (M+H)

[0149] TIFF2024542204000077.tif62165Bromo-1-(3-fluoro-4-methylbenzyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-14) Phosphorus tribromide (306 ul, 3.21 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (24.7 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-Fluoro-4-methylbenzyl)-9-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (770 mg, 2.47 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80°C and stirred for an additional 1 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 x 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 610 mg (purity=91%) of a yellow solid compound in 61% yield. TLC R f = 0.6 (PE:EA=2:1); LCMS (m / z) = 404.00 (M+H)

[0150] TIFF2024542204000078.tif531655-Bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-15) A mixture of 8-bromo-1-(3-fluoro-4-methylbenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (1 g, 2.658 mmol, 1.0 equiv.), (Ph3P)2PdCl2 (23.369 mg, 0.05315 mmol, 0.02 equiv.) and CuI (2.453 mg, 0.02658 mmol, 0.01 equiv.) in a flask was degassed for 10 min, then Et3N (0.2 M relative to substrate) was added under argon atmosphere. To this solution was added ethynyltrimethylsilane (1.878 mL, 13.289 mmol, 5 equiv.) via syringe. The mixture was warmed to 65° C. for 12 h. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was concentrated and purified by chromatography to give 1.045 g (purity=89.40%) of the product as a brown solid. Yield: 99%. TLC R f = 0.7 (PE:EA=2:1) LCMS (m / z) = 394.10 (M+H)

[0151] Tribromophosphane (271 uL, 2.854 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (21.95 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-Fluoro-4-methylbenzyl)-8-((trimethylsilyl)ethynyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (865 mg, 2.195 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 968 mg (purity=99%) of a brown solid compound in 69.53% yield. TLC R f = 0.6 (PE:EA=4:1) LCMS (m / z) = 485.80 (M+H)

[0152] TIFF2024542204000079.tif581655-Bromo-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-15) Phosphorus tribromide (986 μL, 10.4 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (80 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(4-Methoxybenzyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (2.3 g, 8 mmol, 1.0 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 1 h. The orange solution was diluted with ice water, neutralized with 20% sodium acetate solution, and extracted with EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 2.14 g (purity=82%) of a yellow oily compound in 71% yield. TLC R f = 0.65 (PE:EA = 1:1); LCMS (m / z) = 385.90 (M+H)

[0153] Example 9: Representative synthesis of compounds of formula 8: TIFF2024542204000080.tif631655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-1) A dry round bottom flask was charged with toluenesulfonylmethyl isocyanide (TosMIC, 234 mg, 0.35 mmol) and dry MeOH (9 mL) was added under argon atmosphere. At room temperature, solid K2CO3 (92.2 g, 0.87 mmol) and 5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-1 (100 mg, 0.29 mmol) were added to the mixture and the mixture was heated to reflux for 1.5 h. After completion of the reaction as indicated by the absence of aldehyde starting material by TLC analysis, the mixture was quenched with cold water. After the mixture was quenched, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure white solid (78 mg, yield=70%, purity=99%). TLC R f = 0.3 (PE:EA=2:1) LCMS (m / z) = 383.60 (M+H) 1 H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.94 (s, 1H), 7.77 (dd, J = 8.0, 1.4 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.52 - 7.43 (m, 1H), 7.37 - 7.28 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.78 - 6.66 (m, 2H), 5.32 (d, J = 16.1 Hz, 1H), 4.93 (d, J = 16.1 Hz, 1H), 3.75 (d, J = 13.2 Hz, 1H), 3.03 (d, J = 13.2 Hz, 1H), 2.12 (s, 3H)

[0154] TIFF2024542204000081.tif631655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-2) A dry round bottom flask was charged with toluenesulfonylmethyl isocyanide (TosMIC, 25.35 mg, 0.13 mmol) and dry MeOH (3.5 mL) was added under argon atmosphere. At room temperature, solid K2CO3 (35 mg, 0.33 mmol) and 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-2 (41 mg, 0.11 mmol) were added to the mixture and the mixture was heated to reflux for 1.5 h. The mixture was quenched with cold water. After the mixture was quenched, all the solvents were removed under reduced pressure and the product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure yellow solid (purity=99%, 35 mg, yield=74%). TLC R f = 0.6 (EA:PE=1:2) LCMS (m / z) = 429.20 (M+H) 1 H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.01 (s, 1H), 7.76 (dd, J = 8.0, 1.5 Hz, 1H), 7.54 (dd, J = 8.3, 0.9 Hz, 1H), 7.48 - 7.40 (m, 1H), 7.34 - 7.25 (m, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.70 (t, J = 8.6 Hz, 2H), 5.36 (d, J = 16.1 Hz, 1H), 4.91 (d, J = 16.1 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.01 (d, J = 13.1 Hz, 1H), 2.12 (s, 3H). 13C NMR (100 MHz, DMSO) δ 168.98, 162.23, 159.82, 152.82, 148.48, 139.71, 137.79, 137.71, 133.64, 132.01, 131.96, 131.11, 130.69, 128.67, 125.92, 125.48, 123.40, 123.25, 123.08, 122.77, 122.73, 116.35, 113.57, 113.34, 49.36, 38.71, 14.22, 14.18

[0155] TIFF2024542204000082.tif631655,8-Dibromo-1-(3-fluoro-4-methylbenzyl)-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-3) A dry two-neck round bottom flask was charged with toluenesulfonylmethyl isocyanide (TosMIC, 251 mg, 1.28 mmol) and dry MeOH (40 mL) was added under argon atmosphere. At room temperature, solid K2CO3 (443 mg, 3.21 mmol) and 5,8-dibromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-3 (500 mg, 1.07 mmol) were added to the mixture and the mixture was heated to reflux for 1.5 h. After completion of the reaction as indicated by the absence of aldehyde starting material by TLC analysis, the mixture was quenched with cold water. After the mixture was quenched, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure yellow solid (purity=95%, 420 mg, yield=77%). TLC R f = 0.6 (EA:PE=1:2) LCMS (m / z) = 506.90 (M+H)

[0156] TIFF2024542204000083.tif571655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(oxazol-5-yl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-8-carbonitrile (8-4) A dry two-neck round bottom flask was charged with toluenesulfonylmethyl isocyanide (TosMIC, 89 mg, 0.456 mmol, 1.2 equiv.) and dry MeOH (11.8 mL) was added under nitrogen atmosphere. At room temperature, solid K2CO3 (121 mg, 1.14 mmol, 3 equiv.) and 5-chloro-1-(3-fluoro-4-methylbenzyl)-4-formyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-8-carbonitrile (7-4) (140 mg, 0.38 mmol, 1 equiv.) were added to the mixture and the mixture was heated to reflux for 1 h. After completion of the reaction as indicated by the absence of aldehyde starting material by TLC analysis, the mixture was quenched with cold water. After the mixture was quenched, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure yellow solid (purity=95%, 65 mg, yield=42%). TLC R f = 0.25 (PE:EA=2:1) LCMS (m / z) = 408.50 (M+H)

[0157] TIFF2024542204000084.tif631655-Chloro-1-(3-fluoro-4-methylbenzyl)-8-methoxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-5) A dry round bottom flask was charged with toluenesulfonylmethyl isocyanide (215 mg, 1.10 mmol, 1.2 equiv.) and dry MeOH (30 mL) was added under argon atmosphere. At room temperature, solid K2CO3 (292 mg, 2.75 mmol, 3 equiv.) and 5-chloro-1-(3-fluoro-4-methylbenzyl)-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (7-5) (343 mg, 0.918 mmol, 1 equiv.) were added to the mixture and the mixture was heated to reflux for 1.5 h. After completion of the reaction as indicated by the absence of aldehyde starting material by TLC analysis, the mixture was quenched with cold water. After the mixture was quenched, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure white solid (purity=99%, 235 mg, yield=62%). TLC R f = 0.3 (EA:PE=1:2) LCMS (m / z) = 413.60 (M+H) 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.9, 2.5 Hz, 1H), 6.72 (t, J = 8.9 Hz, 2H), 5.32 (d, J = 16.1 Hz, 1H), 4.97 (d, J = 16.1 Hz, 1H), 3.79 (s, 3H), 3.73 (d, J = 13.1 Hz, 1H), 3.02 (d, J = 13.1 Hz, 1H), 2.12 (s, 3H)

[0158] TIFF2024542204000085.tif631655-Bromo-1-(3-fluoro-4-methylbenzyl)-8-methoxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-6) A dry two-neck round bottom flask was charged with toluenesulfonylmethyl isocyanide (TosMIC, 139 mg, 0.71 mmol, 1.2 equiv.) and dry MeOH (19 mL) was added under nitrogen atmosphere. At room temperature, solid K2CO3 (189 mg, 1.78 mmol, 3 equiv.) and 7-6 (248 mg, 0.593 mmol, 1 equiv.) were added to the mixture and the mixture was heated to reflux for 3 h. After completion of the reaction as indicated by the absence of aldehyde starting material by TLC analysis, the mixture was quenched with cold water. After quenching the mixture, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give 180 mg (purity=97%) of pale yellow solid compound in 66% yield. TLC R f = 0.3 (EA:PE=1:2) LCMS (m / z) = 457.40 (M+H) 1 H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.94 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 6.92 (dd, J = 9.0, 2.5 Hz, 1H), 6.71 (dd, J = 12.6, 9.4 Hz, 2H), 5.36 (d, J = 16.1 Hz, 1H), 4.94 (d, J = 16.1 Hz, 1H), 3.79 (s, 3H), 3.67 (d, J = 13.0 Hz, 1H), 3.01 (d, J = 13.0 Hz, 1H), 2.13 (s, 3H)

[0159] TIFF2024542204000086.tif631655-Chloro-1-(3-fluoro-4-methylbenzyl)-8-hydroxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-7) A stirred solution of 5-chloro-1-(3-fluoro-4-methylbenzyl)-8-methoxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-5) (203 mg, 0.492 mmol, 1 equiv.) in dry DCM (3 mL) was cooled to −78° C., then BBr3 (240 mg, 2.5 mmol, 5 equiv.) was added. The resulting mixture was allowed to warm slowly to ambient temperature and then stirred for 6 h. The solution was quenched with saturated NaHCO3 solution and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 180 mg (purity=96%) of a pale yellow solid compound in 92% yield. TLC R f = 0.15 (EA:PE=1:2) LCMS (m / z) = 399.60 (M+H) 1 H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.57 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.06 - 6.54 (m, 4H), 5.15 (d, J = 16.2 Hz, 1H), 4.90 (d, J = 16.3 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.05 (d, J = 13.0 Hz, 1H), 2.15 (s, 3H)

[0160] TIFF2024542204000087.tif631655-Chloro-1-(3-fluoro-4-methylbenzyl)-8-(2-morpholinoethoxy)-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-8) To a solution of 5-chloro-1-(3-fluoro-4-methylbenzyl)-8-hydroxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one 8-7 (50 mg, 0.125 mmol, 1 eq.) in 1 mL DMF, add K2CO3 (86 mg, 0.625 mmol, 5 eq.) and 4-(2-chloroethyl)morpholine hydrochloride (46 mg, 0.25 mmol, 2 eq.) and NaI (19 mg, 0.125 mmol, 1 eq.). The mixture is stirred at 80° C. for 7 h. The mixture is then poured into 150 mL of water and extracted with 3×200 mL of dichloromethane. The organic layer is washed with 2×150 mL of NaOH (20%), dried over Na 2 SO 4 , evaporated in vacuo, and purified by silica gel chromatography to give 15 mg (purity=94%) in 23% yield. TLC R f = 0.5 (DCM:MeOH = 20:1) LCMS (m / z) = 512.30 (M+H)

[0161] TIFF2024542204000088.tif621655-Chloro-1-(3-fluoro-4-methylbenzyl)-8-(2-methoxyethoxy)-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-9) To a solution of 5-chloro-1-(3-fluoro-4-methylbenzyl)-8-hydroxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one 8-7 (79 mg, 0.2 mmol, 1 equiv.) in 1.5 mL DMF, K2CO3 (110 mg, 0.8 mmol, 4 equiv.) and 1-iodo-2-methoxyethane (31 μL, 0.3 mmol, 1.5 equiv.) are added. The mixture is stirred at 80° C. for 7 h. The mixture is then poured into 150 mL water and extracted with 3×200 mL dichloromethane. The organic layer is washed with 2×150 mL NaOH (20%), dried over MgSO4, evaporated in vacuum and purified by silica gel chromatography to give 48 mg (purity=93%) in 52% yield. TLC R f = 0.6 (DCM:MeOH = 20:1) LCMS (m / z) = 457.70 (M+H)

[0162] TIFF2024542204000089.tif631655-Bromo-1-(3-fluoro-4-methylbenzyl)-8-hydroxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-10) To a stirred solution of 5-6 (135 mg, 0.295 mmol, 1 equiv) in DCM (2 mL) was added BBr3 (0.141 mL, 1.48 mmol, 1.2 equiv) at -78 °C. The resulting mixture was slowly warmed to ambient temperature and then stirred for 12 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3 x 20 mL). The organic solutions were combined, washed with H2O (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 116 mg (purity = 99%) of pale yellow solid compound in 88% yield. TLC R f = 0.2 (EA:PE=1:2) LCMS (m / z) = 443.40 (M+H) 1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.58 (s, 1H), 7.92 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.87 - 6.66 (m, 4H), 5.20 (d, J = 16.3 Hz, 1H), 4.87 (d, J = 16.3 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.04 (d, J = 13.0 Hz, 1H), 2.15 (s, 3H)

[0163] TIFF2024542204000090.tif581655-Bromo-8-ethoxy-1-(3-fluoro-4-methylbenzyl)-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-11) To a solution of 5-chloro-1-(3-fluoro-4-methylbenzyl)-8-hydroxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-10) (116 mg, 0.262 mmol, 1 equiv.) in 2 mL DMF was added K2CO3 (145 mg, 1.05 mmol, 4 equiv.) and 1-iodo-2-methoxyethane (31 μL, 0.393 mmol, 1.5 equiv.). The mixture was stirred at 80° C. for 2 h. The mixture was then poured into 150 mL of water and extracted with 3×200 mL of dichloromethane. The organic solutions were combined, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated by rotary evaporation. The resulting concentrate was then purified by silica gel chromatography to give 96 mg (purity=99%) in 78% yield. TLC R f = 0.4 (EA:PE=1:2) LCMS (m / z) = 471.60 (M+H)

[0164] TIFF2024542204000091.tif521655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(oxazol-5-yl)-2-oxo-2,3-dihydro-1H-benzo[b]azepin-8-yl acetate (8-12) To a solution of 8-10 (100 mg, 0.226 mmol, 1 equiv) in DCM (2 mL) was added DIEA (39 uL, 0.0391 mmol, 1.3 equiv) under nitrogen. To this solution was added acetyl chloride (19 uL, 0.0268 mmol, 1.2 equiv) and the reaction mixture was allowed to stir at room temperature for 4 h. H2O (4 mL) was then added to the reaction mixture, the organic solution was separated and the aqueous solution was extracted with DCM (3 x 50 mL). The organic solutions were combined, washed with H2O (2 x 50 mL) and brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 95 mg (purity = 99%) of a pale yellow oily compound in 87% yield. TLC R f = 0.6 (EA:PE=1:1) LCMS (m / z) = 485.30 (M+H) 1 H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.19 - 7.07 (m, 2H), 6.67 (t, J = 9.4 Hz, 2H), 5.41 (d, J = 16.1 Hz, 1H), 4.83 (d, J = 16.1 Hz, 1H), 3.71 (d, J = 13.2 Hz, 1H), 3.05 (d, J = 13.2 Hz, 1H), 2.29 (s, 3H), 2.12 (s, 3H)

[0165] TIFF2024542204000092.tif681655-Bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (8-13) A dry two-neck round bottom flask was charged with toluenesulfonylmethyl isocyanide (TosMIC, 58.5 mg, 0.3 mmol) and dry MeOH (8 mL) was added under argon atmosphere. At room temperature, solid K2CO3 (103.5 mg, 0.75 mmol) and 5-bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-7 (100 mg, 0.25 mmol) were added to the mixture and the mixture was heated to reflux for 1.5 h. After completion of the reaction as indicated by the absence of aldehyde starting material by TLC analysis, the mixture was quenched with cold water. After the mixture was quenched, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water, brine and dried over (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure yellow solid (purity=95%, 83 mg, yield=75%). TLC R f = 0.5 (EA:PE=1:2) LCMS (m / z) = 441.40(M+H)

[0166] Example 10: Representative synthesis of compounds of formula 10: TIFF2024542204000093.tif481658-Bromo-1-(3-fluoro-4-methylbenzyl)-5-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (10-1) To a stirred solution of methyl 8-bromo-1-(3-fluoro-4-methylbenzyl)-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 5-2 (868 mg, 2 mmol, 1 equiv.) and DIEA (496 μL, 3 mmol, 1.5 equiv.) in MeOH (6 mL) and xylene (6 mL) was added TMSCHN2 (3 mL, 6 mmol, 3 equiv.) at ambient temperature. The reaction mixture was then stirred at room temperature for 4 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with H2O (2×10 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 850 mg (purity=94%) of a white solid compound in 94% yield. TLC R f = 0.6 (EA:PE=1:2) LCMS (m / z) = 417.90 (M-29) 1 H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 7.47 (s, 2H), 7.14 (t, J = 7.9 Hz, 1H), 6.92 - 6.65 (m, 2H), 5.47 (d, J = 15.9 Hz, 1H), 4.88 (d, J = 15.8 Hz, 1H), 3.77 (s, 3H), 3.43 (d, J = 13.5 Hz, 1H), 3.38 (s, 3H), 2.64 (d, J = 13.5 Hz, 1H), 2.11 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 170.78, 165.32, 162.17, 159.76, 158.95, 142.61, 137.58, 137.51, 132.09, 132.03, 129.88, 128.69, 128.05, 127.16, 124.58, 123.53, 123.36, 123.33, 114.05, 113.83, 112.42, 60.55, 52.52, 48.70, 34.28, 14.20, 14.17

[0167] To a solution of the resulting 9 (methyl 8-bromo-1-(3-fluoro-4-methylbenzyl)-5-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate) (89 mg, 0.2 mmol, 1 equiv.) and (E)-N'-hydroxyacetimidamide (36 mg, 0.48 mmol, 2.4 equiv.) in THF (1.5 mL) was added a 60% dispersion of NaH in mineral oil (21 mg, 0.52 mmol, 2.6 equiv.) at ambient temperature under N2 atmosphere. The reaction mixture was then stirred at room temperature (rt) for 4 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3 x 10 mL). The organic solutions were combined, washed with H2O (2 x 10 mL) and brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 30 mg (purity=99%) of a white solid compound in 32% yield. TLC R f = 0.3 (PE:EA=4:1) LCMS (m / z) = 472.40 (M+H)

[0168] Example 11: Representative synthesis of compounds of formula 13: TIFF2024542204000094.tif53165(E)-5-Chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde oxime (11-1) A solution of 5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-1 (343 mg, 1 mmol, 1 equiv.) in methanol (25 mL) was treated with hydroxylamine hydrochloride (90 mg, 1.3 mmol, 1.3 equiv.) and pyridine (0.1 mL, 1.2 mmol, 1.2 equiv.). The reaction was stirred at room temperature for 2 h and then concentrated. The residue was purified by silica gel chromatography to give 340 mg (purity=98%) of a white solid compound in 94% yield. TLC R f= 0.15 (DCM:MeOH=10:1) LCMS (m / z) = 359.30 (M+H)

[0169] TIFF2024542204000095.tif531655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(5-(trimethylsilyl)isoxazol-3-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (12-1) To a solution of (E)-5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde oxime 11-1 (179 mg, 0.11 mmol, 1 equiv.) and trimethylsilylacetylene (133 μL, 1 mmol, 2 equiv.) in methanol (6.8 mL) and water (1.4 mL) was added bis(trifluoroacetoxy)-iodobenzene (237 mg, 0.55 mmol, 1.1 equiv.) and the reaction was stirred overnight. The reaction mixture was poured into MTBE and washed with water and saturated aqueous NaHCO3. The organic layer was concentrated and the residue was purified by silica gel chromatography to give 166 mg (purity=95%) of a white solid compound in 73% yield. TLC R f = 0.4 (DCM) LCMS (m / z) = 455.60 (M+H)

[0170] TIFF2024542204000096.tif581655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(isoxazol-3-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (13-1) 5-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(5-(trimethylsilyl)isoxazol-3-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (166 mg, 0.36 mmol) in 7M ammonia / methanol solution (100 mL, 306 mmol) was stirred at room temperature for 0.5 h. The reaction was concentrated in vacuo and purified by silica gel chromatography to give an oil, 95 mg (purity=99%) in 69% yield. TLC R f = 0.5 (PE:EA=2:1) LCMS (m / z) = 383.60 (M+H) 1 H NMR (400 MHz, DMSO) δ 9.13 (d, J = 1.7 Hz, 1H), 7.79 (dd, J = 8.0, 1.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.42 - 7.29 (m, 1H), 7.18 (d, J = 1.7 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.75 (dd, J = 8.9, 4.6 Hz, 2H), 5.35 (d, J = 16.1 Hz, 1H), 4.94 (d, J = 16.1 Hz, 1H), 3.81 (d, J = 13.0 Hz, 1H), 3.09 (d, J = 13.0 Hz, 1H), 2.13 (s, 3H)

[0171] TIFF2024542204000097.tif63165(E)-5-Bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde oxime (11-2) A solution of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-2 (194.12 mg, 0.5 mmol, 1 equiv.) in methanol (12.5 mL) was treated with hydroxylamine hydrochloride (45.16 mg, 0.65 mmol, 1.3 equiv.) and pyridine (49.6 uL, 0.6 mmol, 1.2 equiv.). The reaction was stirred at room temperature for 1 h and then concentrated. The residue was purified by silica gel chromatography to give 134.4 mg (purity=99%) of a white solid compound in 66.6% yield. TLC R f = 0.5 (PE:EA=4:1) LCMS (m / z) = 403.30 (M+H)

[0172] TIFF2024542204000098.tif58165Bromo-1-(3-fluoro-4-methylbenzyl)-4-(5-(trimethylsilyl)isoxazol-3-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (12-2) To a solution of (E)-5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde oxime 11-2 (134.4 mg, 0.33 mmol, 1 equiv.) and trimethylsilylacetylene (94 μL, 0.67 mmol, 2 equiv.) in methanol (20.4 mL) and water (4.2 mL) was added bis(trifluoroacetoxy)-iodobenzene (157.66 mg, 0.37 mmol, 1.1 equiv.) and the reaction was stirred overnight. The reaction mixture was poured into MTBE and washed with water and saturated aqueous NaHCO3. The organic layer was concentrated and the residue was purified by silica gel chromatography to give 105.5 mg (purity=99%) of a white solid compound in 64% yield. TLC R f = 0.5 (PE:EA=4:1) LCMS (m / z) = 499.10(M+H)

[0173] TIFF2024542204000099.tif63165Bromo-1-(3-fluoro-4-methylbenzyl)-4-(isoxazol-3-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (13-2) 5-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(5-(trimethylsilyl)isoxazol-3-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one 12-2 (105.5 mg, 0.21 mmol) in 7 M ammonia / methanol solution (58.3 mL, 178 mmol) was stirred at room temperature for 0.5 h. The reaction was concentrated in vacuo and purified by silica gel chromatography to give 95 mg (purity=99%) of a yellow oil in 66.6% yield. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 426.90 (M+H) 1 H NMR (400 MHz, DMSO) δ 9.12 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 8.0, 1.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.75 (t, J = 8.4 Hz, 2H), 5.41 (d, J = 16.0 Hz, 1H), 4.91 (d, J = 16.1 Hz, 1H), 3.64 (d, J = 12.9 Hz, 1H), 3.11 (d, J = 12.9 Hz, 1H), 2.13 (s, 3H)

[0174] Example 12: Representative synthesis of compounds of formula 16: TIFF2024542204000100.tif581654-(5-amino-1,3,4-thiadiazol-2-yl)-5-chloro-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (15-1) The reaction was carried out by adding aqueous NaClO2 (461 mg, 4.61 mmol, 1.76 equiv) to 5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-1 (1 g, 2.92 mmol, 1 equiv) and (414 mg, 2.67 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4.3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted HOCI and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 770 mg (purity=97%) of a white solid compound in 73% yield. TLC R f = 0.2 (DCM:MeOH=10:1) LCMS (m / z) = 360.10 (M+H)

[0175] A stirred mixture of 5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-1 (71 mg, 0.2 mmol, 1 equiv.), N-aminothiourea (37 mg, 0.4 mmol, 2 equiv.) and POCl3 (0.5 mL) was heated at 75° C. for 0.5 h. After cooling to room temperature, water (30 ml) was added. The reaction mixture was refluxed for 4 h. After cooling, the mixture was basified to PH=8 by dropwise addition of 50% NaOH solution with stirring and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 30 mg of a pale yellow solid compound (purity=96%) in a yield of 36%. TLC R f = 0.5 (DCM:MeOH = 10:1) LCMS (m / z) = 415.70 (M+H)

[0176] TIFF2024542204000101.tif531654-(5-amino-1,3,4-thiadiazol-2-yl)-5-bromo-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (15-2) The reaction was carried out by adding aqueous NaClO2 (324.7 mg, 3.61 mmol, 3.6 equiv) to 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-2 (795 mg, 2.05 mmol, 1 equiv) and (237 mg, 2.09 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 0.5 g) was added to destroy unreacted HOCI and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 528 mg (purity=96%) of a white solid compound in 63% yield. TLC R f = 0.2 (DCM:MeOH=10:1) LCMS (m / z) = 405.90 (M+H) 1H NMR (400 MHz, DMSO) δ 13.61 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.75 (dd, J = 8.0, 6.1 Hz, 2H), 5.38 (d, J = 16.1 Hz, 1H), 4.89 (d, J = 16.1 Hz, 1H), 3.41 (d, J = 13.2 Hz, 1H), 2.85 (d, J = 13.2 Hz, 1H), 2.13 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 169.48, 167.13, 162.28, 159.86, 139.79, 137.82, 137.75, 132.75, 132.30, 131.98, 131.93, 131.11, 130.88, 125.90, 123.53, 123.23, 123.06, 122.83, 122.80, 120.43, 113.64, 113.42, 49.45, 38.42, 14.23, 14.20

[0177] A stirred mixture of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-2 (194 mg, 0.5 mmol, 1 equiv.), N-aminothiourea (91 mg, 1 mmol, 2 equiv.) and POCl3 (1.2 mL) was stirred at room temperature for 5 h. Then water (30 ml) was added. The mixture was basified to pH=8 by dropwise addition of 50% NaOH solution under stirring and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 30 mg (purity=91%) of a pale yellow solid compound in 56% yield. TLC R f = 0.5 (DCM:MeOH = 10:1) LCMS (m / z) = 458.90 (M+H)

[0178] TIFF2024542204000102.tif63165N-(5-(5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide (16-1) Acetyl chloride (13 uL, 0.17 mmol, 1 equiv) was added to a solution of 15-2 (80 mg, 0.17 mmol, 1 equiv), DIEA (56 uL, 0.34 mmol, 2 equiv) in DCM (0.5 mL), and the reaction mixture was then stirred at room temperature for 4 h. H2O (4 mL) was added to the reaction mixture, which was then extracted with EA (3 x 20 mL). The organic solutions were combined, washed with H2O (2 x 20 mL) and brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 30 mg (purity = 89%) of a pale yellow solid compound in 56% yield. TLC R f = 0.4 (DCM:MeOH = 10:1) LCMS (m / z) = 503.0 (M+H)

[0179] Example 13: Representative synthesis of compound of formula 18: TIFF2024542204000103.tif631655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (18-1) To a solution of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-2) (271 mg, 0.67 mmol, 1 equiv.) in DCM (9.6 mL) was added SOCl2 (243 μL, 3.35 mmol, 5 equiv.) and the mixture was stirred under reflux for 3 h. After the corresponding acid chloride reaction occurred as shown by TLC, MeOH (3 mL) was added to the mixture and stirred for 0.5 h. After the mixture was quenched, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure yellow solid (purity=99%, 255 mg, yield=90%). TLC R f = 0.9 (DCM:MeOH=10:1) LCMS (m / z) = 418.00 (M+H)

[0180] N-Hydroxyacetimidamide (64.20 mg, 0.87 mmol, 2.4 equiv) suspended in THF (2.7 mL) under N2 was stirred with a 60% dispersion of NaH in oil (22.46 mg, 0.94 mmol, 2.6 equiv) for 1 h. 1-(3-Fluoro-4-methylbenzyl)-5-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate 17 (151.2 mg, 0.36 mmol, 1 equiv) in THF (0.2 mL) was added and the reaction was heated to reflux for 1.5 h. After cooling, the solution was quenched with saturated ammonium chloride and extracted with EA (3 x 10 mL). The organic solutions were combined, washed with H2O (2 x 10 mL) and brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 54.5 mg (purity=99%) of a yellow oily compound in a yield of 34.38%. TLC R f = 0.5 (PE:EA=4:1) LCMS (m / z) = 442.20 (M+H) 1 H NMR (400 MHz, DMSO) δ 7.91 - 7.73 (m, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.35 (dd, J = 11.1, 4.0 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 9.1 Hz, 2H), 5.39 (d, J = 16.0 Hz, 1H), 4.91 (d, J = 16.0 Hz, 1H), 3.85 (d, J = 13.4 Hz, 1H), 3.13 (d, J = 13.4 Hz, 1H), 2.46 (s, 3H), 2.13 (s, 3H)

[0181] Example 14: Representative synthesis of compound of formula 20: TIFF2024542204000104.tif681655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-1) To a solution of 5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-1) (200 mg, 0.56 mmol, 1 equiv.) in dichloromethane (7.5 mL), acetohydrazide (62.2 mg, 0.84 mmol, 1.5 equiv.), triethylamine (116.7 μL, 0.84 mmol, 1.5 equiv.), and HATU (425.6 mg, 1.12 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 18.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / EtOAc, 5:1 to 3:1) to give 160 mg (purity=96%) of the product as a white solid. Yield: 68%. TLC R f = 0.55 (DCM:MeOH=10:1) LCMS (m / z) = 416.70 (M+H)

[0182] N'-acetyl-5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (19-1) (160 mg, 0.38 mmol, 1 equiv.) was dissolved in phosphorus oxychloride (3.7 mL), and the mixture was stirred at 60° C. for 4 h. After the reaction mixture was cooled to room temperature, it was poured into a mixture of ice and water. The resulting solution was extracted with several portions of ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 2:1) to give the product (44 mg) as a white solid. Yield: 29%. Purity: 99%. TLC R f = 0.8 (DCM:MeOH=10:1) LCMS (m / z) = 398.30 (M+H) 1 H NMR (400 MHz, DMSO) δ 7.88 - 7.75 (m, 1H), 7.62 - 7.48 (m, 2H), 7.41 - 7.29 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.82 - 6.68 (m, 2H), 5.34 (d, J = 16.1 Hz, 1H), 4.95 (d, J = 16.1 Hz, 1H), 3.94 (d, J = 13.3 Hz, 1H), 3.13 (d, J = 13.3 Hz, 1H), 2.63 (s, 3H), 2.13 (s, 3H)

[0183] TIFF2024542204000105.tif621655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-2) To 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-2) (200 mg, 0.56 mmol, 1 equiv.) in dichloromethane (6.6 mL) was added acetohydrazide (55 mg, 0.743 mmol, 1.5 equiv.), triethylamine (103 μL, 0.743 mmol, 1.5 equiv.), and HATU (376.2 mg, 0.99 mmol, 2 equiv.). The mixture was stirred at room temperature for 18.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 71 mg (purity=92%) of the product as a white solid. Yield: 31%. TLC R f = 0.3 (DCM:MeOH = 10:1) LCMS (m / z) = 462.40 (M+H)

[0184] Compound 5-bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (19-2) (100 mg, 0.21 mmol, 1 equiv.) was dissolved in phosphorus oxychloride (2.1 mL) and the mixture was stirred at 60°C for 2 h. After the reaction mixture was cooled to room temperature, it was poured into a mixture of ice and water. The resulting solution was extracted with several portions of ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography to give the product (22 mg) as a white solid. Yield: 28%. Purity: 93%. TLC R f =0.8 (PE:EA=1:1) LCMS (m / z) = 442.40 (M+H) 1H NMR (400 MHz, DMSO) δ 7.80 (dd, J = 8.0, 1.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.84 - 6.65 (m, 2H), 5.38 (d, J = 16.1 Hz, 1H), 4.92 (d, J = 16.1 Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.09 (d, J = 13.2 Hz, 1H), 2.62 (s, 3H), 2.12 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 169.09, 164.91, 162.94, 162.24, 159.82, 139.85, 137.69, 137.62, 133.37, 132.03, 131.97, 131.54, 131.24, 126.00, 123.54, 123.32, 123.15, 123.12, 122.91, 122.88, 122.45, 113.75, 113.53, 49.34, 38.99, 14.21, 14.18, 11.24

[0185] TIFF2024542204000106.tif681655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-3) To 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-2) (300 mg, 0.74 mmol, 1 equiv.) in dichloromethane (6.6 mL) was added cyclopropanecarboxylic acid hydrazide (111.1 mg, 1.11 mmol, 1.5 equiv.), triethylamine (154 μL, 1.11 mmol, 1.5 equiv.), and HATU (562.4 mg, 1.48 mmol, 2 equiv.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 342 mg (purity=93%) of the product as a white solid. Yield: 98%. TLC R f = 0.45 (DCM:MeOH=10:1) LCMS (m / z) = 488.20 (M+H)

[0186] Compound (5-bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide) 19-3 (524 mg, 1.08 mmol, 1 equiv.) was dissolved in phosphorus oxychloride (11 mL), and the mixture was stirred at 60°C for 2 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the diluted solution was slowly poured into room temperature water under a water bath. The resulting solution was extracted with several portions of ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography to give 356 mg of product as a yellow solid. Yield: 70%. Purity: 99%. TLC R f = 0.7 (DCM:MeOH = 10:1); LCMS (m / z) = 468.40 (M+H) 1H NMR (400 MHz, DMSO) δ 7.79 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.73 (t, J = 8.3 Hz, 2H), 5.37 (d, J = 16.1 Hz, 1H), 4.91 (d, J = 16.1 Hz, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.06 (d, J = 13.2 Hz, 1H), 2.42 - 2.29 (m, 1H), 2.12 (s, 3H), 1.30 - 1.19 (m, 2H), 1.12 (d, J = 3.0 Hz, 2H). 13 C NMR (100 MHz, DMSO) δ 169.21, 169.03, 162.25, 162.12, 159.83, 139.87, 137.69, 137.62, 133.39, 132.02, 131.96, 131.53, 131.23, 126.01, 123.59, 123.32, 123.15, 122.93, 122.90, 122.83, 122.29, 113.70, 113.48, 49.46, 38.93, 14.22, 14.19, 9.05, 8.91, 6.48

[0187] TIFF2024542204000107.tif631655-Bromo-1-(3-fluoro-4-methylbenzyl)-7-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-3) The reaction was carried out by adding aqueous NaClO2 (572 mg, 6.32 mmol, 3.6 equiv) to 5-bromo-1-(3-fluoro-4-methylbenzyl)-7-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-6 (734 mg, 1.76 mmol, 1 equiv) and (61 mg, 1.79 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 0.5 g) was added to destroy unreacted HOCI and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 682 mg (purity=99%) of a white solid compound in 89% yield. TLC R f = 0.05 (EA:PE=1:2) LCMS (m / z) = 434.60 (M+H)

[0188] TIFF2024542204000108.tif571655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-8-methoxy-1,3-dihydro-2H-benzo[b]azepin-2-one (20-4) To 5-bromo-1-(3-fluoro-4-methylbenzyl)-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-3) (682 mg, 1.57 mmol, 1 equiv.) in dichloromethane (14 mL) was added cyclopropanecarboxylic acid hydrazide (236 mg, 2.36 mmol, 1.5 equiv.), triethylamine (0.327 mL, 2.36 mmol, 1.5 equiv.), and HATU (1193 mg, 3.14 mmol, 2 equiv.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 714 mg (purity=83%) of product as a white solid. Yield: 88%. TLC R f = 0.5 (DCM:MeOH = 10:1) LCMS (m / z) = 518.10 (M+H)

[0189] Compound (5-bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-7-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide) 19-4 (714 mg, 1.38 mmol, 1 equiv.) was dissolved in phosphorus oxychloride (13 mL), and the mixture was stirred at 60°C for 2 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added to dilute it, and the solution was poured slowly into room temperature water under a water bath. The resulting solution was extracted with several portions of ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give 310 mg (purity = 97%) of crude compound as a pale yellow oil in 45% yield. TLC R f = 0.85 (MeOH:DCM=1:10) LCMS (m / z) = 498.00 (M+H) 1H NMR (400 MHz, DMSO) δ 7.72 (d, J = 8.9 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 9.0, 2.4 Hz, 1H), 6.74 (dd, J = 12.8, 9.6 Hz, 2H), 5.36 (d, J = 16.0 Hz, 1H), 4.94 (d, J = 16.0 Hz, 1H), 3.85 (d, J = 13.1 Hz, 1H), 3.80 (s, 3H), 3.07 (d, J = 13.1 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.13 (s, 3H), 1.28 - 1.19 (m, 2H), 1.12 (dt, J = 7.5, 3.6 Hz, 2H)

[0190] TIFF2024542204000109.tif681655-Chloro-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-5) To 5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-1) (829 mg, 2.31 mmol, 1 equiv.) in dichloromethane (31 mL) was added cyclopropanecarboxylic acid hydrazide (347 mg, 3.465 mmol, 1.5 equiv.), triethylamine (481 μL, 3.465 mmol, 1.5 equiv.), and HATU (1755.6 mg, 4.62 mmol, 2 equiv.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 996 mg (purity=99%) of the product as a white solid. Yield: 97%. TLC R f = 0.45 (DCM:MeOH = 10:1); LCMS (m / z) = 442.10 (M+H)

[0191] Compound (5-chloro-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide) 19-5 (952 mg, 2.15 mmol, 1 equiv.) was dissolved in phosphorus oxychloride (21.5 mL), and the mixture was stirred at 60°C for 4.5 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added to dilute it, and the diluted solution was poured slowly into room temperature water under a water bath. The resulting solution was extracted with several portions of ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 2:3) to give the product (150 mg) as a yellow solid. Yield: 16%. Purity: 92%. TLC R f = 0.8 (DCM:MeOH = 10:1); LCMS (m / z) = 424.40 (M+H)

[0192] TIFF2024542204000110.tif671655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-7-hydroxy-1,3-dihydro-2H-benzo[b]azepin-2-one (20-6) To a stirred solution of 20-4 (240 mg, 0.482 mmol, 1 equiv) in DCM (6 mL) was added BBr3 (0.185 mL, 2.41 mmol, 5 equiv) at -78 °C. The reaction mixture was then stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC until the complete disappearance of compound LCL174. The solution was quenched with saturated ammonium chloride and extracted with EA (3 x 20 mL). The organic solutions were combined, washed with H2O (2 x 20 mL) and brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 30 mg (purity = 95%) of pale yellow solid compound in 14% yield. TLC R f = 0.2 (EA:PE=1:1) LCMS (m / z) = 486.10 (M+H)

[0193] TIFF2024542204000111.tif481655-Bromo-7-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-4) The reaction was carried out by adding aqueous NaClO2 (274.51 mg, 3.05 mmol, 1.76 equiv) to 5-bromo-8-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-8 (704 mg, 1.73 mmol, 1 equiv) and (60 mg, 1.76 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4.3 with KH2PO4. The reaction mixture was stirred for 4.5 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted HOCI and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the resulting concentrate was then purified on a silica column to give 679 mg (purity=99.27%) of a yellow solid compound in 92.95% yield. TLC R f = 0.2 (DCM:MeOH=10:1) LCMS (m / z) = 422.0 (M+H)

[0194] TIFF2024542204000112.tif581655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-7) To 5-bromo-8-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-4 (340 mg, 0.805 mmol, 1 equiv.) in dichloromethane (7 mL), cyclopropanecarboxylic acid hydrazide (120.93 mg, 1.208 mmol, 1.5 equiv.), triethylamine (167 μL, 1.208 mmol, 1.5 equiv.), and HATU (612.37 mg, 1.610 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 367 mg (purity=89.52%) of product as a white solid. Yield: 90.40%. TLC R f = 0.6 (DCM:MeOH=10:1) LCMS (m / z) = 505.80 (M+H)

[0195] Bromo-N'-(cyclopropanecarbonyl)-8-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 19-6 (167 mg, 0.33 mmol, 1 equiv.) was dissolved in 1,4-dioxane (4.86 mL), phosphoryl chloride (202 μL, 2017 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (19 mg) as a yellow solid. Yield: 11.84%, purity: 91%. TLC R f = 0.8 (DCM:MeOH=20:1) LCMS (m / z) = 487.80 (M+H)

[0196] TIFF2024542204000113.tif621655-Bromo-8-fluoro-1-(3-fluoro-4-methylbenzyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-8) To 5-bromo-7-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (339 mg, 0.803 mmol, 1 equiv.) in dichloromethane (7 mL), acetohydrazide (89.216 mg, 1.204 mmol, 1.5 equiv.), triethylamine (167 μL, 1.204 mmol, 1.5 equiv.), and HATU (609.90 mg, 1.604 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 260 mg (purity=93.92%) of product as a white solid. Yield: 67.70%. TLC R f = 0.8 (DCM:MeOH=20:1) LCMS (m / z) = 479.90 (M+H)

[0197] N'-acetyl-5-bromo-8-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 19-7 (260 mg, 0.54 mmol, 1 equiv.) was dissolved in 1,4-dioxane (7.95 mL), phosphoryl chloride (332.89 μL, 3.57 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (145 mg) as an orange solid. Yield: 58.33%, purity: 98.91%. TLC R f = 0.5 (DCM:MeOH = 20:1) LCMS (m / z)=461.90 (M+H)

[0198] TIFF2024542204000114.tif571655-Bromo-8-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-5) The reaction was carried out by adding aqueous NaClO2 (766.5 mg, 8.52 mmol, 3.6 equiv.) to 5-bromo-8-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-9 (1 g, 2.37 mmol, 1 equiv.) and (242 μL, 2.41 mmol, 1.02 equiv.) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 400 mg) was added to destroy unreacted HOCI and H2O2. The mixture was acidified with NH4CI and diluted with H2O (20 mL). The compound was extracted with EA (3 × 10-20 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 890 mg (purity=90%) of a white solid compound in 86% yield. TLC R f = 0.7 (PE:EA=4:1); LCMS (m / z) = 439.80 (M+H)

[0199] TIFF2024542204000115.tif621655-Bromo-8-chloro-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-9) To 5-bromo-8-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-5 (890 mg, 2.03 mmol, 1 eq.) in dichloromethane (20 mL) was added cyclopropanecarboxylic acid hydrazide (304.3 mg, 3.32 mmol, 1.5 eq.), triethylamine (423 μL, 3.32 mmol, 1.5 eq.), and HATU (1.54 g, 4.42 mmol, 2 eq.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 1.02 g (purity=99%) of product as a white solid. Yield: 96%. TLC R f = 0.4 (DCM:MeOH = 10:1) LCMS (m / z) = 521.90 (M+H)

[0200] Phosphorus oxychloride (1.12 ml, 12.87 mmol, 6.57 equiv) was added to 5-bromo-8-chloro-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 19-8 (1.02 g, 1.96 mmol, 1 equiv) in 1,4-dioxane (20 mL), and the mixture was stirred at 90°C for 3 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the diluted solution was slowly poured into room temperature water under a water bath. The resulting solution was extracted with several portions of ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography to give 670 mg of the product as a yellow solid. Yield: 70%. Purity: 99%. TLC R f = 0.4 (PE:EA=2:1); LCMS (m / z) = 503.90 (M+H)

[0201] TIFF2024542204000116.tif631655-Bromo-8-chloro-1-(3-fluoro-4-methylbenzyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-10) To 5-bromo-8-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-5 (400 mg, 0.91 mmol, 1 eq.) in dichloromethane (10 mL), cyclopropanecarboxylic acid hydrazide (101.5 mg, 1.37 mmol, 1.5 eq.), triethylamine (190 μL, 1.37 mmol, 1.5 eq.), and HATU (693.4 g, 1.82 mmol, 2 eq.) were added. The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 470 mg (purity=89%) of the product as a white solid. Yield: 93%. TLC R f = 0.5 (DCM:MeOH = 10:1) LCMS (m / z) = 495.80 (M+H)

[0202] Phosphorus oxychloride (582ul, 6.24mmol, 6.57eq) was added to N'-acetyl-5-bromo-8-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 19-9 (470mg, 0.95mmol, 1eq) in 1,4-dioxane (15mL), and the mixture was stirred at 90°C for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the diluted solution was poured slowly into room temperature water under water bath. The resulting solution was extracted with several portions of ethyl acetate (3x20mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography to give 220mg of product as a yellow solid. Yield: 49%. Purity: 98%. TLC R f = 0.6 (PE:EA=1:1); LCMS (m / z) = 478.3 (M+H)

[0203] TIFF2024542204000117.tif571655-Bromo-8-cyano-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-6) The reaction was carried out by adding aqueous NaClO2 (144.62 mg, 1.607 mmol, 1.76 equiv) to 5-bromo-1-(3-fluoro-4-methylbenzyl)-4-formyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-8-carbonitrile (7-4) (377 mg, 0.913 mmol, 1 equiv) and (31.65 mg, 0.931 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 0.5 g) was added to destroy unreacted HOCI and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 380 mg (purity=96%) of a white solid compound in 96% yield. TLC R f = 0.3 (DCM:MeOH = 10:1); LCMS (m / z) = 430.70 (M+H)

[0204] TIFF2024542204000118.tif631655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-8-carbonitrile (20-11) To 5-bromo-8-cyano-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-6) (380 mg, 0.885 mmol, 1 equiv.) in dichloromethane (11.9 mL), cyclopropanecarboxylic acid hydrazide (133 mg, 1.33 mmol, 1.5 equiv.), triethylamine (184.6 μL, 1.33 mmol, 1.5 equiv.), and HATU (673 mg, 1.77 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 370 mg (purity=92%) of the product as a white solid. Yield: 81%. TLC R f = 0.45 (DCM:MeOH = 10:1); LCMS (m / z) = 513.00 (M+H)

[0205] 5-Bromo-8-cyano-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (19-10) (370 mg, 0.724 mmol, 1 equiv.) was dissolved in 1,4-dioxane (10.6 mL), phosphoryl chloride (443 μL, 5.36 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (21 mg) as a yellow solid. Yield: 20%, purity: 99%. TLC R f = 0.8 (PE:EA=1:1); LCMS (m / z) = 494.80 (M+H)

[0206] TIFF2024542204000119.tif631655-Bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-7) The reaction was carried out by adding aqueous NaClO2 (194.52 mg, 2.16 mmol, 1.76 equiv) to a solution of 5-bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-7 (494 mg, 1.23 mmol, 1 equiv) and (42.59 mg, 127.89 uL, 1.76 mmol, 1.02 equiv) in acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4.3 with KH2PO4. The reaction mixture was stirred for 4.5 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted HOCI and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with Et2O (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated. The product was purified by column chromatography using 60-120 mesh silica gel (hexane / EtOAc), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column to obtain 490 mg (purity=96.69%) of yellowish solid compound in 95.24% yield. TLC R f = 0.3 (DCM:MeOH = 10:1) LCMS (m / z) = 420.20 (M+H)

[0207] TIFF2024542204000120.tif621655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-8-methyl-1,3-dihydro-2H-benzo[b]azepin-2-one (20-12) Bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-7 (250 mg, 0.598 mmol, 1 equiv.) in dichloromethane (5.33 mL) was added with acetohydrazide (89.76 mg, 0.896 mmol, 1.5 equiv.), triethylamine (124.62 μL, 0.896 mmol, 1.5 equiv.), and HATU (454.55 mg, 1.195 mmol, 2 equiv.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 179 mg (purity=90.60%) of product as a white solid. Yield: 59.82%. TLC R f = 0.5 (DCM:MeOH = 10:1) LCMS (m / z) = 502.20 (M+H)

[0208] N'-acetyl-5-bromo-8-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 19-11 (179 mg, 0.357 mmol, 1 equiv.) was dissolved in 1,4-dioxane (5.25 mL), phosphoryl chloride (219 μL, 2.35 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (74 mg) as a yellow oil. Yield: 58.33%, purity: 97.52%. TLC R f = 0.5 (PE:EA=1:1) LCMS (m / z) = 482.40 (M+H)

[0209] TIFF2024542204000121.tif681655-Bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-13) Bromo-1-(3-fluoro-4-methylbenzyl)-8-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-7 (240 mg, 0.574 mmol, 1 equiv.) in dichloromethane (5.12 mL) was added with acetohydrazide (63.76 mg, 0.861 mmol, 1.5 equiv.), triethylamine (119.63 μL, 0.861 mmol, 1.5 equiv.), and HATU (436.36 mg, 1.147 mmol, 2 equiv.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 223 mg (purity=93.51%) of product as a white solid. Yield: 81.90%. TLC R f = 0.5 (DCM:MeOH = 10:1) LCMS (m / z) = 474.30 (M+H)

[0210] N'-acetyl-5-bromo-8-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 19-12 (223 mg, 0.47 mmol, 1 equiv.) was dissolved in 1,4-dioxane (6.9 mL), phosphoryl chloride (287.90 μL, 33.08 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (138 mg) as an orange solid. Yield: 64.34%, purity: 99%. TLC R f = 0.4 (PE:EA=1:1) LCMS (m / z) = 456.40 (M+H)

[0211] TIFF2024542204000122.tif671655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(5-methyloxazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (23-1) A mixture of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 14-2 (0.137 g, 0.34 mmol, 1 equiv.), 1-aminoacetone HCl salt (0.047 g, 0.425 mmol, 1.25 equiv.), BOP reagent (0.188 g, 0.425 mmol, 1.25 equiv.), and triethylamine (0.116 mL, 0.833 mmol, 2.45 equiv.) in DMF (1 mL) was stirred at 50° C. for 2 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (5 mL). The ethyl acetate layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The resulting concentrate was then purified on a silica column to give 100 mg of a yellowish solid compound (purity=99%) in a yield of 64%. TLC R f = 0.7 (DCM:MeOH=10:1) LCMS (m / z) = 461.30 (M+H)

[0212] The above carboxamide (100 mg, 0.21 mmol) was stirred with POCl3 (3 mL) at 120 °C for 4 h. Excess POCl3 was removed in vacuo and the residue was partitioned between dichloromethane (10 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting concentrate was then purified on a silica column to give 20 mg (purity = 95%) of a yellowish solid compound in 21% yield. TLC R f = 0.5 (PE:EA=2:1) LCMS (m / z) = 441.10 (M+H)

[0213] TIFF2024542204000123.tif781655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepine-2-thione (24-1) A round-bottom flask was charged with 20-3 (0.1 g, 0.21 mmol, 1 equiv), 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (0.13 g, 0.32 mmol, 1.5 equiv) and THF (1.5 mL). The mixture was stirred at 60° C. for 1 h. The mixture was then partitioned between DCM (50 mL) and saturated NaHCO3(aq) (20 mL). The organic phase was washed with water and brine. The solution was then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the product (50 mg) as a yellow oil. Yield: 50%, purity: 96%. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 485.90 (M+H)

[0214] Example 15: Representative synthesis of compound of formula 20: TIFF2024542204000124.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-(trifluoromethyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-8) The reaction was carried out by adding aqueous NaClO2 (1.003 g, 11.14 mmol, 1.76 equiv) to 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-(trifluoromethyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (2.889 g, 6.33 mmol, 1 equiv) and (666 μL, 6.52 mmol, 1.02 equiv) of 30% H2O2 in aqueous acetonitrile at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 2.865 g (purity=98%) of a yellow solid compound in 95% yield. TLC R f = 0.2 (DCM:MeOH = 10:1); LCMS (m / z) = 474.70 (M+H)

[0215] TIFF2024542204000125.tif481655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-8-(trifluoromethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-14) To 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-(trifluoromethyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (1 g, 2.12 mmol, 1 eq.) in dichloromethane (28.5 mL) was added cyclopropanecarboxylic acid hydrazide (318 mg, 3.18 mmol, 1.5 eq.), triethylamine (442 μL, 2.18 mmol, 1.5 eq.), and HATU (1611.2 mg, 4.24 mmol, 2 eq.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 1.227 g (purity=97%) of product as a white solid. Yield: 99%. TLC R f = 0.45 (DCM:MeOH = 10:1); LCMS (m / z) = 556.90 (M+H)

[0216] 5-Bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-(trifluoromethyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (1.227 g, 2.21 mmol, 1 equiv.) was dissolved in 1,4-dioxane (32.26 mL), phosphoryl chloride (1355 μL, 14.54 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 1.5 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (543 mg) as a yellow solid. Yield: 45%, purity: 94%. TLC R f = 0.9 (PE:EA = 1:1); LCMS (m / z) = 537.20 (M+H)

[0217] TIFF2024542204000126.tif531655-Bromo-9-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-9) The reaction was carried out by adding aqueous NaClO2 (506.9 mg, 5.63 mmol, 1.76 equiv) to 5-bromo-9-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (1.3 g, 3.2 mmol, 1 equiv) and (333.27 uL, 3.26 mmol, 1.02 equiv) of 30% H2O2 in aqueous acetonitrile at 0 °C buffered to pH 4.3 with KH2PO4. The reaction mixture was stirred for 4.5 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain the crude compound, which was then purified on a silica column to obtain 865 mg (purity=90.73%) of yellowish solid compound in 64.02% yield. TLC R f =0.3 (DCM:MeOH=10:1) LCMS (m / z) = 422.70 (M+H)

[0218] TIFF2024542204000127.tif581655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-9-fluoro-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-15) To 5-bromo-9-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (100 mg, 0.236 mmol, 1 eq.) in dichloromethane (3.4 mL), cyclopropanecarboxylic acid hydrazide (35.56 mg, 0.355 mmol, 1.5 eq.), triethylamine (49.38 μL, 0.355 mmol, 1.5 eq.), and HATU (178 mg, 0.473 mmol, 2 eq.) were added. The mixture was stirred at room temperature for 1.5 hours. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 117 mg (purity=98.86%) of the product as a white solid. Yield: 99%. TLC R f = 0.5 (DCM:MeOH = 10:1) LCMS (m / z) = 504.80 (M+H)

[0219] 5-Bromo-N'-(cyclopropanecarbonyl)-9-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (117 mg, 0.234 mmol, 1 equiv.) was dissolved in 1,4-dioxane (3.5 mL), phosphoryl chloride (145.71 μL, 51.563 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (43 mg) as a yellow solid. Yield: 37.15%, purity: 97.95%. TLC R f = 0.7 (PE:EA=1:1); LCMS (m / z) = 486.80 (M+H)

[0220] Example 16: Representative synthesis of compound of formula 20: TIFF2024542204000128.tif531655-Bromo-6-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-10) The reaction was carried out by adding aqueous NaClO2 (1549 mg, 17.12 mmol, 1.76 equiv) to 5-bromo-6-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (3.95 g, 9.73 mmol, 1 equiv) and (337 mg, 9.92 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 1.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column to obtain 900 mg of white solid compound in 22% yield. Purity=92%. TLC R f = 0.1 (DCM:MeOH = 10:1); LCMS (m / z) = 424.20 (M+H)

[0221] TIFF2024542204000129.tif531655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-fluoro-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-16) To 5-bromo-6-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (900 mg, 2.13 mmol, 1 eq.) in dichloromethane (21 mL) was added cyclopropanecarboxylic acid hydrazide (320 mg, 3.20 mmol, 1.5 eq.), triethylamine (0.55 mL, 4.26 mmol, 2 eq.), and HATU (1.215 g, 3.20 mmol, 1.5 eq.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 852 mg of product as a white solid. Yield: 79%. Purity=96%. TLC R f = 0.4 (DCM:MeOH = 10:1); LCMS (m / z) = 504.10 (M+H)

[0222] 5-Bromo-N'-(cyclopropanecarbonyl)-6-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (852 mg, 1.79 mmol, 1 equiv.) was dissolved in 1,4-dioxane (7.5 mL) followed by phosphorus oxychloride (1.1 mL), and then the mixture was stirred at 90°C for 2 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added to dilute it, and the diluted solution was poured slowly into room temperature water under water bath. The resulting solution was extracted with several portions of ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 2:3) to give the product (463 mg) as a yellow solid. Yield: 56%. Purity: 98%. TLC R f = 0.3 (EA:PE=1:1); LCMS (m / z) = 488.10 (M+H)

[0223] Example 17: Representative synthesis of compounds of formula 22-17: TIFF2024542204000130.tif581655-Bromo-7-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-11) The reaction was carried out by adding aqueous NaClO2 (1.568 g, 17.34 mmol, 1.76 equiv) to 5-bromo-7-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (4 g, 9.85 mmol, 1 equiv) and (342 mg, 10.05 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 1.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to obtain the crude compound.The resulting concentrate was then purified on a silica column to obtain 4.16g of white solid compound in 99% yield. Purity=97%. TLC R f = 0.2 (DCM:MeOH = 10:1); LCMS (m / z) = 423.50 (M+H)

[0224] TIFF2024542204000131.tif531655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-7-fluoro-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-17) To 5-bromo-7-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (4.16 g, 9.84 mmol, 1 eq.) in dichloromethane (100 mL), cyclopropanecarboxylic acid hydrazide (1.476 g, 14.76 mmol, 1.5 eq.), triethylamine (2.54 mL, 19368 mmol, 2 eq.), and HATU (5.609 g, 14.76 mmol, 1.5 eq.) were added. The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give the product 5 g as a white solid compound in 99% yield. Purity=96%. TLC R f = 0.3 (DCM:MeOH = 20:1); LCMS (m / z) = 506.00 (M+H)

[0225] 5-Bromo-N'-(cyclopropanecarbonyl)-7-fluoro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (5 g, 9.91 mmol, 1 equiv.) was dissolved in 1,4-dioxane (39.6 mL), phosphorus oxychloride (6.07 mL) was added, and the mixture was stirred at 90° C. for 2 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added to dilute it, and the diluted solution was poured slowly into room temperature water under water bath. The resulting solution was extracted with several portions of ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA, 1:1) to give 3.16 g of product as a white solid compound in 66% yield. Purity: 97%. TLC R f = 0.45 (EA:PE=1:1); LCMS (m / z) = 488.00 (M+H)

[0226] Example 18: Representative synthesis of compounds of formula 20-18: TIFF2024542204000132.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-12) The reaction was carried out by adding aqueous NaClO2 (410.7 mg, 4.56 mmol, 3.6 equiv.) to 5-bromo-1-(3-fluoro-4-methylbenzyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (510 mg, 1.27 mmol, 1 equiv.) and (130 μL, 1.29 mmol, 1.02 equiv.) aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 300 mg) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with NH4Cl and diluted with H2O (10-20 mL). The compound was extracted with EA (3 × 10-20 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 310 mg (purity=83%) of a white solid compound in 58% yield. TLC R f = 0.1 (PE:EA=10:1); LCMS (m / z) = 418.0(M+H)

[0227] TIFF2024542204000133.tif631655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-9-methyl-1,3-dihydro-2H-benzo[b]azepin-2-one (20-18) To 5-bromo-1-(3-fluoro-4-methylbenzyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (310 mg, 0.74 mmol, 1 eq.) in dichloromethane (7.3 mL), cyclopropanecarboxylic acid hydrazide (111.3 mg, 1.11 mmol, 1.5 eq.), triethylamine (155 μL, 1.11 mmol, 1.5 eq.), and HATU (563.6 mg, 1.48 mmol, 2 eq.) were added. The mixture was stirred at room temperature for 1.5 hours. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 250 mg (purity=91%) of the product as a white solid. Yield: 68%. TLC R f = 0.7 (DCM:MeOH=10:1) LCMS (m / z) = 502.40 (M+H)

[0228] Phosphorus oxychloride (306 μL, 3.28 mmol, 6.57 eq.) was added to 5-bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (250 mg, 0.5 mmol, 1 eq.) in 1,4-dioxane (5.1 mL), and the mixture was stirred at 90° C. for 3 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added, and the diluted solution was slowly poured into room temperature water under a water bath. The resulting solution was extracted with several portions of ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography to give 130 mg of the product as a yellow solid. Yield: 54%. Purity: 92%. TLC R f = 0.5 (PE:EA=1:1); LCMS (m / z) = 484.0 (M+H)

[0229] Example 19: Representative synthesis of compounds of formula 20-20: TIFF2024542204000134.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-13) The reaction was carried out by adding aqueous NaClO2 (330.245 mg, 3.669 mmol, 1.76 equiv.) to a solution of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (1.01 g, 2.084 mmol, 1 equiv.) and (72.303 mg, 217 μL, 2.126 mmol, 1.02 equiv.) 30% H2O2 in water at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred for 4.5 h. After completion of the reaction, a small amount of Na2SO3 (approximately 0.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated. The resulting concentrate was then purified on a silica column to give 1.025 g (purity=87.79%) of a yellow solid compound in 98.28% yield. TLC R f = 0.3 (DCM:MeOH = 10:1) LCMS (m / z) = 501.80 (M+H)

[0230] TIFF2024542204000135.tif531655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-8-ethynyl-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-20) To 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (1.025 g, 2.048 mmol, 1 equiv.) in dichloromethane (18.22 mL) was added cyclopropanecarboxylic acid hydrazide (307.59 mg, 3.072 mmol, 1.5 equiv.), triethylamine (427.04 μL, 3.072 mmol, 1.5 equiv.), and HATU (1.557 g, 4.096 mmol, 2 equiv.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 604 mg (purity=97.70%) of the product as a yellow solid. Yield: 50.62%. TLC R f = 0.55 (DCM:MeOH=10:1) LCMS (m / z) = 582.10 (M+H)

[0231] 5-Bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-8-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (604 mg, 1.036 mmol, 1 equiv.) was dissolved in 1,4-dioxane (113.917 mL), phosphoryl chloride (634.93 μL, 6.812 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (206 mg) as a yellow solid. Yield: 35.22%, purity: 95.44%. TLC R f = 0.7 (PE:EA=1:1); LCMS (m / z) = 564.30 (M+H)

[0232] 5-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-8-((trimethylsilyl)ethynyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (206 mg, 0.365 mmol, 1 equiv.) was dissolved in MeOH (0.2 M with respect to substrate) and K2CO3 (5.04 mg, 0.036 mmol, 0.1 equiv.) was added. Desilylation was carried out at room temperature for 2 h and concentrated. The final product was purified by chromatography to give 140 mg (purity = 87.22%) of product as a yellow oil. Yield: 77.90%. TLC R f = 0.6 (PE:EA=1:1) LCMS (m / z) = 492.35 (M+H)

[0233] Example 20: Representative synthesis of compounds of formula 20-21: TIFF2024542204000136.tif531655-Bromo-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-14) The reaction was carried out by adding aqueous NaClO2 (877.5 mg, 9.75 mmol, 1.76 equiv) to 5-bromo-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (2.14 g, 5.54 mmol, 1 equiv) and (577 μL, 5.65 mmol, 1.02 equiv) of 30% H2O2 in aqueous acetonitrile at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred for 2.5 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 1.62 g (purity=98%) of a yellow solid compound in 72.7% yield. TLC R f= 0.2 (DCM:MeOH = 10:1); LCMS (m / z) = 403.60 (M+H)

[0234] TIFF2024542204000137.tif631655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-21) To 5-bromo-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (1.62 g, 4.027 mmol, 1 eq.) in dichloromethane (53 mL), cyclopropanecarboxylic acid hydrazide (604.8 mg, 6.04 mmol, 1.5 eq.), triethylamine (839.7 μL, 6.02 mmol, 1.5 eq.), and HATU (3.06 g, 8.05 mmol, 2 eq.) were added. The mixture was stirred at room temperature for 4 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 1:4) to give 1.931 g (purity=93%) of product as a white solid. Yield: 99%. TLC R f = 0.5 (DCM:MeOH = 10:1); LCMS (m / z) = 484.20 (M+H)

[0235] 5-Bromo-N'-(cyclopropanecarbonyl)-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (1.931 g, 4 mmol, 1 equiv.) was dissolved in 1,4-dioxane (58.8 mL), phosphoryl chloride (2.466 mL, 26.46 mmol, 6.57 equiv.) was added, and the mixture was heated at 90°C for 2.5 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (857 mg) as a yellow solid. Yield: 46%, purity: 91%. TLC Rf = 0.3 (PE:EA = 1:1); LCMS (m / z) = 468.00 (M+H)

[0236] Example 21: Representative synthesis of compounds of formulas 20-22: TIFF2024542204000138.tif631655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-8-carboxamide (20-22) A mixture of 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-8-carbonitrile (150 mg, 0.304 mmol, 1 eq.) and concentrated H2SO4 (290.7 μL) was heated to 65 °C for 8 h. The reaction mixture was poured slowly into ice and the pH was brought to 8-9 by 6M aqueous NaOH or NH4OH (if the product precipitated, it was filtered off and washed with ice-cold H2O). Otherwise, it was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The resulting concentrate was then purified on a silica column to give 79 mg (purity = 97.05%) of a white solid compound in 50.82% yield. TLC R f = 0.3 (DCM:EA=1:1) LCMS (m / z) = 513.30 (M+H)

[0237] Example 22: Representative synthesis of compounds of formulas 20-23: TIFF2024542204000139.tif581655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-8-(3-morpholinopropoxy)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-23) To 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-8-hydroxy-1-(4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (59 mg, 0.122 mmol, 1 equiv.) in DMF (1 mL) was added 4-(3-chloropropyl)morpholine (23 μL, 0.146 mmol, 1.2 equiv.) and K2CO3 (28 mg, 0.20 mmol, 1.61 equiv.) and the mixture was stirred at 85 °C for 3 h. After the reaction mixture was cooled to room temperature, ethyl acetate was added and the diluted solution was poured slowly into room temperature water under a water bath. The resulting solution was extracted with several portions of ethyl acetate (3 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The concentrate obtained was then purified on a silica column to give 40 mg of the product as a yellow solid. Yield: 54%. Purity: 84%. TLC R f = 0.5 (CH2Cl2:MeOH=1:1); LCMS (m / z) = 613.10(M+H)

[0238] Example 23: Representative synthesis of compounds of formulas 20-24: TIFF2024542204000140.tif631655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-24) To a 9:1 acetonitrile / water suspension (7 mL) of 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (500 mg, 1.07 mmol, 1 equiv.), CAN (1.74 g, 0.837 mmol, 3 equiv.) was added at 0 °C. After stirring at 0 °C for 48 h, the reaction mixture was quenched with water (10 mL) and the pH was adjusted to 7-9 using saturated Na2CO3. The resulting mixture was extracted with EA. The extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column to give 223 mg (purity = 85%) of a white solid compound in 55% yield. TLC R f = 0.25 (PE:EA = 1:1); LCMS (m / z) = 347.60 (M+H)

[0239] Example 24: Representative synthesis of compounds of formulas 20-25 TIFF2024542204000141.tif681655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methoxybenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-25) To a stirred solution of 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (69 mg, 0.2 mmol, 1 equiv.) and K2CO3 (83 mg, 0.6 mmol, 3 equiv.) in DMF (0.8 mL) was added 4-(bromomethyl)-2-fluoro-1-methoxybenzene (52.5 mg, 0.24 mmol, 1.2 equiv.) at ambient temperature. The reaction mixture was then stirred at room temperature for 66.5 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 8.5 mg (purity=91%) of a white solid compound in 9% yield. TLC R f = 0.2 (PE:EA = 1:1); LCMS (m / z) = 484.30 (M+H)

[0240] Example 25: Representative synthesis of compounds of formulas 20-26: TIFF2024542204000142.tif481654-(Bromomethyl-d)-2-fluoro-1-methylbenzene (D-2) To a stirred suspension of 3-fluoro-4-methylbenzaldehyde (122 μL, 1 mmol, 1 equiv) in MeOH (5 mL) at 0 °C under N was added sodium borodeuteride (84 mg, 2 mmol, 2 equiv) in portions. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated in vacuo and then diluted with CHCl (50 mL). The organic phase was washed with HO (50 mL), dried (NaSO), filtered, and concentrated in vacuo to give the title compound D-1 (117 mg, 83% yield, 87% purity) as a colorless solid. TLC R f = 0.35 (PE:EA = 4:1)

[0241] To a stirred suspension of D-1 (117 mg, 0.83 mmol, 1 equiv) in CHCl (2.5 mL) at 0 °C under N was added phosphorus tribromide (135 mg, 0.5 mmol, 0.5 equiv) dropwise. After 15 min, the mixture was warmed to room temperature and allowed to stir for 2 h, at which point the reaction mixture was quenched with H0 (20 mL). The aqueous phase was extracted with CHCl (3 x 20 mL) and the combined organic layers were washed with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL), dried (NaSO), filtered, and concentrated in vacuo to give the title compound D-2 (67 mg, 40% yield, 98% purity) as a colorless oil. TLC R f = 0.8 (PE:EA = 4:1)

[0242] TIFF2024542204000143.tif581655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-((3-fluoro-4-methylphenyl)methyl-d)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-26) To a stirred solution of 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (50 mg, 0.15 mmol, 1 equiv.) and K2CO3 (62 mg, 0.45 mmol, 3 equiv.) in DMF (0.5 mL) was added 4-(bromomethyl-d)-2-fluoro-1-methylbenzene D-2 (36 mg, 0.18 mmol, 1.2 equiv.) at ambient temperature. The reaction mixture was then stirred at room temperature for 12 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 43 mg (purity=98%) of a white solid compound in 61% yield. TLC R f = 0.5 (PE:EA = 1:1); LCMS (m / z) = 469.20 (M+H)

[0243] Example 26: Representative synthesis of compounds of formulas 20-27: TIFF2024542204000144.tif481654-(Bromomethyl-d2)-2-fluoro-1-methylbenzene (D-4) To a 25 mL round bottom flask was added sodium borodeuteride (168 mg, 4 mmol, 2.00 equiv) and ZnCl2 (272 mg, 2 mmol, 1.00 equiv). Anhydrous 1,4-dioxane (10 mL) and N,N-dimethylaniline (0.254 mL, 2 mmol, 1.0 equiv) were then added and the solution was allowed to stir at room temperature. After 3 hours, methyl 3-fluoro-4-methylbenzoate (336 mg, 2 mmol, 1.0 equiv) was added and the solution was allowed to stir at room temperature for 10 minutes. The reaction mixture was heated to reflux for 10 hours at which point the reaction mixture was cooled to 0° C. and 1.0 M aqueous HCl (15 mL) and CHCl2 (15 mL) were added. The aqueous phase was extracted and the organic phase was washed with water (15 mL) and brine (15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting concentrate was then purified on a silica column to give 196 mg (purity=98%) of a white solid compound in 69% yield. TLC R f = 0.2 (PE:EA = 4:1)

[0244] To a stirred suspension of (3-fluoro-4-methylphenyl)methane-d2-ol D-3 (196 mg, 1.38 mmol, 1.00 equiv) in CHCl (5 mL) at 0 °C under N was added phosphorus tribromide (0.065 mL, 0.69 mmol, 0.500 equiv) dropwise. After 15 min, the mixture was warmed to room temperature and allowed to stir for 2 h, at which point the reaction mixture was quenched with H0 (10 mL). The aqueous phase was extracted with CHCl (3 x 10 mL) and the combined organic layers were washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (NaSO), filtered, and concentrated in vacuo to afford 157 mg (purity = 99%) of the title compound as a yellow oil in 55% yield.

[0245] TIFF2024542204000145.tif731655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-((3-fluoro-4-methylphenyl)methyl-d2)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-27) To a stirred solution of 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (69 mg, 0.2 mmol, 1 equiv.) and K2CO3 (83 mg, 0.6 mmol, 3 equiv.) in DMF (0.8 mL) was added 4-(bromomethyl-d2)-2-fluoro-1-methylbenzene (49 mg, 0.24 mmol, 1.2 equiv.) at ambient temperature. The reaction mixture was then stirred at room temperature for 12 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 75 mg (purity=99%) of a white solid compound in 79% yield. TLC R f = 0.5 (PE:EA = 1:1); LCMS (m / z) = 472.20 (M+H)

[0246] Example 27: Representative synthesis of compounds of formulas 20-28: TIFF2024542204000146.tif631655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(2,5-difluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-28) To a stirred suspension of (2,5-difluoro-4-methylphenyl)methanol (100 mg, 0.63 mmol, 1 equiv) in CHCl (2 mL) at 0° C. under N was added phosphorus tribromide (26 mg, 0.32 mmol, 0.5 equiv) dropwise. After 15 min, the mixture was warmed to room temperature and allowed to stir for 2 h, at which point the reaction mixture was quenched with H0 (20 mL). The aqueous phase was extracted with CHCl (3×20 mL) and the combined organic layers were washed with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL), dried (NaSO), filtered, and concentrated in vacuo to afford the title compound (70 mg, 50% yield) as a colorless oil. TLC R f = 0.9 (PE:EA = 1:1)

[0247] To a stirred solution of 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (91 mg, 0.26 mmol, 1 equiv.) and K2CO3 (109 mg, 0.79 mmol, 3 equiv.) in DMF (0.9 mL) was added 1-(bromomethyl)-2,5-difluoro-4-methylbenzene 2F-1 (70 mg, 0.32 mmol, 1.2 equiv.) at ambient temperature. The reaction mixture was then stirred at room temperature for 12 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3 x 20 mL). The organic solutions were combined, washed with H2O (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 109 mg (purity=97%) of a white solid compound in 87% yield. TLC R f = 0.6(PE:EA = 2:1); LCMS (m / z) = 486.20 (M+H)

[0248] Example 28: Representative synthesis of compounds of formulas 20-29: TIFF2024542204000147.tif631659-Cyclopropyl-5-(3-fluoro-4-methylbenzyl)-6-oxo-6,7-dihydro-5H-benzo[7]annulene-8-carboxylic acid (14-15) K3PO4 (2M in 1.5 mL of H2O) and Pd(OAc)2 (15 mg, 5 mol%) were added successively to a solution of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (582 mg, 1.5 mmol, 1 equiv.) and cyclopropylboronic acid (155 mg, 1.8 mmol, 1.2 equiv.) in THF (3 mL) under N2. The reaction mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EA (3 x 10 mL). The combined organic fractions were dried and concentrated. The residue was purified by chromatography to give the product (155 mg) as a yellow solid. Yield: 67%, purity: 92%. TLC R f = 0.4 (PE:EA = 2:1); LCMS (m / z) = 350.60 (M+H)

[0249] The reaction was carried out by adding aqueous NaClO2 (160 mg, 1.78 mmol, 1.76 equiv) to 9-cyclopropyl-5-(3-fluoro-4-methylbenzyl)-6-oxo-6,7-dihydro-5H-benzo[7]annulene-8-carbaldehyde (353 mg, 1.01 mmol, 1 equiv) and (105 μL, 1.03 mmol, 1.02 equiv) of 30% H2O2 in aqueous acetonitrile at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred for 1.5 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted NaClO2 and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 329 mg (purity=84%) of a white solid compound in 89% yield. TLC R f = 0.2 (DCM:MeOH = 10:1); LCMS (m / z) = 366.70 (M+H)

[0250] TIFF2024542204000148.tif681659-Cyclopropyl-8-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-(3-fluoro-4-methylbenzyl)-5,7-dihydro-6H-benzo[7]annulen-6-one (20-29) To 5-cyclopropyl-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (329 mg, 0.9 mmol, 1 eq.) in dichloromethane (8 mL), cyclopropanecarboxylic acid hydrazide (135 mg, 1.35 mmol, 1.5 eq.), triethylamine (186.8 μL, 1.35 mmol, 1.5 eq.), and HATU (684 mg, 1.8 mmol, 2 eq.) were added. The mixture was stirred at room temperature for 2 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 1:4) to give 398 mg (purity=87%) of the product as a white solid. Yield: 99%. TLC R f = 0.35 (DCM:MeOH=10:1) LCMS (m / z) = 448.90 (M+H)

[0251] N'-(cyclopropanecarbonyl)-9-cyclopropyl-5-(3-fluoro-4-methylbenzyl)-6-oxo-6,7-dihydro-5H-benzo[7]annulene-8-carbohydrazide (398 mg, 0.75 mmol, 1 equiv.) was dissolved in 1,4-dioxane (9 mL), phosphoryl chloride (545.5 μL, 5.85 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 3 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (217 mg) as a white solid. Yield: 56.8%, purity: 83%. TLC R f = 0.7 (DCM:MeOH = 10:1); LCMS (m / z) = 430.90 (M+H)

[0252] Example 29: Representative synthesis of compounds of formulas 20-30: TIFF2024542204000149.tif73165(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-5-methyl-1,3-dihydro-2H-benzo[b]azepin-2-one(20-30) A round bottom flask was charged with 5-bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (100 mg, 0.21 mmol, 1 equiv), Pd(OAc) (2.4 mg, 0.011 mmol, 0.05 equiv), SPhos (8.8 mg, 0.021 mmol, 0.1 equiv), KPO (226 mg, 1.07 mmol, 5 equiv) and dioxane:HO (1.5:0.15 mL). Then 3.5 M trimethylboroxine in THF (183 μL, 0.64 mmol, 3 equiv) was added to the mixture at room temperature under N and heated to 70 °C for 2.5 h. The reaction mixture was filtered through Celite, followed by extraction with ethyl acetate. The combined organic fractions were dried and concentrated. The residue was purified by chromatography to give the product (74 mg) as a yellow solid. Yield: 87%, purity: 90%. TLC R f = 0.3 (PE:EA = 2:1); LCMS (m / z) = 404.60 (M+H)

[0253] Example 30: Representative synthesis of compounds of formulas 20-32: TIFF2024542204000150.tif681651-(3-Fluoro-4-methylbenzyl)-2-oxo-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-16) A mixture of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (500 mg, 1.287 mmol, 1.0 equiv.), (Ph3P)2PdCl2 (11.323 mg, 0.02575 mmol, 0.02 equiv.) and CuI (2.453 mg, 0.01287 mmol, 0.01 equiv.) in a flask was degassed for 10 min, then Et3N (0.2 M relative to substrate) was added under argon atmosphere. To this solution was added ethynyltrimethylsilane (910 μL, 6.440 mmol, 5 equiv.) via syringe. The mixture was warmed to 65° C. for 12 h. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was concentrated and purified by chromatography to give 506 mg (purity=63.78%) of the product as an orange solid. Yield: 96.94%. TLC R f = 0.7 (PE:EA=2:1) LCMS (m / z) = 406.40 (M+H)

[0254] The reaction was carried out by adding aqueous NaClO2 (197.64 mg, 2.196 mmol, 1.76 equiv.) to a solution of 1-(3-fluoro-4-methylbenzyl)-2-oxo-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (506 mg, 1.247 mmol, 1 equiv.) and (43.27 mg, 1.27 mmol, 1.02 equiv.) 30% H2O2 in water at 0 °C buffered to pH 4.3 with KH2PO4. The reaction mixture was stirred for 4.5 h. After completion of the reaction, a small amount of Na2SO3 (approximately 0.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with Et2O (10 mL). The organic layer was separated and extracted with water and brine, then dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to obtain the crude compound. The resulting concentrate was then purified on a silica column to obtain 488 mg (purity=79.22%) of a yellow solid compound in 92.83% yield. TLC R f= 0.3 (DCM:MeOH = 10:1) LCMS (m / z) = 422.10 (M+H)

[0255] TIFF2024542204000151.tif531654-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-ethynyl-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (20-32) To 1-(3-fluoro-4-methylbenzyl)-2-oxo-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (100 mg, 0.237 mmol, 1 equiv.) in dichloromethane (2.1 mL) was added cyclopropanecarboxylic acid hydrazide (35.625 mg, 0.355 mmol, 1.5 equiv.), triethylamine (49.46 μL, 0.355 mmol, 1.5 equiv.), and HATU (180.405 mg, 0.474 mmol, 2 equiv.). The mixture was stirred at room temperature for 1.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography to give 50 mg (purity=95.28%) of the product as a yellow solid. Yield: 41.88%. TLC R f = 0.45 (DCM:MeOH=10:1) LCMS (m / z) = 504.30 (M+H)

[0256] N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzyl)-2-oxo-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (50 mg, 0.099 mmol, 1 equiv.) was dissolved in 1,4-dioxane (1.33 mL), phosphoryl chloride (60.79 μL, 0.652 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (37 mg) as a yellow solid. Yield: 76.95%, purity: 92.86%. TLC R f = 0.7 (DCM:MeOH = 10:1); LCMS (m / z) = 486 (M+H)

[0257] 4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzyl)-5-((trimethylsilyl)ethynyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (72 mg, 0.148 mmol, 1 equiv.) was dissolved in MeOH (0.2 M with respect to substrate) and K2CO3 (2.049 mg, 0.0148 mmol, 0.1 equiv.) was added. Desilylation was carried out at room temperature for 2 h and concentrated. The final product was purified by chromatography to give 52 mg (purity=94.84%) of product as an orange solid. Yield: 84.98%. TLC R f = 0.6 (PE:EA=1:1) LCMS (m / z) = 414.10 (M+H)

[0258] Example 31: Representative synthesis of compounds of formula 22: TIFF2024542204000152.tif481655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (22-1) HATU (127 mg, 0.335 mmol, 2.7 equiv) and DIPEA (64.6 μL, 0.372 mmol, 3 equiv) were added to a 0° C. solution of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (14-2) (536 mg, 3.04 mmol) in DMF (0.6 mL). The mixture was stirred for 30 min, followed by the addition of ammonia (7M in MeOH) (135.5 μL, 0.95 mmol, 7.6 equiv). The reaction was then stirred overnight at room temperature. The reaction mixture was concentrated and purified by flash column chromatography to give the title compound (quantity: 42 mg, yield: 84%, purity: 96%) as a white solid. TLC R f =0.5 (DCM:MeOH =10:1) LCMS (m / z) = 404.90 (M+H)

[0259] 5-Bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxamide (21) (100 mg, 0.248 mmol) in dimethylformamide dimethyl acetal (DMF-DMA, 0.33 mL, 2.48 mmol) was heated to 95 °C. After heating at this temperature for about 30 minutes, the reaction was cooled and concentrated in vacuo. It was then concentrated to give a crude product, which was azeotroped twice with water (40 mL) to ensure complete removal of residual DMF-DMA. The resulting intermediate containing the crude DMF-DMA adduct was dissolved in 0.25 mL of ethanol and used immediately in the next step. A mixture of ethanol (0.75 mL) and acetic acid (0.25 mL) was prepared in a separate flask, and the resulting solution was cooled in an ice bath. After cooling, hydrazine hydrate (150.5 μL, 2.48 mmol) was added dropwise, followed by the previously prepared ethanolic solution of the crude DMF-DMA adduct via cannula over about 15 min with stirring. After the addition was complete, the resulting mixture was allowed to warm to room temperature and stirred for about 4 h. The reaction mixture was concentrated in vacuo to remove ethanol, which was purified by silica gel column chromatography to give 21 mg of product as a white solid. Yield: 20%. Purity: 90%. TLC R f = 0.75 (DCM:MeOH = 10:1); LCMS (m / z) = 429.40 (M+H)

[0260] Example 32: Representative synthesis of compound of formula 24: TIFF2024542204000153.tif631655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(hydroxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (23-1) To a solution of methyl 5-chloro-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-1 (50 mg, 0.14 mmol, 1 equiv.) in MeOH (0.5 mL) was added NaBH4 (0.43 mL, 3.11 mmol, 1.2 equiv.) at 0° C. The reaction mixture was then stirred at room temperature for 19 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 36 mg (purity=99%) of a pale yellow oily compound in 74% yield. TLC R f = 0.25 (EA:PE=1:2) LCMS (m / z) = 346.00 (M+H)

[0261] TIFF2024542204000154.tif571655-Chloro-1-(3-fluoro-4-methylbenzyl)-4-(methoxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (24-1) To a stirred solution of methyl(1-(5-chloro-1-(3-fluoro-4-methylbenzyl)-4-(hydroxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one) 23 (200 mg, 0.58 mmol, 1 equiv.) and MeI (72 μL, 1.16 mmol, 2 equiv.) in DMF (2 mL) was added a 60% dispersion of NaH in mineral oil (28 mg, 1.16 mmol, 2 equiv.) at ambient temperature under N2. The reaction mixture was stirred at room temperature (rt) for 19 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with H2O (2×10 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 65 mg (purity=98%) of a white solid compound in 31% yield. TLC R f = 0.3 (PE:EA=2:1) LCMS (m / z) = 360.00 (M+H) 1 H NMR (400 MHz, DMSO) δ 7.76 - 7.62 (m, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.49 - 7.38 (m, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.73 (t, J = 8.0 Hz, 2H), 5.33 (d, J = 16.1 Hz, 1H), 4.91 (d, J = 16.1 Hz, 1H), 4.37 (d, J = 12.9 Hz, 1H), 4.23 (d, J = 13.0 Hz, 1H), 3.33 - 3.21 (m, 4H), 2.70 (d, J = 12.8 Hz, 1H), 2.12 (s, 3H)

[0262] TIFF2024542204000155.tif581655-Chloro-4-(ethoxymethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (24-2) To a stirred solution of methyl(5-chloro-1-(3-fluoro-4-methylbenzyl)-4-(hydroxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one) 23 (100 mg, 0.29 mmol, 1 equiv.) and EtI (47 μL, 0.58 mmol, 2 equiv.) in DMF (1 mL) was added a 60% dispersion of NaH in mineral oil (14 mg, 0.58 mmol, 2 equiv.) at ambient temperature under a N2 atmosphere. The reaction mixture was then stirred at room temperature (rt) for 19 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with H2O (2×10 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 67 mg of a yellow solid compound (purity=99%) in a yield of 62%. TLC R f = 0.8 (PE:EA=2:1) LCMS (m / z) = 374.60 (M+H)

[0263] Example 33: Representative synthesis of compounds of formula 26-1: TIFF2024542204000156.tif581651-(3-Fluoro-4-methylbenzyl)-5-methoxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one (26-1) To a stirred solution of 7-1 (0.29 mmol) in MeOH (2.5 mL) was added sodium carbonate (307.4 mg, 2 mol%) and the reaction mixture was refluxed for 5 h (MeOH = 65 °C). Upon completion, the reaction mixture was filtered, washed with methanol and dried in vacuum. The residue was taken up in ethyl acetate (20 mL), washed with water, dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified on a silica column to give 54 mg (purity = 94%) of a yellow solid compound in 55% yield. TLC R f = 0.4 (PE:EA=2:1) LCMS (m / z) = 340.60 (M+H)

[0264] A dry round bottom flask was charged with toluenesulfonylmethyl isocyanide (TosMIC, 234 mg, 0.35 mmol) and dry MeOH (9 mL) was added under argon atmosphere. At room temperature, solid K2CO3 (92.2 g, 0.87 mmol) and 1-(3-fluoro-4-methylbenzyl)-5-methoxy-4-(oxazol-5-yl)-1,3-dihydro-2H-benzo[b]azepin-2-one 25 (100 mg, 0.29 mmol) were added to the mixture and the mixture was heated to reflux for 1.5 h. After completion of the reaction as indicated by the absence of aldehyde starting material by TLC analysis, the mixture was quenched with cold water. After the mixture was quenched, all the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (silica gel) to give a pure yellow solid (purity=99%, 41 mg, yield=37%). TLC R f = 0.3 (EA:PE=1:2) LCMS (m / z) = 379.60 (M+H)

[0265] Example 34: Representative synthesis of compound of formula 28: TIFF2024542204000157.tif631651-(3-Fluoro-4-methylbenzyl)-4-(hydroxymethyl)-5-methoxy-1,3-dihydro-2H-benzo[b]azepin-2-one (27) To a solution of methyl 1-(3-fluoro-4-methylbenzyl)-5-methoxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 25 (300 mg, 0.88 mmol, 1 equiv.) in MeOH (3 mL) was added NaBH4 (166 mg, 4.4 mmol, 5 equiv.) at 0° C. The reaction mixture was then stirred at room temperature for 2.5 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 237 mg (purity=99%) of a white solid compound in 79% yield. TLC R f = 0.2 (EA:PE=1:2) LCMS (m / z) = 324.50 (M+H)

[0266] TIFF2024542204000158.tif631651-(3-Fluoro-4-methylbenzyl)-5-methoxy-4-(methoxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (28-1) To a stirred solution of 1-(3-fluoro-4-methylbenzyl)-4-(hydroxymethyl)-5-methoxy-1,3-dihydro-2H-benzo[b]azepin-2-one 27-1 (100 mg, 0.29 mmol, 1 equiv.) and MeI (90 μL, 1.45 mmol, 5 equiv.) in DMF (1 mL) was added a 60% dispersion of NaH in mineral oil (14 mg, 0.58 mmol, 2 equiv.) at ambient temperature under N2 atmosphere. The reaction mixture was then stirred at room temperature (rt) for 17 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with H2O (2×10 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 62 mg (purity=99%) of a white solid compound in 60% yield. TLC R f = 0.8 (PE:EA=2:1) LCMS (m / z) = 378.80 (M+Na)

[0267] Example 35: Representative synthesis of compounds of formula 34-1: TIFF2024542204000159.tif631651-(3-Fluoro-4-methylbenzoyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (30-1) To a stirred solution of 1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 29 (329 mg, 2.04 mmol, 1 equiv.) in THF (11.6 mL) was added sodium hydride (60% in oil) (163.2 mg, 4.08 mmol, 2 equiv.). The mixture was stirred at room temperature for 1 h and treated with 3-fluoro-4-methylbenzoyl chloride (1.056 g, 6.12 mmol, 3 equiv.). After stirring at room temperature for 4.5 h, the mixture was treated with H2O and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 319 mg (purity=96%) of a white solid compound in 52.6% yield. TLC R f= 0.2 (PE:EA = 4:1); LCMS (m / z) = 297.90 (M+H)

[0268] TIFF2024542204000160.tif581655-Bromo-1-(3-fluoro-4-methylbenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (31-1) Phosphorus tribromide (119.8 μL, 1.26 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (9.7 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methylbenzoyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 30-1 (289 mg, 0.97 mmol, 1.0 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 1 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and diethyl ether (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 279 mg (purity=90%) of a yellow solid compound in 74% yield. TLC R f = 0.25 (PE:EA = 4:1); LCMS (m / z) = 389.60 (M+H)

[0269] TIFF2024542204000161.tif581655-Bromo-1-(3-fluoro-4-methylbenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (32-1) The reaction was carried out by adding aqueous NaClO2 (114 mg, 1.27 mmol, 1.76 equiv) to 5-bromo-1-(3-fluoro-4-methylbenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 31-1 (279 mg, 0.72 mmol, 1 equiv) and (74.8 μL, 0.73 mmol, 1.02 equiv) of 30% H2O2 in aqueous acetonitrile at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred for 4 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted NaClO2 and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 190 mg (purity=95%) of a white solid compound in 65% yield. TLC R f = 0.25 (DCM:MeOH = 10:1); LCMS (m / z) = 405.60 (M+H)

[0270] TIFF2024542204000162.tif631655-Bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (33-1) To 5-bromo-1-(3-fluoro-4-methylbenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 32-1 (190 mg, 0.47 mmol, 1 equiv.) in dichloromethane (6.2 mL), cyclopropanecarbohydrazide (70.6 mg, 0.705 mmol, 1.5 equiv.), triethylamine (98 μL, 0.705 mmol, 1.5 equiv.), and HATU (357.2 mg, 0.94 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 4 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 1:4) to give 226 mg (purity=97%) of product as a white solid. Yield: 99%. TLC Rf = 0.5 (DCM:MeOH = 10:1); LCMS (m / z) = 488.10 (M+H)

[0271] TIFF2024542204000163.tif68165(5-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1H-benzo[b]azepin-1-yl)(3-fluoro-4-methylphenyl)methanone(34-1) 5-Bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methylbenzoyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 33-1 (228 mg, 0.47 mmol, 1 equiv.) was dissolved in 1,4-dioxane (6.9 mL), phosphoryl chloride (287.8 μL, 3.09 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 1.5 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (108 mg) as a yellow solid. Yield: 49%, purity: 90%. TLC R f = 0.3 (PE:EA = 1:1); LCMS (m / z) = 468.20 (M+H)

[0272] Example 36: Representative synthesis of compounds of formula 34-2 TIFF2024542204000164.tif581651-(3-Fluoro-4-methoxybenzoyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (30-2) To a stirred solution of 1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 29 (300 mg, 1.86 mmol, 1 equiv.) in THF (10.5 mL) was added sodium hydride (60% in oil) (149 mg, 3.72 mmol, 2 equiv.). The mixture was stirred at room temperature for 1 h and treated with 3-fluoro-4-methylbenzoyl chloride (1 g, 5.58 mmol, 3 equiv.). After stirring at room temperature for 3.5 h, the mixture was treated with H2O and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 577 mg (purity=95%) of a white solid compound in 99% yield. TLC R f = 0.3 (PE:EA = 4:1); LCMS (m / z) = 297.90 (M+H)

[0273] TIFF2024542204000165.tif581655-Bromo-1-(3-fluoro-4-methoxybenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (31-2) Phosphorus tribromide (230 μL, 2.42 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (18.6 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15 min. 1-(3-fluoro-4-methoxybenzoyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 30-2 (577 mg, 1.84 mmol, 1.0 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 2.5 h. The orange solution was diluted with ice water and neutralized with 20% sodium acetate solution and EA (3 × 10-20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), and water (3×50 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 406 mg (purity=65%) of a yellow oily compound in 54% yield. TLC Rf = 0.35 (PE:EA = 1:1); LCMS (m / z) = 406.90 (M+H)

[0274] TIFF2024542204000166.tif581655-Bromo-1-(3-fluoro-4-methoxybenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (32-2) The reaction was carried out by adding aqueous NaClO2 (158.4 mg, 1.76 mmol, 1.76 equiv) to 5-bromo-1-(3-fluoro-4-methoxybenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 31-2 (406 mg, 1 mmol, 1 equiv) and (104 μL, 1.02 mmol, 1.02 equiv) of 30% H2O2 in aqueous acetonitrile at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred for 4 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted NaClO2 and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 259 mg (purity=84%) of a white solid compound in 62% yield. TLC R f = 0.1 (DCM:MeOH = 10:1); LCMS (m / z) = 422.80 (M+H)

[0275] TIFF2024542204000167.tif631655-Bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methoxybenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (33-2) To 5-bromo-1-(3-fluoro-4-methoxybenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 32-2 (259 mg, 0.62 mmol, 1 equiv.) in dichloromethane (8.1 mL), cyclopropanecarbohydrazide (93 mg, 0.93 mmol, 1.5 equiv.), triethylamine (130 μL, 0.93 mmol, 1.5 equiv.), and HATU (471.2 mg, 1.24 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 3.5 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 1:4) to give 255 mg (purity=92%) of product as a white solid. Yield: 82%. TLC R f = 0.3 (DCM:MeOH = 10:1) LCMS (m / z) = 505.10 (M+H)

[0276] TIFF2024542204000168.tif63165(5-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1H-benzo[b]azepin-1-yl)(3-fluoro-4-methoxyphenyl)methanone(34-2) 5-Bromo-N'-(cyclopropanecarbonyl)-1-(3-fluoro-4-methoxybenzoyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 33-2 (255 mg, 0.51 mmol, 1 equiv.) was dissolved in 1,4-dioxane (5.2 mL), phosphoryl chloride (312 μL, 3.35 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 3 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (155 mg) as a yellow solid. Yield: 62%, purity: 88.9%. TLC R f = 0.45 (DCM:MeOH = 10:1); LCMS (m / z) = 486.60 (M+H)

[0277] Example 37: Representative synthesis of compound of formula ZLS43 TIFF2024542204000169.tif581651-((3-fluoro-4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (30-3) To a solution of compound 29 (200 mg, 1.24 mmol, 1 equiv) in anhydrous DCM (7.8 mL) was added pyridine (145 μL, 1.8 mmol, 1.45 equiv). After cooling the solution to 0° C. using an ice bath, 3-fluoro-4-methoxybenzenesulfonyl chloride (557.4 mg, 2.48 mmol, 2 equiv) was added dropwise via syringe. After addition, the resulting mixture was refluxed at 50° C. for 1.5 h. After completion, the mixture was adjusted to neutral pH with 0.5 M HCl and extracted three times with DCM (3×30 mL). The combined organic layers were rinsed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with petroleum ether / EtOAc to give the desired compound (405 mg, 93%) as a yellow oil with purity=99%. TLC R f = 0.25 (PE:EA = 2:1); LCMS (m / z) = 350.58 (M+H)

[0278] TIFF2024542204000170.tif581655-Bromo-1-((3-fluoro-4-methoxyphenyl)sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (MBICR-ZLS-499) Under argon atmosphere, a solution of PBr3 (620 μL, 6.53 mmol, 4 equiv) was added dropwise to an ice-cold solution of DMF (652 μL, 8.42 mmol, 5.16 equiv) in DCM (3.2 mL). Then, a solution of 1-((3-fluoro-4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 30-3 (570 mg, 1.63 mmol, 1 equiv) was added to the prepared solution at 0 °C via syringe. After addition, the resulting mixture was refluxed at 40 °C for 3.5 h. After completion, the mixture was cooled using an ice bath and ice water (20 mL) was added to quench the reaction. The mixture was then extracted three times with DCM (3 × 40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the desired compound as a white solid (289 mg, yield=40%, purity=99%). TLC R f = 0.5 (PE:EA = 2:1); LCMS (m / z) = 442.63(M+H)

[0279] TIFF2024542204000171.tif581655-Bromo-1-((3-fluoro-4-methoxyphenyl)sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (32-3) The reaction was carried out by adding aqueous NaClO2 (104 mg, 1.16 mmol, 1.76 equiv) to 5-bromo-1-((3-fluoro-4-methoxyphenyl)sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 31-3 (289 mg, 0.66 mmol, 1 equiv) and (68 μL, 0.67 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted NaClO2 and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated, and the concentrate was then purified on a silica column to give 296 mg (purity=42%) of a white solid compound in 99% yield. TLC R f = 0.1 (DCM:MeOH = 10:1); LCMS (m / z) = 422.80 (M+H)

[0280] TIFF2024542204000172.tif631655-Bromo-N'-(cyclopropanecarbonyl)-1-((3-fluoro-4-methoxyphenyl)sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (MBICR-ZLS-513) To 5-bromo-1-((3-fluoro-4-methoxyphenyl)sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 32-3 (298 mg, 0.65 mmol, 1 equiv.) in dichloromethane (8.5 mL) was added cyclopropanecarbohydrazide (98 mg, 0.98 mmol, 1.5 equiv.), triethylamine (136 μL, 0.98 mmol, 1.5 equiv.), and HATU (496 mg, 1.31 mmol, 2 equiv.). The mixture was stirred at room temperature for 2 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 1:4) to give 346 mg (purity=99%) of product as a white solid. Yield: 99%. TLC R f = 0.2 (DCM:MeOH=10:1) LCMS (m / z) = 540.30 (M+H)

[0281] TIFF2024542204000173.tif731652-(5-Bromo-1-((3-fluoro-4-methoxyphenyl)sulfonyl)-2,3-dihydro-1H-benzo[b]azepin-4-yl)-5-cyclopropyl-1,3,4-oxadiazole (34-3) 5-Bromo-N'-(cyclopropanecarbonyl)-1-((3-fluoro-4-methoxyphenyl)sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 33-3 (350 mg, 0.65 mmol, 1 equiv.) was dissolved in 1,4-dioxane (6.6 mL), phosphoryl chloride (398 μL, 4.27 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 1 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (155 mg) as a white solid. Yield: 68%, purity: 99%. TLC R f = 0.8 (DCM:MeOH = 10:1); LCMS (m / z) = 522.20 (M+H)

[0282] Example 38: Representative synthesis of compounds of formula 34-4 TIFF2024542204000174.tif631651-Tosyl-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (30-4) To a solution of compound 29 (5 g, 31 mmol, 1 equiv) in anhydrous DCM (194 mL) was added pyridine (3.637 mL, 45 mmol, 1.45 equiv). After cooling the solution to 0° C. using an ice bath, 3-fluoro-4-methoxybenzenesulfonyl chloride (557.4 mg, 2.48 mmol, 1.2 equiv) was added dropwise via syringe. After addition, the resulting mixture was refluxed at 50° C. for 2 h. After completion, the mixture was adjusted to neutral pH with 0.5 M HCl and extracted three times with DCM (3×30 mL). The combined organic layers were rinsed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with petroleum ether / EtOAc to give the desired compound (4.32 g, 44%) as a white solid with purity=97%. TLC R f = 0.55 (PE:EA = 2:1); LCMS (m / z) = 316.60 (M+H)

[0283] TIFF2024542204000175.tif581655-Bromo-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (31-4) Under argon atmosphere, a solution of PBr3 (5.08 mL, 53.49 mmol, 4 equiv) was added dropwise to an ice-cold solution of DMF (5.342 mL, 69 mmol, 5.16 equiv) in DCM (20.4 mL). Then, a solution of 1-tosyl-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 30-4 (4.22 g, 13.37 mmol, 1 equiv) was added to the prepared solution at 0 °C via syringe. After addition, the resulting mixture was refluxed at 80 °C for 3.5 h. After completion, the mixture was cooled using an ice bath and ice water (20 mL) was added to quench the reaction. The mixture was then extracted three times with DCM (3 × 40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure to give the desired compound as a white solid (2.078 g, yield=38%, purity=92%). TLC R f = 0.7 (PE:EA = 2:1); LCMS (m / z) = 408.50 (M+H)

[0284] TIFF2024542204000176.tif581655-Bromo-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (32-4) The reaction was carried out by adding aqueous NaClO2 (584.8 mg, 6.5 mmol, 1.76 equiv) to 5-bromo-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 31-4 (1.5 g, 3.69 mmol, 1 equiv) and (3.845 mL, 3.77 mmol, 1.02 equiv) in aqueous acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4-3 with KH2PO4. The reaction mixture was stirred overnight. After completion of the reaction, a small amount of Na2SO3 (ca. 0.5 g) was added to destroy unreacted NaClO2 and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated, extracted with water and brine, then dried over sodium sulfate and concentrated. The resulting concentrate was then purified on a silica column to give 1.54 g (purity=94%) of a white solid compound in 99% yield. TLC R f = 0.2 (DCM:MeOH = 10:1); LCMS (m / z) = 424.42 (M+H)

[0285] TIFF2024542204000177.tif631655-Bromo-N'-(cyclopropanecarbonyl)-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (33-4) To 5-bromo-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 32-4 (1.59 g, 3.69 mmol, 1 equiv.) in dichloromethane (48 mL), cyclopropanecarbohydrazide (554 mg, 5.54 mmol, 1.5 equiv.), triethylamine (769 μL, 5.54 mmol, 1.5 equiv.), and HATU (2.804 g, 7.38 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 2 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA, 1:4) to give 1.84 g (purity=94%) of product as a white solid. Yield: 99%. TLC R f = 0.6 (DCM:MeOH=10:1) LCMS (m / z) = 506.50 (M+H)

[0286] TIFF2024542204000178.tif731652-(5-Bromo-1-tosyl-2,3-dihydro-1H-benzo[b]azepin-4-yl)-5-cyclopropyl-1,3,4-oxadiazole (34-4) 5-Bromo-N'-(cyclopropanecarbonyl)-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 33-4 (1.85 g, 3.69 mmol, 1 equiv.) was dissolved in 1,4-dioxane (37.5 mL), phosphoryl chloride (2.259 mL, 24.24 mmol, 6.57 equiv.) was added, and the mixture was heated at 90°C for 1 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (1.476 g) as a white solid. Yield: 82%, purity: 89.78%. TLC R f = 0.3 (PE:EA=2:1); LCMS (m / z) = 488.50 (M+H)

[0287] Example 39: Representative synthesis of compound of formula 40 TIFF2024542204000179.tif1251654-(1-Bromoethyl)-2-fluoro-1-methylbenzene (Intermediate 2) To fluoro-4-methylbenzaldehyde (1 g, 7.4 mmol, 1 equiv.) in THF (10 mL) was added dropwise a 3M THF solution of methylmagnesium bromide (2896 μL, 8.69 mmol, 1.2 equiv.). The temperature of the reaction mixture was allowed to return to room temperature, and the reaction mixture was stirred at that temperature for 4.5 hours. Then, 1 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resulting concentrate was then purified on a silica column to give 967 mg (purity=82%) of an oily compound in 87% yield. TLC R f =0.6 (PE:EA=1:1)

[0288] To a stirred suspension of intermediate 1 (964 mg, 6.25 mmol, 1 equiv) in CHCl (18.8 mL) at 0 °C under N was added phosphorus tribromide (293 μL, 3.13 mmol, 0.5 equiv) dropwise. After 15 min, the mixture was warmed to room temperature and allowed to stir for 3 h, at which point the reaction mixture was quenched with H0 (20 mL). The aqueous phase was extracted with CHCl (3×20 mL) and the combined organic layers were washed with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL), dried (NaSO), filtered, and concentrated in vacuo to afford the title compound (658 mg, 49% yield, 80% purity) as a colorless oil. TLC R f = 0.85 (PE:EA=1:1)

[0289] TIFF2024542204000180.tif671651-(3-Fluoro-4-methylphenyl)ethyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (36) To a stirred solution of ketone 35 (360 mg, 2.07 mmol, 1 equiv), tetrabutylammonium bromide (67 mg, 0.21 mmol, 0.1 equiv), and KOH (162.5 mg, 2.9 mmol, 1.4 equiv) in THF (7.8 mL) was added 3,4-dihydro-1H-benzo[b]azepine-2,5-dione 35 (540 mg, 2.49 mmol, 1.2 equiv) at ambient temperature. The reaction mixture was then stirred at room temperature for 7.5 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 248 mg (purity=92%) of a pure yellow solid compound in 38% yield. TLC R f = 0.55 (PE:EA = 1:1); LCMS (m / z) = 312.20 (M+H)

[0290] TIFF2024542204000181.tif531655-Bromo-1-(1-(3-fluoro-4-methylphenyl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde (37) Tribromophosphane (98 μL, 270.68 mmol, 1.3 equiv) was added to a flask containing N,N-dimethylformamide (8 mL) in an ice bath and stirred for 10 min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10–15 min. 36 (248 mg, 0.8 mmol, 1 equiv) was added and stirred for 15 min. The reaction mixture was heated to 80 °C and stirred for an additional 3.5 h. The orange solution was diluted with ice water, neutralized with 20% sodium acetate solution, and extracted with EA (3 × 10–20 mL). The combined organic extracts were washed with 50 mL of saturated aqueous sodium bicarbonate and 50 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 210 mg (purity = 94%) of orange solid compound in 65% yield. TLC R f = 0.7 (PE:EA=1:1) LCMS (m / z) = 404.10 (M+H)

[0291] TIFF2024542204000182.tif581655-Bromo-1-(1-(3-fluoro-4-methylphenyl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid (38) The reaction was carried out by adding aqueous NaClO2 (83 mg, 0.92 mmol, 1.76 equiv) to a solution of 37 (210 mg, 0.52 mmol, 1 equiv) and (54.4 uL, 0.53 mmol, 1.02 equiv) in acetonitrile containing 30% H2O2 at 0 °C buffered to pH 4.3 with KH2PO4. The reaction mixture was stirred for 16.5 h. After completion of the reaction, a small amount of Na2SO3 (~0.5 g) was added to destroy unreacted HOCl and H2O2. The mixture was acidified with 10% HCl and diluted with H2O (10-20 mL). The compound was extracted with EA (10 mL). The organic layer was separated and extracted with water and brine, then dried over sodium sulfate and concentrated. The resulting concentrate was then purified on a silica column to give 215 mg (purity = 96%) of a yellow solid compound in 99% yield. TLC R f = 0.1 (DCM:MeOH=1:1) LCMS (m / z) = 418.10 (M+H)

[0292] TIFF2024542204000183.tif631655-Bromo-N'-(cyclopropanecarbonyl)-1-(1-(3-fluoro-4-methylphenyl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide (39) To 5-bromo-1-(1-(3-fluoro-4-methylphenyl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid 38 (221 mg, 0.51 mmol, 1 equiv.) in dichloromethane (6.7 mL) was added cyclopropanecarbohydrazide (76.6 mg, 0.77 mmol, 1.5 equiv.), triethylamine (106 μL, 0.77 mmol, 1.5 equiv.), and HATU (387.6 mg, 1.02 mmol, 2 equiv.). The mixture was stirred at room temperature for 2 h. Then it was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 206 mg (purity=94%) of product as a yellow oil. Yield: 80%. TLC R f = 0.5 (DCM:MeOH = 10:1); LCMS (m / z) = 500.30 (M+H)

[0293] TIFF2024542204000184.tif681655-Bromo-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-fluoro-4-methylbenzoyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (40) 5-Bromo-N'-(cyclopropanecarbonyl)-1-(1-(3-fluoro-4-methylphenyl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbohydrazide 39 (206 mg, 0.41 mmol, 1 equiv.) was dissolved in 1,4-dioxane (4.2 mL), phosphoryl chloride (252 μL, 2.7 mmol, 6.57 equiv.) was added, and the mixture was heated at 90° C. for 3 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (58 mg) as a white solid. Yield: 29%, purity: 98%. TLC R f = 0.4 (PE:EA = 2:1); LCMS (m / z) = 484.40 (M+H)

[0294] Example 40: Representative synthesis of compound of formula 42 TIFF2024542204000185.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(hydroxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (41) To a solution of 5-bromo-1-(3-fluoro-4-methylbenzyl)-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carbaldehyde 7-2 (970 mg, 2.5 mmol, 1 equiv.) in MeOH (8 mL) was added NaBH4 (463 mg, 12.5 mmol, 5 equiv.) at 0° C. The reaction mixture was then stirred at room temperature for 3.5 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 965 mg (purity=98%) of a pale yellow oily compound in 99% yield. TLC R f = 0.2 (PE:EA=2:1) LCMS (m / z) = 372.10 (M-17)

[0295] TIFF2024542204000186.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(methoxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (42) NaH (30 mg, 0.75 mmol, 2.5 equiv) was added to dry THF (0.5 mL) in a round bottom flask. 5-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(hydroxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 41 (117 mg, 0.3 mmol, 1 equiv) was dissolved in THF (0.5 mL) and slowly added to the NaH solution at 0 °C and stirring was continued for 20 min. MeI (37 μL, 0.6 mmol, 2 equiv) was added and the reaction was stirred at room temperature for 2 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3 × 10 mL). The organic solutions were combined, washed with H2O (2 × 10 mL) and brine (1 × 20 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 42 mg (purity=98%) of a yellow oily compound in 34% yield. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 404.60 (M+1)

[0296] Example 41: Representative synthesis of compound of formula 44-1 TIFF2024542204000187.tif581655-Bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (43) 5-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(hydroxymethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 41 (1.1 g, 2.8 mmol, 1 eq.) and carbon tetrachloride solvent (9 mL) were placed in a round-bottom flask. PBr3 (134 μL, 1.4 mmol, 0.5 eq.) was then added and heated at 60° C. for 30 min. Stirring was then continued at room temperature for 0.5 h. The reaction mixture was washed with sodium bicarbonate solution and the combined organic matter was extracted by dichloromethane solvent. The solution was dried over anhydrous Na2SO4 and the crude product was obtained after evaporating the solvent. The resulting concentrate was then purified on a silica column to obtain 1.2 g (purity=99%) of a yellow oily compound in 94% yield. TLC R f = 0.6 (PE:EA=2:1) LCMS (m / z) = 454.50 (M+1)

[0297] TIFF2024542204000188.tif631655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (44-1) A round bottom flask was charged with NaH (30 mg, 0.75 mmol, 2.5 equiv) and dry THF (1 mL). Tetrahydrofuran-3-ol (53 μL, 0.6 mmol, 2 equiv) was added to the ice-cold NaH solution. The resulting mixture was continuously stirred for 30 min at 0° C., and then 5-bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 43 (135 mg, 0.3 mmol, 1 equiv) in THF (1 mL) was added to it. After completion of the reaction (2 h), the solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with H2O (2×10 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 64 mg (purity=91%) of a yellow oily compound in 46% yield. TLC R f = 0.2 (PE:EA=2:1) LCMS (m / z) = 460.60 (M+1)

[0298] Example 42: Representative synthesis of compounds of formula 44-2 TIFF2024542204000189.tif531655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (44-2) A round-bottom flask was charged with NaH (22 mg, 0.55 mmol, 2.5 equiv) and dry THF (1 mL). Tetrahydro-2H-pyran-4-ol (41.75 μL, 0.44 mmol, 2 equiv) was added to the ice-cold NaH solution. The resulting mixture was continuously stirred for 30 min at 0° C., and then 5-bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 43 (100 mg, 0.22 mmol, 1 equiv) in THF (1 mL) was added to it. After completion of the reaction (2 h), the solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with HO (2×10 mL) and brine (1×20 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 69 mg (purity=80.69%) of a yellow oily compound in 66% yield. TLC R f = 0.2 (PE:EA=2:1) LCMS (m / z) = 474.60 (M+1)

[0299] Example 43: Representative synthesis of compound of formula 44-3 TIFF2024542204000190.tif48165Bromo-1-(3-fluoro-4-methylbenzyl)-4-(((tetrahydrofuran-3yl)methoxy)methyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (44-3) A round bottom flask was charged with NaH (22 mg, 0.55 mmol, 2.5 equiv) and dry THF (1 mL). (Tetrahydrofuran-3-yl)methanol (43.44 μL, 0.44 mmol, 2 equiv) was added to the ice-cold NaH solution. The resulting mixture was continuously stirred for 30 min at 0° C., and then 5-bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 43 (100 mg, 0.22 mmol, 1 equiv) in THF (1 mL) was added to it. After completion of the reaction (2 h), the solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with HO (2×10 mL) and brine (1×20 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 54 mg (purity=96.44%) of a yellow oily compound in 51.74% yield. TLC R f = 0.2 (PE:EA=2:1) LCMS (m / z) = 476.60 (M+1)

[0300] Example 44: Representative synthesis of compound of formula 44-4 TIFF2024542204000191.tif481655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(((tetrahydrofuran-2-yl)methoxy)methyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (44-4) A round bottom flask was charged with NaH (22 mg, 0.55 mmol, 2.5 equiv) and dry THF (1 mL). (Tetrahydrofuran-2-yl)methanol (43.44 μL, 0.44 mmol, 2 equiv) was added to the ice-cold NaH solution. The resulting mixture was continuously stirred for 30 min at 0° C., and then 5-bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 43 (100 mg, 0.22 mmol, 1 equiv) in THF (1 mL) was added to it. After completion of the reaction (2 h), the solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with HO (2×10 mL) and brine (1×20 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 76 mg (purity=93.03%) of a yellow oily compound in 72.82% yield. TLC R f = 0.2 (PE:EA=2:1) LCMS (m / z) = 474.60 (M+1)

[0301] Example 45: Representative synthesis of compound of formula 44-5 TIFF2024542204000192.tif63165(R)-5-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (44-5) A round bottom flask was charged with NaH (28 mg, 0.71 mmol, 2.5 equiv) and dry THF (1 mL). (R)-Tetrahydrofuran-3-ol (46.09 μL, 0.57 mmol, 2 equiv) was added to the ice-cold NaH solution. The resulting mixture was continuously stirred for 30 min at −15° C., and then 5-bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 43 (100 mg, 0.22 mmol, 1 equiv) in THF (1 mL) was added to it. After completion of the reaction (2 h), the solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with HO (2×10 mL) and brine (1×20 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 56 mg (purity=88.62%) of a yellow oily compound in 43.44% yield. TLC R f = 0.25 (PE:EA=2:1) LCMS (m / z) = 460.60 (M+1)

[0302] Example 46: Representative synthesis of compound of formula 44-6 TIFF2024542204000193.tif63165(S)-5-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (44-6) A round bottom flask was charged with NaH (28 mg, 0.71 mmol, 2.5 equiv) and dry THF (1 mL). (S)-Tetrahydrofuran-3-ol (46.09 μL, 0.57 mmol, 2 equiv) was added to the ice-cold NaH solution. The resulting mixture was continuously stirred at −15° C. for 30 min, and then 5-bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 43 (100 mg, 0.22 mmol, 1 equiv) in THF (1 mL) was added to it. After completion of the reaction (2 h), the solution was quenched with saturated ammonium chloride and extracted with EA (3×10 mL). The organic solutions were combined, washed with HO (2×10 mL) and brine (1×20 mL), dried over anhydrous NaSO, filtered, and concentrated by rotary evaporation to give the crude compound, which was then purified on a silica column to give 66 mg (purity=84.08%) of a yellow oily compound in 51.20% yield. TLC R f = 0.25 (PE:EA=2:1) LCMS (m / z) = 460.60 (M+1)

[0303] Example 47: Representative synthesis of compound of formula 45 TIFF2024542204000194.tif581655-Bromo-1-(3-fluoro-4-methylbenzyl)-4-(pyrrolidin-1-ylmethyl)-1,3-dihydro-2H-benzo[b]azepin-2-one (45) To a solution (1 mL) of 5-bromo-4-(bromomethyl)-1-(3-fluoro-4-methylbenzyl)-1,3-dihydro-2H-benzo[b]azepin-2-one 43 (135 mg, 0.3 mmol, 1 equiv.) and TEA (42 μL, 0.3 mmol, 1.2 equiv.) in DMF was added pyrrolidine (21 μL, 0.25 mmol, 1 equiv.) at room temperature. The reaction mixture was then stirred at 60° C. for 2 h. The solution was quenched with saturated ammonium chloride and extracted with EA (3×20 mL). The organic solutions were combined, washed with H2O (2×20 mL) and brine (1×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give the crude compound. The resulting concentrate was then purified on a silica column to give 110 mg (purity=96%) of a pale yellow oily compound in 82% yield. TLC R f = 0.2 (PE:EA=2:1) LCMS (m / z) = 445.20 (M+1)

[0304] Example 48: In vitro assay Cell culture and treatment Human cancer cell lines were obtained from ATCC and cultured in DMEM (Gibco, Cleveland, TN, USA) supplemented with 5% fetal bovine serum (Gibco), penicillin (100 U / mL)-streptomycin (100 μg / mL) (Gibco, Cat. No. 15140-122), 2 mM L-glutamine (Gibco, 200 mM solution, Cat. No. 25030081), and 1 mM sodium pyruvate (Gibco, 100 mM solution, Cat. No. 11360070) at 37 °C in a humidified incubator maintained at 5% CO2.

[0305] Phenotypic screening assays and MTT assays Screening was performed as previously reported (Li et al. 2019). Briefly, RPE-Neo or RPE-MYC, or RPE-MYC expressing EGFP-Histone 2B fusion protein, were passaged as batches in 96-well plates 18-24 hours before exposure to compounds of the present disclosure at concentrations ranging from 20 nM to 20 μM. Cells were analyzed for mitotic arrest or changes in DNA content by GE IN-Cell Analyzer 2000 24, 48 or 72 hours after the start of treatment. MTT assays for cell proliferation were performed as previously reported (Li et al. 2019).

[0306] Immunofluorescence staining The immunofluorescence staining procedure was previously described (Yang et al. 2010). Briefly, cells were cultured on coverslips in 6-well plates, fixed with 4% paraformaldehyde, and then permeabilized with 0.3% Triton X-100 in PBS. After incubation with primary antibodies, cells were detected with TRITC- or FITC-conjugated secondary antibodies purchased from Jackson ImmunoResearch. After immunostaining, cells were mounted on microscope slides using Vectashield mounting solution containing DAPI (Vector Laboratories, USA), and fluorescence was detected using an EVOS Auto FL fluorescence microscope (ThermoFisher, USA).

[0307] Antibodies used in this study Primary antibody: Histone H3 (phospho-Ser10), Mouse monoclonal antibody, Upstate, Cat. No. 05-806, 1:1000 Phospho-Aurora A(Thr288)(C39D8), rabbit mAb, Cell Signalling, #3079, 1:1000 Aurora B Antibody, Rabbit, Absin, Antibody 1460~100ug, Lot# AH22, 1:50 dilution CREST antibody, Thermofisher, product number PA5-30500, diluted 1:200 Mouse anti-β-tubulin, Sigma, Cat. No. F 2043, clone TUB 2.1, diluted 1:50

[0308] Secondary antibody: Rhodamine (TRITC) AffiniPure Goat Anti-Mouse IgG (H+L), Proteintech, SA00007-1, 1:100 Rhodamine (TRITC) AffiniPure Goat Anti-Rabbit IgG (H+L), Jackson, 111-025-003, 1:100 Fluorescein (FITC)-conjugated Affinipure Goat Anti-Rabbit IgG (H+L), Jackson, 111-095-144, 1:100 Rhodamine Red™-X conjugated AffiniPure donkey anti-human IgG (H+L), Jackson, 709-295-149, 1:100

[0309] Crystal violet assay Cells were fixed with 4% PFA and stained with 0.1% crystal violet (Aladdin, 548-62-9). Bound crystal violet was eluted with 95% ethanol, and the absorbance of the eluate was measured at 570 nm using a microplate reader (BioTek ELX808iu).

[0310] Soft agar assay The assay was performed in a 6-well plate containing two layers of agar. First, 0.75% agar in DMEM medium was melted in a microwave oven and poured to form the bottom layer. Once solidified, 10,000–100,000 cells in 1 ml of DMEM containing 0.35% agar were added to form the top layer, which was then covered with 0.5 ml of DMEM. The cell culture medium was changed every 2 days until colonies were ready to be photographed.

[0311] The results of these assays are summarized in Table 2. Values ​​between 1 nM and 1.0 μM inclusive are designated "A," values ​​between 1.00 μM and 10.0 μM inclusive are designated "B," values ​​between 10.0 μM and 30.0 μM inclusive are designated "C," and values ​​between 30.0 μM and 1000 μM inclusive are designated "D," as shown in Table 2 below.

[0312] [Table 2] TIFF2024542204000196.tif217139TIFF2024542204000197.tif58139

[0313] Example 49: Xenograft Studies Xenografts were initiated in immunodeficient (Nu / Nu) mice using the human lung adenocarcinoma cell line NCI-H23 (Figure 1) and the human breast tumor-derived cell line MDA-MB-231 (Figure 2). Five million cells were injected subcutaneously into the mice, resulting in a mean tumor volume of 150–200 mm. 3 Treatment was initiated when the β-amyloid level reached 1.0 (n=8 / group). The indicated compounds were administered by oral gavage twice daily for 5 days, followed by a 2-day washout period. Day 0 on the x-axis indicates the day treatment was initiated. In these experiments, 55 and 58 were first dissolved in DMSO and then diluted 1:10 in a mixture containing 70% PEG300 and 30% PBS, pH 7.4. 100 ml of drug solution was administered per dose.

[0314] References Li et al., 2019 Purification,identification,and characterization of two benzophenanthridine alkaloids from Corydalis longicalcarata rhizomes with anti-mitotic and polyploidy-inducing activities Jinhua Li,Ziqi Yan,Hongmei Li,Qiong Shi,Linfang Huang,Thaddeus D.Allen,Dun Yang,Jing Zhang,bioRxiv 821124;doi: https: / / doi.org / 10.1101 / 821124 Yang et al.2010 Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase Dun Yang,Hong Liu,Andrei Goga,Suwon Kim,Mariia Yuneva,and J.Michael Bishop PNAS August 3,2010 107(31)13836-13841; https: / / doi.org / 10.1073 / pnas.1008366107

Claims

1. Formula (I): or a pharmaceutically acceptable salt thereof, During the ceremony, X is O= or S=, Ring A is selected from the group consisting of optionally substituted phenyl, optionally substituted 5-membered heteroaryl, and optionally substituted 6-membered heteroaryl; L is a bond, optionally substituted C １ ~C ３ Alkylene, —CH(D)—, —C(D) ２ -, -C(O)-, -C(O)O-, -C(O)NH-, and -S(O) ２ - selected from the group consisting of The group C is C １ ~C ６ Aliphatic, -C≡CR ３ , optionally substituted phenyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, optionally substituted 6-membered carbocyclyl, and optionally substituted 6-membered heterocyclyl; Each R Ａ is halogen, -CN, -C≡CR ３ , optionally substituted C １ ~C ６ Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, optionally substituted 3- to 7-membered heterocyclyl, -OR １ , -SR １ , -N(R １ ) ２ , -C(O)OR １ , C(O)N(R １ ) ２ , -N(H)C(O)R １ , and —N(H)C(O)N(R １ ) ２ or R Ｂ is a halogen, -C≡CR ３ , optionally substituted 5- to 6-membered heteroaryl, optionally substituted C １ ~C ３ Aliphatic, optionally substituted C １ ~C ３ independently selected from the group consisting of alkoxy, and optionally substituted 3- to 6-membered carbocyclyl; Each R Ｃ is a halogen, —CN, optionally substituted C １ ~C ６ Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, optionally substituted 3- to 7-membered heterocyclyl, -OR ３ , -SR ３ , -N(R ３ ) ２ , -C(O)OR ３ , -C(O)N(R ３ ) ２ , -N(H)C(O)R ３ , and —N(H)C(O)N(R ３ ) ２ are independently selected from the group consisting of: Here, optionally, R Ｃ two examples of which, taken together with the atom to which they are attached, form an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl; R Ｄ is an optionally substituted 5-membered heteroaryl, —C(O)OR ３ , C(O)N(R ３ ) ２、 - (CH ２ ) １～３ N (R ２ ) ２ , -(CH ２ ) １～３ OR ２ , -(CH ２ ) １～３ O (CH ２ ) １～３ R ２ and —CHO; Each R １ is hydrogen, -C(O)R ３ , -(CH ２ ) １～３ OR ３ , optionally substituted C １ ~C ６ independently selected from the group consisting of aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl; Each R ２ is hydrogen, optionally substituted C １ ~C ６ independently selected from the group consisting of aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl; Here, optionally, R ２ two examples of: taken together to form an optionally substituted 3- to 7-membered heterocyclyl ring; Each R ３ is hydrogen, optionally substituted C １ ~C ６ independently selected from the group consisting of aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered carbocyclyl, and optionally substituted 3- to 7-membered heterocyclyl; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; The compound or a pharmaceutically acceptable salt thereof.

2. Formula (Ia), (Ib), or (Ic): or a pharmaceutically acceptable salt thereof.

3. 3. The compound of claim 2, wherein group C is an optionally substituted phenyl.

4. 3. The compound of claim 2, wherein group C is an optionally substituted pyridinyl.

5. R Ｃ is halogen, optionally substituted C １ ~C ６ Aliphatic, -COOR ３ , -CN, and -OR ３ 2. The compound of claim 1 selected from:

6. The compound of claim 1 wherein p is 2.

7. R Ｃ One example is halogen, and the other example is optionally substituted C １ ~C ６ Aliphatic, or -OR ３ 7. The compound of claim 6, wherein:

8. R Ｃ The compound of claim 1 , wherein is selected from —F, -Me, and —OMe.

9. p is 2 and R Ｃ 2. The compound of claim 1, wherein one instance of is fluoro and the other instance is -Me or -OMe.

10. L and the group C together form The compound of claim 1 , wherein

11. Formula (I-a1), (I-b1), or (I-c1): or a pharmaceutically acceptable salt thereof.

12. R Ｄ The compound of claim 1 , wherein is an optionally substituted 5-membered heteroaryl.

13. R Ｄ But -(CH ２ ) １～３ OR ２ 2. The compound of claim 1, wherein:

14. R Ｄ The compound of claim 1, wherein is —CHO.

15. R Ｄ but, 2. The compound of claim 1 selected from the group consisting of:

16. Formula (I-b2): or a pharmaceutically acceptable salt thereof.

17. Formula (I-c2), (I-c3), or (I-c4) or a pharmaceutically acceptable salt thereof.

18. R Ａ The compound of claim 1 , wherein is optionally substituted phenyl.

19. R Ａ but, 2. The compound of claim 1 selected from the group consisting of:

20. The compound of claim 1 as set forth in Table 1.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

22. A pharmaceutical composition for treating cancer in a patient, comprising a compound according to any one of claims 1 to 20.

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