3,4-dihydroquinoxalin-2(1H)-ones as bet bromodomain inhibitors and therapeutic methods using the same

Abstract

The disclosure relates to inhibitors of bromodomain and extra-terminal domain (BET) proteins and use thereof for the treatment of disease.

Description

3,4-DIHYDROQUINOXALIN-2(1H)-ONES AS BET BROMODOMAIN INHIBITORS AND THERAPEUTIC METHODS USING THE SAME CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 709,059, filed October 18, 2024, which is incorporated by reference herein in its entirety for all purposes. FIELD

[0002] The disclosure relates generally to compounds that inhibit the activity of bromodomain and extra-terminal domain (BET) proteins, and methods of using such compounds as treatments for disease. BACKGROUND

[0003] The bromodomain and extra-terminal domain (BET) family proteins, which include BRD2, BRD3, BRD4, and testis-specific BRDT, modulate gene expression by recruiting transcriptional regulatory complexes via two highly conserved bromodomains (BD1 and BD2) to acetylated chromatin. A well-studied member of the BET family, the BRD4 protein plays a crucial role in transcription, replication, epigenetic regulation, and DNA repair and stability. Moreover, BRD4 is involved in the development of inflammatory and autoimmune diseases through its influence on alternative splicing, gene expression, innate immune responses, and the transcriptional control of inflammatory genes, primarily those regulated by NF-kB-mediated inflammatory response.

[0004] The first bromodomain (BD1) and second bromodomain (BD2) of BRD4 are both essential to the protein’s functions, such as transcription factor binding and recruitment to target gene regulatory sites on DNA, transcriptional regulation by binding to lysine-acetylated histones and transcription factors, and transcriptional elongation. The structural differences between BD1 and BD2 lead to different interactions with lysine-acetylated histones and non-histone proteins, thus resulting in functional differences. Pan-BET inhibitors that bind with similar affinities to the BD1 and BD2 bromodomains of BRD2, BRD3, and BRD4 exhibit on-target, dose-limiting toxicities, such as thrombocytopenia, fatigue, gastrointestinal bleeding, and hypertension.Targeting only one of the two bromodomains of BRD4 may result in greater response selectivity with minimal adverse toxic effects. For example, while BRD4(BD1) controls genes for overall homeostasis and survival, BRD4(BD2) primarily controls genes associated with inflammation and inflammatory diseases.

[0005] Despite a deepening understanding of the BET family of proteins, the need for BET inhibitors and BRD4-selective inhibitors that can be used for therapeutic purposes in the treatment of inflammation / inflammatory diseases and / or autoimmune diseases remains unmet in the art. SUMMARY

[0006] In aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:, wherein in formula (I): X is a moiety comprising one or more groups selected from -NRa-, -S-, -S(O)-, -S(O)2-, -O-, C(O), -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)S-, -SC(O)-, -OC(O)S-, -SC(O)O-, -C(O)NRa-, -NRaC(O)-, -CRa=N-NRa-, -C(O)NRaSO2-, -SO2NRaC(O)-, -OC(O)NRa-, -NRaC(O)O-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; A1is N or CR5; A2is N or CR6; A3is N or CR8; R1is selected from optionally substituted C1-C6alkyl and optionally substituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C3-C6cycloalkyl, and optionally substituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety comprising one or more groups selected from C(O), -C(O)O-, -C(O)S-, -C(O)NRa-,-S(O)-, -S(O)2-, -C(O)NRaSO2-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroalkylene, optionallysubstituted heteroarylene, and optionally substituted heterocycloalkylene; R4is selected from - C(O)Ra, C(O)ORa, C(O)N(Ra)2, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; R5, R6, and R8are each independently selected from H, deuterium, halide, -CN, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, -OH, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; t is 1 or 2; R7is selected from -ORa, -C(O)Ra, C(O)ORa, C(O)N(Ra)2, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; and Rais independently at each occurrence selected from H, deuterium, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

[0007] In embodiments, the compound of formula (I), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (II):, wherein in formula (II): X is a moiety comprising one or more groups selected from -NRa-, -S-, -S(O)-, -S(O)2-, -O-, C(O), -C(O)NRa-, -NRaC(O)-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene; A1is N or CR5; A2is N or CR6; R1is selected from optionally substituted C1-C4alkyl and unsubstituted C3-C6cycloalkyl; R3is selected from H,optionally substituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety selected from -C(O)-, -C(O)NRa-, -S(O)-, -S(O)2-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heteroalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; R5, R6, and R8are each independently selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -S(O)tORa, -P(O)(ORa)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted C1-C6alkoxy, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; t is 1 or 2; R7is selected from -ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, deuterium, optionally substituted C1-C4alkyl, optionally substituted C1-C4haloalkyl, optionally substituted phenyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0008] In embodiments, the compound of formula (I) and / or formula (II), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (III):(III),wherein in formula (III): W is a bond or a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted C1-C6alkylene, optionally substituted C1-C6haloalkylene, optionally substituted C6-C10arylene, optionally substituted C3-C6cycloalkylene, and unsubstituted 3- to 6-membered heterocycloalkylene; X1 is a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, and optionally substituted C1-C4alkylene; R1is selected from optionally substituted C1-C4alkyl and unsubstituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety selected from -C(O)-, optionally substituted C1-C6alkylene, optionally substituted C1-C6haloalkylene, and optionally substituted C3-C6cycloalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; R5and R6are each independently selected from H, halide, -OH, -ORa, -N(Ra)2, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, and unsubstituted C1-C4alkoxy; R8is selected from H, halide, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, unsubstituted C3-C5cycloalkyl, and unsubstituted C1-C3alkoxy; R7is selected from-ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, optionally substituted phenyl, optionally substituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl.

[0009] In embodiments, the compound of formula (I), formula (II), and / or formula (III), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (IVa) or formula (IVb):

[0010] In embodiments, the compound of formula (I), formula (II), formula (III), and / or formula (IVa), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (V):, wherein in formula (V): W is a bond or a moiety selected from optionally substituted C1-C4alkylene, optionally substituted C1-C3haloalkylene, optionally substituted phenylene, and unsubstituted C3-C6cycloalkylene; R1is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, deuterated methyl (-CD3), -CH2CH2OH, unsubstituted cyclopropyl, and unsubstituted cyclobutyl; R3is selected from H, optionally substituted C1-C3alkyl, unsubstituted C1-C4fluoroalkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted oxetane, unsubstituted azetidine, unsubstituted tetrahydrofuran, unsubstituted pyrrolidine, unsubstituted tetrahydropyran, and unsubstituted piperidine; L is a bond or a moiety selected from C(O), optionally substituted C1-C3alkylene, and unsubstituted C1-C3haloalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; R5and R6are each independently selected fromH, halide, -ORa, -NHRa, unsubstituted C1-C4alkyl, optionally substituted phenyl, and unsubstituted C1-C3alkoxy; and R8is selected from H, halide, and unsubstituted C1-C3alkyl; R7is selected from -ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, -CH3, optionally substituted phenyl, optionally substituted benzyl, and unsubstituted C3-C6cycloalkyl.

[0011] In embodiments, the compound of formula (I), formula (II), formula (III), formula (IVa), and / or formula (V), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (VIa) or formula (VIb):formula (VIa) formula (VIb).

[0012] In embodiments, the compound of formula (I), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to any one of formula 1001-1595.

[0013] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

[0014] In aspects, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In aspects, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein. In someembodiments, the disease or disorder is an inflammatory disease or an autoimmune disease. In some embodiments, the disease or disorder is alleviated by inhibiting BET bromodomain and extra-terminal domain (BET) protein activity in the patient. In some embodiments, the disease or disorder is alleviated by inhibiting BRD4 protein activity in the patient.

[0015] In some embodiments, the disease or disorder is selected from chronic or acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis (RA), cardiovascular disease, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, reactive arthritis, Reiter’s syndrome, gouty arthritis, psoriasis, erythrodermic psoriasis, pustular psoriasis, dermatitis, scleroderma, Raynaud’s syndrome, Sjögren’s syndrome, inflammatory bowel disease, intestinal fibrosis, Crohn’s disease, enteropathic arthritis, ulcerative colitis, colitis, diverticulitis, nephritis, urethritis, salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupus erythematosus, multiple sclerosis (MS), meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis, thrombophlebitis, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), inflammatory lung disease, allergic rhinitis, endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valve disease, rheumatic aortic valve disease, prostatitis, prostatocystitis, spondyloarthritis, ankylosing spondylitis, synovitis, tenosynovotis, myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis, bursitis, gout, pseudogout, vasculitides, granulomatous thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis, acute thyroiditis, Hashimoto’s disease, Kawasaki’s disease, neuroinflammatory disease, sepsis, conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis, lymphadenitis, nasopharyngitis, sinusitis, pharyngitis, tonsillitis, laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis, esophagitis, gastritis, peritonitis, hepatitis, cholelithiasis, cholecystitis, glomerulonephritis, Goodpasture syndrome, crescentic glomerulonephritis, pancreatitis, endometritis, myometritis, metritis, cervicitis, endocervicitis, exocervicitis, parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis, pneumoconiosis, hidradenitis suppurativa (HS), obesity, obesity-related inflammation, Still’s disease, systemic juvenile idiopathic arthritis (SJIA), adult-onset Still’s disease (AOSD), macrophage activation syndrome, and inflammatory polyarthritis. In some embodiments, the disease or disorder is selected from rheumatoid arthritis (RA), cardiovascular disease, multiple sclerosis (MS), osteoarthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa (HS), obesity-relatedinflammation, Still’s disease, systemic juvenile idiopathic arthritis (SJIA), adult-onset Still’s disease (AOSD), and macrophage activation syndrome.

[0016] In some embodiments, the compound, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has a cellular activity of at least about 10 μM as measured by an in vitro cellular assay. In some embodiments, the compound, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has an IC50of about 1 μM or less. DETAILED DESCRIPTION

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entireties. Definitions

[0018] Unless defined otherwise, all technical and scientific terms used in the description of the present disclosure have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entireties.

[0019] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-10alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range, e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (nPr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and 3-methylhexyl. “Alkylene” by itself or as part of another term, as used herein, refers to an alkyl group, as defined above, linking at least two other groups (i.e., a divalent alkyl radical). The twomoieties linked to the alkylene group can be attached to the same carbon atom or different carbon atoms of the alkylene group. Unless stated otherwise specifically in the specification, an alkyl group (or alkylene group) is optionally substituted by one or more of substituents which independently are: deuterium, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0020] “Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively. “Benzyl” is a non-limiting example of an alkylaryl group.

[0021] “Alkylcycloalkyl” refers to an -(alkyl)cycloalkyl radical where cycloalkyl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkyl respectively.

[0022] “Alkylheteroaryl” refers to an -(alkyl)heteroaryl radical where heteroaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl respectively.

[0023] “Alkylheterocycloalkyl” refers to an -(alkyl)heterocycloalkyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.

[0024] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C2-10)alkenyl or C2-10alkenyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, - S(O)tR′ (where t is 1 or 2), -OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, -N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, - N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0025] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C2-10)alkynyl or C2-10alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′(where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0026] “Acyl” refers to a -(C=O)R radical group, wherein the group is attached to the parent structure through the carbonyl functionality, and R is selected from alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl. If the R radical is heteroaryl, heteroalkyl, or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyl group (i.e., -(C=O)R) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0027] “Acyloxy” refers to a -O(C=O)R radical group, wherein R is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl. If the R radical is heteroaryl, heteroalkyl, or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyloxy group (i.e., -O(C=O)R) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl,trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0028] “Acylsulfonamide” refers to the group –C(=O)NR′-S(=O)2R′, where each R′ is independently hydrogen, deuterium, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0029] “Carboxaldehyde” refers to a -(C=O)H radical group.

[0030] “Carbonyl” refers to a -C(=O)- functional group.

[0031] “Carboxyl” refers to a -(C=O)OH radical.

[0032] “Cyano” refers to a -CN radical.

[0033] “Cycloalkyl” refers to a cyclic hydrocarbon radical consisting of only carbon and hydrogen atoms, which may be completely saturated or partially unsaturated, and having from 3 to 12 ring atoms (i.e., (C3-12)cycloalkyl or C3-12cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 12” refers to each integer in the given range - e.g., “3 to 12 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 12 carbon atoms. A cycloalkyl group can be a single ring (e.g., monocyclic) or multiple rings (e.g., polycyclic). Illustrative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Polycyclic cycloalkyl groups are composed of 2 or more rings (e.g., bicyclic, tricyclic or tetracyclic ring system) and include fused cycloalkyl, bridged cycloalkyl, and spiro cycloalkyl ring systems. A fused cycloalkyl group refers to a polycyclic cycloalkyl ring system in which 2 or more rings share adjacent pairs of ring atoms. Illustrative examples of fused cycloalkyl groups include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, octahydropentalenyl, bicyclo[4.2.0]octyl, octahydro-1H-indenyl, decahydronaphthalenyl,decahydroazulenyl, decahydro-1H-benzo[7]annulenyl, dodecahydro-1H-phenalenyl, tetradecahydroanthracenyl, and the like. A bridged cycloalkyl group refers to a polycyclic cycloalkyl ring system in which a cycloalkyl ring contains at least one linkage of one or more atoms connecting non-adjacent ring atoms of the cycloalkyl. Illustrative examples of bridged cycloalkyl groups include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, norbornenyl, adamantanyl, and the like. A spiro cycloalkyl group refers to a polycyclic cycloalkyl ring system in which one atom is shared between 2 single rings. Illustrative examples of spiro cycloalkyl groups include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl, spiro[5.6]dodecyl, spiro[5.7]tridecyl, and the like. “Cycloalkylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from a cycloalkyl group, as defined above. For a cycloalkyl group (or cycloalkylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, a cycloalkyl group (or cycloalkylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0034] “Cycloalkylalkyl” refers to a -(cycloalkyl)alkyl radical where cycloalkyl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkyl, respectively.

[0035] “Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.

[0036] “Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0037] The term “alkoxy” refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, cyclopropyloxy and cyclohexyloxy. Unless stated otherwise specifically in the specification, the alkyl constituent of an alkoxy group is optionally substituted by one or more of substituents which independently are: deuterium, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, - S(O)tR′ (where t is 1 or 2), -OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, -N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, - N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0038] The term “alkoxycarbonyl” refers to a group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (C1-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. Unless stated otherwise specifically in the specification, the alkyl constituent of an alkoxycarbonyl group is optionally substituted by one or more of substituents which independently are: deuterium, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0039] “Amino” or “amine” refers to a -N(R′)2radical group, where each R′ is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl (bonded through a ring carbon), heteroaryl (bonded through a ring carbon), or heteroarylalkyl (bonded through a ring carbon), unless stated otherwise specifically in the specification. When a -N(R′)2group has two R′ substituents other than hydrogen, they may be combined with the nitrogen atom to form a 4-, 5-, 6-, 7-, or 8- membered heterocyclic ring. For example, -N(R′)2is intended to include, but is not limited to, 1- pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, one or both R′ of a -N(R′)2group is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0040] The term “substituted amino” also refers to N-oxides of the groups -NHRd, and - N(R′)2each as described above. N-oxides is prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0041] “Amide” or “amido” refers to a chemical moiety with formula -C(O)NR′R″ or -NR′C(O)R″, where R′ and R″ are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl (bonded through a ring carbon), heteroaryl (bonded through a ring carbon), or heteroarylalkyl (bonded through a ring carbon). The R′ and R″ of -C(O)NR′R″ may optionally be taken together with the nitrogen to which they are attached to form a 4-, 5-, 6-, 7-, or 8- membered heterocyclic ring. Unless stated otherwise specifically in the specification, each R′ and R″ of a -C(O)NR′R″ or -NR′C(O)R″ group is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0042] An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

[0043] “Aromatic” or “aryl” or “Ar” refers to an aromatic radical with 6 to 16 ring atoms (e.g., C6-C16aromatic or C6-C16aryl), 6 to 14 ring atoms (e.g., C6-C14aromatic or C6-C14aryl), 6 to 12 ring atoms (e.g., C6-C12aromatic or C6-C12aryl), or 6 to 10 ring atoms (e.g., C6-C10aromatic or C6-C10aryl), which has at least one cyclic hydrocarbon group with a conjugated pi electron system. Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. An aryl group can be a single ring (e.g., monocyclic aryl) or multiple rings (e.g., polycyclic aryl) that are fused together (i.e., a fused aryl) or linked covalently (e.g., biphenyl). A fused aryl group refers to multiple rings (e.g., bicyclic, tricyclic or tetracyclic ring system) which share adjacent pairs of ring atoms wherein at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, fluorenyl, naphthyl, anthracenyl, tolyl, and xylyl. “Arylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from an aryl group, as defined above. Divalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Divalent radicals derived from univalent polycyclic aromatic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. For an aryl group (or arylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, an aryl group (or arylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, hydroxamate, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -S(O)tR′ (where t is 1 or 2), - N(R′)C(NR′)N(R′)2, -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0044] “Aralkyl” or “arylalkyl” refers to an -(aryl)alkyl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0045] “Ester” refers to a chemical radical of formula -(C=O)OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), heteroalkyl (bonded through a chain carbon), and heterocycloalkyl (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, the R of an ester group (i.e., -(C=O)OR) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), - OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, - N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0046] “Halo,” “halide,” or, alternatively, “halogen” is intended to mean fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy groups, respectively, that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is F.

[0047] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0048] “Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from a heteroatom, i.e., an atom other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof). A numerical range may be given, e.g., 3- to 12-, 3- to 10-, 3- to 8-, or 3- to 6-membered heteroalkyl, which refers to the chain length in total (inclusive of the one or more heteroatoms). “Heteroalkylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from a heteroalkyl group, as defined above. Unless stated otherwise specifically in the specification, a heteroalkyl group (or heteroalkylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, - S(O)tR′ (where t is 1 or 2), -OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, -N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, - N(R′)C(NR′)N(R′)2, -S(O)tR′ (where t is 1 or 2), -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0049] “Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[0050] “Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[0051] “Heteroalkylheterocycloalkyl” refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.

[0052] “Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

[0053] “Heteroaryl” or “heteroaromatic” or “HetAr” refers to a 5- to 18-membered aromatic radical in which 1, 2, 3, 4, 5, or 6 carbon atoms of the aromatic ring system are replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur atom. Heteroaryl groups can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A N- containing heteroaryl moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. A numerical range may be given, e.g., 5- to 18-, 5- to 12-, 5- to 10-, 5- to 9-, or 5- to 6-membered heteroaryl, which refers to the total number of ring atoms in the heteroaryl ring system (inclusive of the one or more heteroatoms). Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range - e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. A heteroaryl group can be a single ring (e.g., monocyclic heteroaryl), or multiple rings (e.g., polycyclic heteroaryl) that are fused together (i.e., a fused heteroaryl) or linked covalently (e.g., bipyridyl). A fused heteroaryl group refers to multiple aromatic rings (e.g., bicyclic, tricyclic or tetracyclic ring system) which share adjacent pairs of ring atoms wherein at least one of the fused aromatic rings is a heteroaromatic ring. The heteroaryl group may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, benzofuranyl, isobenzofuranyl, benzo[d]thiazolyl, benzothiadiazolyl, benzothiofuranyl, benzo[b][1,4]oxazinyl, phenanthro[3,4-b]furanyl, benzoxazolyl, benzoisoxazolyl, benzodioxinyl, benzopyranonyl, benzofurazanyl, benzothieno[3,2-b][1]benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,5]imidazo[1,2-a]pyrimidinyl, benzo[4,5]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, dibenzofuranyl, dibenzothiophen-yl, furanyl, furazanyl, furo[3,2- c]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, oxazolyl, oxatriazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl,pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4- d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, 1isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thienyl. “Heteroarylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from a heteroaryl group, as defined above. Divalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene. For a heteroaryl group (or heteroarylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, a heteroaryl group (or heteroarylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, hydroxamate, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), -OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, - N(R′)C(O)OR′, -N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -S(O)tR′ (where t is 1 or 2), -N(R′)C(NR′)N(R′)2, -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0054] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as, for example, pyridinyl N-oxides.

[0055] “Heteroarylalkyl” refers to a -(heteroaryl)alkyl radical where heteroaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl, respectively.

[0056] “Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring radical in which 1, 2, 3, 4, 5, or 6 carbon atoms of the ring system are replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur atom. The heterocycloalkyl groups maybe completely saturated or partially unsaturated. A numerical range may be given, e.g., 3- to 18-, 3- to 12-, 4- to 11-, 3- to 10-, 3- to 8-, 4- to 7-, 4- to 6-, 3- to 6-, or 3- to 5-membered heterocycloalkyl, which refers to the total number of ring atoms in the heterocycloalkyl ring system (inclusive of the one or more heteroatoms). Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range - e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. A heterocycloalkyl group can be a single ring (e.g., monocyclic heterocycloalkyl) or multiple rings (e.g., polycyclic heterocycloalkyl). Polycyclic heterocycloalkyl groups are composed of 2 or more rings (e.g., bicyclic, tricyclic or tetracyclic ring system) and include fused heterocycloalkyl, bridged heterocycloalkyl, and spiro heterocycloalkyl ring systems. “Heterocycloalkyl” also includes bicyclic, tricyclic, or tetracyclic heterocycloalkyl ring systems wherein one ring is either non-aromatic or aromatic, and another ring is not aromatic. In other words, for a bicyclic, tricyclic, or tetracyclic heterocycloalkyl ring system, if one ring is aromatic (e.g., aryl or heteroaryl), then the other ring(s) is / are not aromatic. For a bicyclic, tricyclic, or tetracyclic heterocycloalkyl ring system, one or all rings can have one or more heteroatoms. For a bicyclic, tricyclic or tetracyclic heterocycloalkyl ring system, one or all rings can be substituted and the like. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).

[0057] Examples of such heterocycloalkyl groups include, but are not limited to, azaspiro[2.2]pentyl, diazaspiro[2.2]pentyl, azaspiro[2.3]hexyl, diazaspiro[2.3]hexyl, diazaspiro[3.3]heptyl, azaspiro[3.3]heptyl, azaspiro[2.4]heptyl, diazaspiro[2.4]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, azaspiro[3.5]nonyl, diazaspiro[3.5]nonyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, azaspiro[5.5]undecyl, diazaspiro[5.5]undecyl, aziridinyl, azetidine, 1,4-benzodioxanyl, benzo[b][1,4]dioxepinyl, benzopyranyl, benzofuranonyl, benzodioxolyl, dioxolanyl, dioxa- tricyclo[3.3.1.03,7]nonyl, thienyl[1,3]dithianyl, 1,4-dihydrobenzotriazinyl, 1,4- dihydrobenzotriazinonyl, decahydroisoquinolyl, dihydroquinazolinonyl, dihydroisoquinolinonyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6- dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, furanonyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, imidazolinyl, imidazolidinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, isoxazol-3-one, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, morpholinyl, 1,6-naphthyridinonyl, octahydroindolyl, octahydroisoindolyl, oxabicyclo[3.1.1]heptyl, oxabicyclo[2.2.1]heptyl, oxabicyclo[3.2.1]octyl, oxabicyclo[2.2.2]octyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxetanyl, oxaspiro[2.2]pentyl, dioxaspiro[2.2]pentyl, oxaspiro[2.3]hexyl, dioxaspiro[2.3]hexyl, oxaspiro[3.3]heptyl, dioxaspiro[3.3]heptyl, oxaspiro[2.4]heptyl, dioxaspiro[2.4]heptyl, oxaspiro[3.4]octyl, dioxaspiro[3.4]octyl, oxaspiro[3.5]nonyl, dioxaspiro[3.5]nonyl, oxaspiro[4.4]nonyl, dioxaspiro[4.4]nonyl, oxaspiro[4.5]decyl, dioxaspiro[4.5]decyl, oxaspiro[5.5]undecyl, dioxaspiro[5.5]undecyl, oxazaspiro[2.2]pentyl, oxazaspiro[2.3]hexyl, oxazaspiro[2.4]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[3.4]octyl, oxazaspiro[3.5]nonyl, oxazaspiro[4.4]nonyl, oxazaspiro[4.5]decyl, oxazaspiro[5.5]undecyl, oxathianyl, 2-oxoazepinyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, piperidonyl, pyranyl, pyrrolidinyl, pyrrolidinonyl, pyrazolidinyl, quinuclidinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3- d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydrobenzazepinyl, tetrahydrobenzazepinonyl, tetrahydrobenzodiazepinyl, tetrahydrobenzodiazepinonyl, tetrahydrobenzoxazepinyl, tetrahydrobenzoxazepinonyl, tetrahydrobenzoxepinyl, tetrahydrobenzoxepinonyl, tetrahydrobenzodioxepinyl, tetrahydrobenzodioxepinonyl, tetrahydropyranyl, tetrahydrothienyl thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, thiapyranyl, thietanyl, and thiiranyl.

[0058] “Heterocycloalkylene,” alone or as part of another substituent, refers to a divalent radical derived from a heterocycloalkyl. For a heterocycloalkyl group (or heterocycloalkylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, a heterocycloalkyl group (or heterocycloalkylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, hydroxamate,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR′, -SR′, -S(O)tR′ (where t is 1 or 2), -OC(O)R′, -N(R′)2, -C(O)R′, -C(O)OR′, -OC(O)N(R′)2, -C(O)N(R′)2, -N(R′)C(O)OR′, -N(R′)C(O)R′, -N(R′)S(O)tR′ (where t is 1 or 2), -N(R′)C(O)N(R′)2, -S(O)tR′ (where t is 1 or 2), -N(R′)C(NR′)N(R′)2, -S(O)tOR′ (where t is 1 or 2), -S(O)tN(R′)2(where t is 1 or 2), or PO(OR′)2, where each R′ is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0059] “Heterocycloalkylalkyl” refers to a -(heterocycloalkyl)alkyl radical where heterocycloalkyl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl, respectively.

[0060] “Hydroxamate” refers to the –C(O)NRaORamoiety, where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0061] “Nitro” refers to the -NO2radical.

[0062] “Oxa” refers to the -O- radical.

[0063] “Oxo” refers to the =O radical.

[0064] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon is specified by either (R) or (S). Resolved compounds whose absolute configuration is unknown is designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of thecompounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that is defined, in terms of absolute stereochemistry, as (R) or (S). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers is prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0065] “Enantiomeric purity” as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%. The enantiomeric purity of a compound is determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0066] In some embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York(1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley- Interscience, New York (1994).

[0067] The terms “enantiomerically enriched” and “non-racemic,” as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the (S)-enantiomer, means a preparation of the compound having greater than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, such as for example, and without limitation, at least 75% by weight, at least 80% by weight, or the like. In some embodiments, the enrichment is significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non- racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, at least 95% by weight, or the like. The terms “enantiomerically pure” or “substantially enantiomerically pure” refer to compositions comprising at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0068] “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0069] “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers is reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4- hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0070] A “leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site.Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.

[0071] “Protecting group” is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction is carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).

[0072] “Solvate” refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.

[0073] “Substituted” means that the referenced group may have one or more hydrogen atoms replaced by one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, deuterium, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, pentafluorosulfanyl, urea, and amino, including mono- and di- substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituentsof organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds

[0074] “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S- (optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).

[0075] “Pentafluorosulfanyl” refers to the -SF5radical.

[0076] “Sulfinyl” refers to groups that include -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl).

[0077] “Sulfonyl” refers to groups that include -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)-(optionally substituted aryl), -S(O2)- (optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).

[0078] “Sulfonamidyl” or “sulfonamido” refers to a -S(=O)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). The R groups in -NRR of the -S(=O)2-NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0079] “Sulfoxyl” refers to a -S(=O)2OH radical.

[0080] “Sulfonate” refers to a -S(=O)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0081] The term “active pharmaceutical ingredient(s)” include the compounds of (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, that inhibit the activity of BETproteins, as described herein. The term “active pharmaceutical ingredient” may also include other additional compounds that inhibit the activity of BET proteins.

[0082] Compounds of the disclosure also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[0083] As used herein, the terms “administer,” “administration,” or “administering” refer to (1) providing, giving, dosing, and / or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and / or (2) putting into, taking or consuming by the mammal, according to the disclosure.

[0084] The terms “combination,” “pharmaceutical combination,” “co-administration,” “co- administering,” “administered in combination with,” “administering in combination with,” “simultaneous,” and “concurrent,” as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and / or their metabolites are present in the subject at the same time. Co-administration includes concurrent administration and sequential administration. The simultaneous administration of two or more separate compositions is an example of concurrent co-administration. Another example of concurrent co-administration is the administration of a single composition in which two or more active pharmaceutical ingredients are present. The administration of two or more separate compositions at different times is an example of sequential co-administration.

[0085] Generally, the terms “inhibit,” “inhibition,” “inhibiting,” “inhibitor activity” refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change relates to the decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and / or decreased expression) for the biological molecule. It is understood that for purposes of quantification, the terms “activity,” “inhibitory activity,” “biological activity,” “cellular activity,” “BET protein activity,”“BRD4 protein activity,” and the like, in the context of an inhibitory compound disclosed herein can be quantified in a variety of ways known in the art. As used herein, half maximal inhibitory concentration (IC50) refers to the amount of an inhibitory compound disclosed herein that achieves 50% inhibition of a maximal biological activity or response (e.g., BET protein activity, BRD4 protein activity, etc.). As used herein, half maximal effective concentration (EC50) refers to the amount of an inhibitory compound disclosed herein that elicits a dose-dependent response at 50% of maximal expression of a particular activity or response that is induced by the inhibitory compound.

[0086] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc., which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in target cells. The specific dose varies depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0087] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0088] As used herein, the terms “treat,” “treatment,” and / or “treating” may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and / or control the disease, disorder, pathological condition or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, “control” may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing thedisease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition). As used herein, the terms “prevent,” “preventing,” and / or “prevention” may refer to reducing the risk of developing a disease, disorder, or pathological condition.

[0089] The term “in vivo” refers to an event that takes place in a subject’s body.

[0090] The term “in vitro” refers to an event that takes places outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.

[0091] The terms “subject” and “patient” are used interchangeably herein to refer to a warm blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and / or conditions described herein.

[0092] “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and non-human animals without excessive toxicity, irritation, allergic response, or other adverse complications commensurate with a reasonable benefit / risk ratio.

[0093] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient(s), its use in the therapeutic compositions of the disclosure is contemplated.

[0094] The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts is formed with inorganic acids and organic acids. Preferred inorganic acids from which salts is derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts is derived include, for example,acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts is formed with inorganic and organic bases. Inorganic bases from which salts is derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts is derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term “cocrystal” refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.

[0095] Acid addition salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as well as organic acids such as acetic, citric, propionic, tartaric, glutamic, salicylic, oxalic, methanesulfonic, para- toluenesulfonic, succinic, and benzoic acid, and related inorganic and organic acids.

[0096] Base addition salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic compounds such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this disclosure thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.

[0097] In addition to pharmaceutically acceptable salts, other salts are included within the scope of this disclosure. They may serve as intermediates in the purification of the compounds,in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.

[0098] The pharmaceutically acceptable salts of compounds of the present disclosure can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, EA and the like. Mixtures of such solvates can also be prepared. The source of such solvates can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Such solvates are also within the scope of the present disclosure.

[0099] “Prodrug” is intended to describe a compound that may be converted under physiological conditions or by solvolysis to a biologically active pharmaceutical ingredient described herein. Thus, the term “prodrug” refers to a precursor of a biologically active pharmaceutical ingredient that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active pharmaceutical ingredient, for example, by hydrolysis. The prodrug compound often offers the advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier, Amsterdam). The term “prodrug” is also intended to include any covalently bonded carriers, which release the active pharmaceutical ingredient in vivo when administered to a subject. Prodrugs of an active pharmaceutical ingredient, as described herein, may be prepared by modifying functional groups present in the active pharmaceutical ingredient in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the active pharmaceutical ingredient. Prodrugs include, for example, compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active pharmaceutical ingredient is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetates, formates and benzoate derivatives of an alcohol, various ester derivatives of a carboxylic acid, or acetamide, formamide and benzamide derivatives of an amine functional group in the active pharmaceutical ingredient.

[0100] Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium,or wherein one or more carbon atoms is replaced by13C- or14C-enriched carbons, are within the scope of this disclosure.

[0101] As will be apparent to anyone skilled in the art, the compounds of the present disclosure may have one or more chiral centers, and in that case, exist in various stereoisomeric forms. The compounds of the present disclosure encompass all such optical isomers, diastereomers and enantiomers. The compounds are normally prepared as a racemic mixture or racemate and can conveniently be used as such, but individual enantiomers can be isolated or synthesized by conventional techniques if so desired. Such racemates and individual enantiomers and mixtures thereof form part of the present disclosure.

[0102] It is well known in the art how to prepare and isolate such optically active forms from a mixture of enantiomers. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as resolution of racemic forms, normal, reverse-phase, and chiral chromatography, recrystallization, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994, and Jacques, J, et al. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, each incorporated by reference herein in their entireties.

[0103] For the avoidance of doubt, it is intended herein that particular features (for example integers, characteristics, values, uses, diseases, formulae, compounds or groups) described in conjunction with a particular aspect, embodiment or example of the disclosure are to be understood as applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Thus such features may be used where appropriate in conjunction with any of the definition, claims or embodiments defined herein. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and / or steps are mutually exclusive. The disclosure is not restricted to any details of any disclosed embodiments. The disclosure extendsto any novel one, or novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. Compounds

[0104] In aspects, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:wherein in formula (I): X is a moiety comprising one or more groups selected from -NRa-, -S-, -S(O)-, -S(O)2-, -O-, C(O), -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)S-, -SC(O)-, -OC(O)S-, -SC(O)O-, -C(O)NRa-, -NRaC(O)-, -CRa=N-NRa-, -C(O)NRaSO2-, -SO2NRaC(O)-, -OC(O)NRa-, -NRaC(O)O-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; A1is N or CR5; A2 is N or CR6; A3 is N or CR8; R1is selected from optionally substituted C1-C6alkyl and optionally substituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C3-C6cycloalkyl, and optionally substituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety comprising one or more groups selected from C(O), -C(O)O-, -C(O)S-, -C(O)NRa-,-S(O)-, -S(O)2-, -C(O)NRaSO2-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene,optionally substituted heteroalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; R4is selected from -C(O)Ra, C(O)ORa, C(O)N(Ra)2, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; R5, R6, and R8are each independently selected from H, deuterium, halide, -CN, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, -OH, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; t is 1 or 2; R7is selected from -ORa, -C(O)Ra, C(O)ORa, C(O)N(Ra)2, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; and Rais independently at each occurrence selected from H, deuterium, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

[0105] In some embodiments, X is a moiety comprising one or more groups selected from - NRa-, -S-, -S(O)-, -S(O)2-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NRa-, -NRaC(O)-, - OC(O)NRa-, -NRaC(O)O-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene.

[0106] In some embodiments, R5, R6, and R8are each independently selected from H, deuterium, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, trimethylsilanyl, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -S(O)tN(Ra)2, -S(O)tORa, -P(O)(ORa)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted C1-C6alkoxy, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and t is 1 or 2.

[0107] In some embodiments, Rais independently at each occurrence selected from H, deuterium, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0108] In some embodiments, A1is N or CR5; A2 is N or CR6; and A3 is CR8.

[0109] In another aspect, the disclosure relates to a compound of formula (II), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:, wherein in formula (II): X is a moiety comprising one or more groups selected from -NRa-, -S-, -S(O)-, -S(O)2-, -O-, C(O), -C(O)NRa-, -NRaC(O)-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene; A1is N or CR5; A2is N or CR6; R1is selected from optionally substituted C1-C4alkyl and unsubstituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl;L is a bond or a moiety selected from -C(O)-, -C(O)NRa-, -S(O)-, -S(O)2-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heteroalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; R5, R6, and R8are each independently selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -S(O)tORa, -P(O)(ORa)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted C1-C6alkoxy, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; t is 1 or 2; R7is selected from -ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, deuterium, optionally substituted C1-C4alkyl, optionally substituted C1-C4haloalkyl, optionally substituted phenyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0110] In some embodiments, X is a moiety comprising one or more groups selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and unsubstituted heterocycloalkylene. In some embodiments, X is a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and unsubstituted heterocycloalkylene.

[0111] In some embodiments, X is a moiety comprising one or more groups selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted C1-C10 alkylene, optionally substituted C1-C10haloalkylene, optionally substituted C6-C10arylene, optionally substituted C3- C6 cycloalkylene, and unsubstituted 3- to 10-membered heterocycloalkylene. In some embodiments, X is a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted C1-C10alkylene, optionally substituted C1-C10haloalkylene, optionally substituted C6-C10arylene, optionally substituted C3-C6cycloalkylene, and unsubstituted 3- to 10-membered heterocycloalkylene. In some embodiments, X is a moiety selected from -C(O)-, -C(O)NRa-, - NRaC(O)-, optionally substituted C1-C6alkylene, optionally substituted C1-C6haloalkylene, optionally substituted C6-C10arylene, optionally substituted C3-C6cycloalkylene, and unsubstituted 3- to 6-membered heterocycloalkylene.

[0112] In some embodiments, X is selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, -C1-C4alkylene-C(O)-, -C(O)-C1-C4alkylene-, -C1-C4alkylene-C(O)NRa-, -C(O)NRa-C1-C4alkylene-, - C1-C4alkylene-NRaC(O)-, -NRaC(O)-C1-C4alkylene-, -C1-C4haloalkylene-C(O)-, -C1-C4haloalkylene-C(O)NRa-, -C1-C4haloalkylene-NRaC(O)-, -phenylene-C(O)-, -phenylene- C(O)NRa-, -phenylene-NRaC(O)-, -C3-C6cycloalkylene-C(O)-, -C3-C6cycloalkylene-C(O)NRa-, and -C3-C6cycloalkylene-NRaC(O)-; wherein alkylene, phenylene, and cycloalkylene are optionally substituted; and wherein Rais H or optionally substituted C1-C3alkyl. In some embodiments, X is selected from -C(O)NH-, -NHC(O)-, -C1-C3alkylene-C(O)NH-, -C(O)NH- C1-C3alkylene-, -C1-C3alkylene-NHC(O)-, -NHC(O)-C1-C3alkylene-, -C1-C3haloalkylene- C(O)NH-, -C1-C3haloalkylene-NHC(O)-, -phenylene-C(O)NH-, -phenylene-NHC(O)-, -C3-C5 cycloalkylene-C(O)NH-, and -C3-C5 cycloalkylene-NHC(O)-; wherein alkylene, phenylene, and cycloalkylene are optionally substituted.

[0113] In some embodiments, X is selected from -C(O)NH-, -NHC(O)-, -CH2-C(O)NH-, -C(O)NH-CH2-, -CH2-NHC(O)-, -CD2-C(O)NH-, -C(O)NH-CD2-, -CD2-NHC(O)-, -CF2- C(O)NH-, -C(O)NH-CF2-, and -CF2-NHC(O)-. In some embodiments, X is selected from -C(O)NH-, -NHC(O)-, -CH2-C(O)NH-, -CH2-NHC(O)-, -CD2-C(O)NH-, -CD2-NHC(O)-, -CF2- C(O)NH-, and -CF2-NHC(O)-. In some embodiments, X is selected from -NHC(O)-, -CH2- NHC(O)-, -CD2-NHC(O)-, and -CF2-NHC(O)-. In some embodiments, X is -CH2-NHC(O)-.

[0114] In some embodiments, L is a bond or a moiety selected from C(O), -S(O)2-, optionally substituted C1-C10 alkylene, optionally substituted C1-C10 haloalkylene, optionally substituted C6-C10arylene, and optionally substituted C3-C6cycloalkylene. In some embodiments, L is a bond or optionally substituted C1-C10 alkylene. In some embodiments, L is optionally substituted C1-C8 alkylene.

[0115] In some embodiments, R5, R6, and R8are each independently selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -S(O)tORa, optionally substituted C1-C6alkyl, unsubstituted C1- C6 haloalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C6alkoxy, unsubstituted 3- to 6-membered heteroalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; and t is 1 or 2.

[0116] In some embodiments, R5is selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -S(O)tORa, optionally substituted C1-C6alkyl, unsubstituted C1-C6haloalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C6alkoxy, unsubstituted 3- to 6-membered heteroalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; and t is 1 or 2.

[0117] In some embodiments, R6is selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -S(O)tORa, optionally substituted C1-C6alkyl, unsubstituted C1-C6haloalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C6alkoxy, unsubstituted 3- to 6-membered heteroalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; and t is 1 or 2.

[0118] In some embodiments, R7is selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -S(O)tORa, optionally substituted C1-C6alkyl, unsubstituted C1-C6haloalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C6alkoxy, unsubstituted 3- to 6-membered heteroalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; and t is 1 or 2.

[0119] In some embodiments, R5and R6are each independently selected from H, halide, - OH, -NO2, -ORa, -N(Ra)2, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl; and R8is selected from H, halide, -CN, -OH, -NO2, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, unsubstituted C3-C5 cycloalkyl, unsubstituted C1-C3alkoxy, and unsubstituted 3- to 5-membered heterocycloalkyl.

[0120] In some embodiments, R5is selected from H, halide, -OH, -NO2, -ORa, -N(Ra)2, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl. In some embodiments, R6is selected from H, halide, -OH, - NO2, -ORa, -N(Ra)2, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl. In some embodiments, R8is selected from H, halide, -CN, -OH, -NO2, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, unsubstituted C3-C5 cycloalkyl, unsubstituted C1-C3alkoxy, and unsubstituted 3- to 5-membered heterocycloalkyl.

[0121] In some embodiments, Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, optionally substituted phenyl, optionally substituted benzyl, unsubstituted C3-C6cycloalkyl, unsubstituted 3- to 6-membered heteroalkyl, unsubstituted 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocycloalkyl.

[0122] In another aspect, the disclosure relates to a compound of formula (III), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:, wherein in formula (III): W is a bond or a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted C1-C6alkylene, optionally substituted C1-C6haloalkylene, optionally substitutedC6-C10arylene, optionally substituted C3-C6cycloalkylene, and unsubstituted 3- to 6-membered heterocycloalkylene; X1is a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, and optionally substituted C1-C4alkylene; R1is selected from optionally substituted C1-C4alkyl and unsubstituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety selected from -C(O)-, optionally substituted C1-C6alkylene, optionally substituted C1-C6haloalkylene, and optionally substituted C3-C6cycloalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; R5and R6are each independently selected from H, halide, -OH, -ORa, -N(Ra)2, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, and unsubstituted C1-C4alkoxy; R8is selected from H, halide, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, unsubstituted C3-C5 cycloalkyl, and unsubstituted C1-C3alkoxy; R7is selected from-ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, optionally substituted phenyl, optionally substituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl.

[0123] In some embodiments, X1is a moiety selected from -C(O)-, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)-, -N(CH3)C(O)-, and unsubstituted C1-C4alkylene. In some embodiments, X1 is a moiety selected from -C(O)-, -C(O)NH-, -NHC(O)-, -N(CH3)C(O)-, and -CH2-. In some embodiments, X1is a moiety selected from -C(O)-, -C(O)NH-, and -NHC(O)-.

[0124] In some embodiments, W is a bond or a moiety selected from -C(O)NH-, optionally substituted C1-C4alkylene, optionally substituted C1-C4haloalkylene, optionally substituted phenylene, and unsubstituted C3-C6cycloalkylene. In some embodiments, W is a bond or a moiety selected from optionally substituted C1-C4alkylene, optionally substituted C1-C4haloalkylene, optionally substituted phenylene, and unsubstituted C3-C6cycloalkylene.

[0125] In another aspect, the disclosure relates to a compound of formula (IVa) or formula (IVb), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:

[0126] In some embodiments, R3is selected from H, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, unsubstituted C3-C5 cycloalkyl, and unsubstituted 4- to 6-membered heterocycloalkyl.

[0127] In some embodiments, R5and R6are each independently selected from H, halide, - ORa, -NHRa, unsubstituted C1-C4alkyl, optionally substituted phenyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl; and R8is selected from H, halide, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, and unsubstituted C1-C3alkoxy.

[0128] In some embodiments, R5is selected from H, halide, -ORa, -NHRa, unsubstituted C1- C4 alkyl, optionally substituted phenyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl. In some embodiments, R6is selected from H, halide, -ORa, -NHRa, unsubstituted C1-C4alkyl, optionally substituted phenyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl. In some embodiments, R8is selected from H, halide, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, and unsubstituted C1-C3alkoxy.

[0129] In some embodiments, Rais independently at each occurrence selected from H, -CH3, -CH2CH3, -CH2CH2CH3, optionally substituted phenyl, optionally substituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl.

[0130] In another aspect, the disclosure relates to a compound of formula (V), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:, wherein in formula (V): W is a bond or a moiety selected from optionally substituted C1-C4alkylene, optionally substituted C1-C3haloalkylene, optionally substituted phenylene, and unsubstituted C3-C6cycloalkylene; R1is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, deuterated methyl (-CD3), -CH2CH2OH, unsubstituted cyclopropyl, and unsubstituted cyclobutyl; R3is selected from H, optionally substituted C1-C3alkyl, unsubstituted C1-C4fluoroalkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted oxetane, unsubstituted azetidine, unsubstituted tetrahydrofuran, unsubstituted pyrrolidine, unsubstituted tetrahydropyran, and unsubstituted piperidine; L is a bond or a moiety selected from C(O), optionally substituted C1-C3alkylene, and unsubstituted C1-C3haloalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; R5and R6are each independently selected from H, halide, -ORa, -NHRa, unsubstituted C1-C4alkyl, optionally substituted phenyl, and unsubstituted C1-C3alkoxy; andR8is selected from H, halide, and unsubstituted C1-C3alkyl; R7is selected from -ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, -CH3, optionally substituted phenyl, optionally substituted benzyl, and unsubstituted C3-C6cycloalkyl.

[0131] In some embodiments, W is a bond or a moiety selected from optionally substituted C1-C3alkylene, unsubstituted C1-C3haloalkylene, optionally substituted phenylene, and unsubstituted C3-C5cycloalkylene. In some embodiments, W is a bond or a moiety selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CD2-, -CD2CD2-, -CH2CD2-, -CD2CH2-, -CF2-, -CF2CF2-, -CH2CF2-, -CF2CH2-, optionally substituted phenylene, unsubstituted cyclopropylene, and unsubstituted cyclobutylene.

[0132] In some embodiments, Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted phenyl, unsubstituted benzyl, unsubstituted C3-C6cycloalkyl, unsubstituted 3- to 6-membered heteroalkyl, unsubstituted 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocycloalkyl. In some embodiments, Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, unsubstituted phenyl, unsubstituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl. In some embodiments, Rais independently at each occurrence selected from H, -CH3, -CH2CH3, -CH2CH2CH3, unsubstituted phenyl, unsubstituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl. In some embodiments, Rais independently at each occurrence selected from H, -CH3, unsubstituted phenyl, unsubstituted benzyl, and unsubstituted C3-C6cycloalkyl.

[0133] In some embodiments, R5is selected from H, Cl, F, Br, optionally substituted -O-phenyl, optionally substituted -NH-phenyl, -CH3, -CH2CH3, -CH2CH2CH3, optionally substituted phenyl, -OCH3, -OCH2CH3, and -OCH2CH2CH3. In some embodiments, R5is selected from H, Cl, F, Br, unsubstituted -O-phenyl, unsubstituted -NH-phenyl, -CH3, -CH2CH3, -CH2CH2CH3, unsubstituted phenyl, -OCH3, -OCH2CH3, and -OCH2CH2CH3. In someembodiments, R6is selected from H, Cl, F, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, and -OCH2CH3. In some embodiments, R8is H or halide.

[0134] In another aspect, the disclosure relates to a compound of formula (VIa) or formula (VIb), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof: formula (VIa) formula (VIb).

[0135] In some embodiments, W is a bond or a moiety selected from -CH2-, -CH2CH2-, -CD2-, -CF2CH2-, unsubstituted -CH2-phenylene, and unsubstituted cyclopropylene. In some embodiments, W is a bond or a moiety selected from -CH2-, -CH2CH2-, -CD2-, -CF2CH2-, , and . In some embodiments, W is a bond or a moiety selected from -CH2-, -CH2CH2-, -CD2-, -CF2CH2-, and . In some embodiments, W is a bond or a moiety selected from -CH2- and -CD2-. In some embodiments, W is -CH2-.

[0136] In some embodiments, R1is selected from -CH3, -CH2CH3, -CH(CH3)2, deuterated methyl (-CD3), -CH2CH2OH, and unsubstituted cyclopropyl. In some embodiments, R1is selected from -CH3, -CH2CH3, -CD3, and unsubstituted cyclopropyl. In some embodiments, R1is selected from -CH3, -CD3, and unsubstituted cyclopropyl. In some embodiments, R1is -CH3or -CD3. In some embodiments, R1is -CH3.

[0137] In some embodiments, R3is selected from H, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CFH2, -CF3, -CH2CHF2, unsubstituted benzyl, unsubstituted cyclopropyl, and unsubstituted oxetane. In some embodiments, R3is selected from -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CFH2, -CF3, -CH2CHF2, unsubstituted cyclopropyl, and unsubstituted oxetane. In someembodiments, R3is selected from -CH3, -CD3, -CF3, unsubstituted cyclopropyl, and unsubstituted oxetane. In some embodiments, R3is selected from -CH3, -CD3, and -CF3. In some embodiments, R3is -CH3.

[0138] In some embodiments, L is a bond or a moiety selected from -C(O)-, -CD2-, -CH2-, -CH2CH2-, and -CH(CH3)-. In some embodiments, L is -CD2- or -CH2-. In some embodiments, L is -CH2-.

[0139] In some embodiments, R4is selected from -C(O)NH2, optionally substituted C1-C4alkyl, optionally substituted C1-C3haloalkyl, optionally substituted phenyl, optionally substituted C3-C4cycloalkyl, optionally substituted 5- to 9-membered heteroaryl, and optionally substituted 4- to 7-membered heterocycloalkyl. In some embodiments, R4is selected from -C(O)NH2, optionally substituted C1-C4alkyl, C1-C3haloalkyl, optionally substituted phenyl, optionally substituted C3-C4 cycloalkyl, optionally substituted 5- to 9-membered heteroaryl, and optionally substituted 4- to 7-membered heterocycloalkyl. In some embodiments, R4is selected from -CH3, -CD3, -CF3, -CH2CH3, -CH2CF3, -CH2CH2CF3, -CH2CH2OH, -CH2CH2OCH3, optionally substituted phenyl, cyclopropyl, optionally substituted 5- to 9-membered heteroaryl, and optionally substituted 4- to 6-membered heterocycloalkyl.

[0140] In some embodiments, R4is selected from -CH3, -CD3, -CF3, -CH2CF3, -CH2CH2OH, phenyl, cyclopropyl, benzoxazolyl, benzotriazolyl, 1-methyl-benzotriazolyl, imidazolyl, indazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, 1-methyl-pyrrolyl, thiazolyl, and optionally substituted 4-membered heterocycloalkyl. In some embodiments, R4is selected from - CH3, -CD3, and optionally substituted 4-membered heterocycloalkyl. In some embodiments, R4is optionally substituted oxetanyl.

[0141] In some embodiments, R5is selected from H, unsubstituted phenyl, unsubstituted -O- phenyl, unsubstituted -NH-phenyl, -OCH3, and F. In some embodiments, R5is H or F. In some embodiments, R5is H. In some embodiments, R6is selected from H, -CH3, -OCH3, F, and Cl. In some embodiments, R6is selected from H, F, and Cl. In some embodiments, R6is H. In some embodiments, R8is selected from H and F. In some embodiments, R8is selected from H.

[0142] In some embodiments, R7is selected from -OH, unsubstituted C1-C6alkyl, unsubstituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C5cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 11-membered heterocycloalkyl. In some embodiments, R7is selected from -CH3, -CH2CF3, optionally substituted C6-C10aryl, optionally substituted C3-C5cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 11-membered heterocycloalkyl.

[0143] In some embodiments, R7is selected from -CH3, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 11-membered heterocycloalkyl. In some embodiments, R7is selected from -CH3, substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, and optionally substituted 4- to 9-membered heterocycloalkyl. In some embodiments, R7is -CH3or substituted phenyl.

[0144] In some embodiments, R7is phenyl substituted with one or more of the following substituents individually and independently selected from deuterium, -CH3, propyl, isopropyl, tert-butyl, -CF3, -OH, -CN, -F, -Cl, -Br, -SF5, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -C(O)CH3, 2, -N(CH3)2, -N(CH2CH3)2, 1-pyrazolyl, phenyl, phenoxy,some embodiments, R7is phenyl substituted with one to three of the following substituents individually and independently selected from deuterium, -CH3, -CF3, -OH, -CN, -F, -Cl, -Br, -SF5, -OCH3, -OCH2CH3, -OCF3, -NHS(O)2CH3, -NH2, -N(CH3)2, 1-pyrazolyl, phenyl, phenoxy,.

[0145] In some embodiments, R7is phenyl substituted with one or more of the following substituents individually and independently selected from deuterium, -CH3, -CF3, -OH, -CN, -F, -Cl, -Br, -OCH3, -OCH2CH3, -OCF3, -NHS(O)2CH3, -NH2, and -N(CH3)2. In some embodiments, R7is phenyl substituted with one to three of the following substituents individually and independently selected from deuterium, -CH3, -CF3, -OH, -F, -Cl, -Br, -OCH3, -OCH2CH3, -OCF3, and -NHS(O)2CH3. In some embodiments, R7is phenyl substituted with one to three of the following substituents individually and independently selected from deuterium, -CH3, -CF3, -OH, -F, -Cl, -Br, and -NHS(O)2CH3. In some embodiments, R7is phenyl substituted with one to three of the following substituents individually and independently selected from deuterium, -F, -Cl, -Br, and -NHS(O)2CH3. In some embodiments, R7is phenyl substituted with one to three ofthe following substituents individually and independently selected from deuterium, -F, -Cl, and -Br. In some embodiments, R7is phenyl substituted with one to three -F. In some embodiments, R7is 2-fluorophenyl.

[0146] Any combination of the groups described above for the variables of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), and formula (VIb), as defined and described herein, is contemplated herein, with the implicit proviso that such combination is in accordance with permitted valences of each specified group, variable, radical, or moiety. The combinations of specified groups, variables, radicals, or moieties of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), and formula (VIb), are limited generally to those which result in the formation of stable or chemically feasible compounds (i.e., compounds which do not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, fragmentation, degradation, etc.). For example, the combination of L and R4of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), and formula (VIb) results in a stable and chemically feasible -L-R4moiety; the combination of X and R7of formula (I) and formula (II) results in a stable and chemically feasible -X-R7moiety; the combination of X1and W of formula (III) results in a stable and chemically feasible -X1-W- moiety; and the combination of W and R7of formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), and formula (VIb) results in a stable and chemically feasible -W-R7moiety.

[0147] In some embodiments, the compound according to formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), and / or formula (VIb), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to any one of formula 1001-1595:

[0148] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a bromodomain and extra-terminal domain (BET) protein inhibitor.

[0149] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a BRD4 protein inhibitor.

[0150] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has a cellular activity of at least about 10 μM as measured by an in vitro cellular assay.

[0151] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has an IC50 of about 1 μM or less. In some embodiments, the compound of formula (I),formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, inhibits a BET protein with an IC50of about 1 μM or less. In some embodiments, the compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, inhibits BRD4 protein with an IC50of about 1 μM or less. Pharmaceutical Compositions

[0152] In one aspect, the disclosure provides a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium. In one embodiment, the disclosure provides a pharmaceutical composition comprising: a compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium. In one embodiment, the disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium.

[0153] In one embodiment, the disclosure provides a pharmaceutical composition comprising: a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium for use in the treatment of the diseases and conditions described herein. In one embodiment, the disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and aphysiologically compatible carrier medium for use in the treatment of the diseases and conditions described herein.

[0154] Each compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is effective over a wide dosage range. Accordingly, the amount or dose of the compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, provided in a pharmaceutical composition of the disclosure may range from 0.001 to 1000 mg. The exact amount or dose will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. The clinically-established dosages of the compound of the disclosure, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, may also be used if appropriate. Methods of Treatment

[0155] The compounds and pharmaceutical compositions described herein can be used in methods for treating diseases and / or disorders. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating an inflammatory disease or an autoimmune disease. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating a disease or disorder alleviated by inhibiting bromodomain and extra-terminal domain (BET) protein activity. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating a disease or disorder alleviated by inhibiting BRDT protein activity. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating a disease or disorder alleviated by inhibiting BRD2 protein activity. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating a disease or disorder alleviated by inhibiting BRD3 protein activity. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating a disease or disorder alleviated by inhibiting BRD4 protein activity. In some embodiments, the compounds and pharmaceutical compositions described herein can beused in methods for treating a disease or disorder alleviated by selectively inhibiting the second bromodomain (BD2) of the BRD4 protein.

[0156] In one aspect, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof. In another aspect, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising: (i) a compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and (ii) a physiologically compatible carrier medium.

[0157] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by inhibiting BET protein activity in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by inhibiting BRD4 protein activity in the patient.

[0158] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease or disorder isalleviated by inhibiting BET protein activity in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease or disorder is alleviated by inhibiting BRD4 protein activity in the patient.

[0159] In some embodiments, the compounds described herein inhibit BRD4 protein activity by selectively binding to the second bromodomain (BD2) of BRD4. Accordingly, in some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001- 1595), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by selectively inhibiting BD2 of the BRD4 protein in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g., a compound of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), or 1001-1595), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease or disorder is alleviated by selectively inhibiting BD2 of the BRD4 protein in the patient.

[0160] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is an inflammatory disease and / or an autoimmune disease. In some embodiments, the disease or disorder is selected from chronic or acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis (RA), cardiovascular disease, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, reactive arthritis, Reiter’s syndrome, gouty arthritis, psoriasis, erythrodermic psoriasis, pustular psoriasis, dermatitis,scleroderma, Raynaud’s syndrome, Sjögren’s syndrome, inflammatory bowel disease, intestinal fibrosis, Crohn’s disease, enteropathic arthritis, ulcerative colitis, colitis, diverticulitis, nephritis, urethritis, salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupus erythematosus, multiple sclerosis (MS), meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis, thrombophlebitis, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), inflammatory lung disease, allergic rhinitis, endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valve disease, rheumatic aortic valve disease, prostatitis, prostatocystitis, spondyloarthritis, ankylosing spondylitis, synovitis, tenosynovotis, myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis, bursitis, gout, pseudogout, vasculitides, granulomatous thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis, acute thyroiditis, Hashimoto’s disease, Kawasaki’s disease, neuroinflammatory disease, sepsis, conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis, lymphadenitis, nasopharyngitis, sinusitis, pharyngitis, tonsillitis, laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis, esophagitis, gastritis, peritonitis, hepatitis, cholelithiasis, cholecystitis, glomerulonephritis, Goodpasture syndrome, crescentic glomerulonephritis, pancreatitis, endometritis, myometritis, metritis, cervicitis, endocervicitis, exocervicitis, parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis, pneumoconiosis, hidradenitis suppurativa (HS), obesity, obesity-related inflammation, Still’s disease, systemic juvenile idiopathic arthritis (SJIA), adult-onset Still’s disease (AOSD), macrophage activation syndrome, and inflammatory polyarthritis.

[0161] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is selected from rheumatoid arthritis (RA), cardiovascular disease, multiple sclerosis (MS), osteoarthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa (HS), obesity-related inflammation, Still’s disease, systemic juvenile idiopathic arthritis (SJIA), adult-onset Still’s disease (AOSD), and macrophage activation syndrome.

[0162] In some embodiments, the patient or subject is a mammal. In an embodiment, the patient or subject is a human. In an embodiment, the patient or subject is a companion animal. In an embodiment, the patient or subject is a canine, feline, or equine.

[0163] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), or formula 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof is administered in a unit dosage form. Dosages and Dosing Regimens

[0164] The amounts of the compounds or pharmaceutical compositions administered using the methods described herein, such as the compounds of any one of formulae (I), (II), (III), (IVa), (IVb), (V), (VIa), (VIb), and 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, will be dependent on the human or mammal being treated, the severity of the disease or disorder, the rate of administration, the disposition of the active pharmaceutical ingredients, and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 600 mg per kg body weight per day.

[0165] An effective amount of the active pharmaceutical ingredients of formula (I), formula (II), formula (III), formula (IVa), formula (IVb), formula (V), formula (VIa), formula (VIb), and formula 1001-1595, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or pharmaceutical compositions thereof, may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0166] In embodiments, the compositions described herein further include controlled-release, sustained release, or extended-release therapeutic dosage forms for administration of the compounds described herein, which involves incorporation of the compounds into a suitable delivery system in the formation of certain compositions. This dosage form controls release of the compound(s) in such a manner that an effective concentration of the compound(s) in thebloodstream may be maintained over an extended period of time, with the concentration in the blood remaining relatively constant, to improve therapeutic results and / or minimize side effects. Additionally, a controlled-release system would provide minimum peak to trough fluctuations in blood plasma levels of the compound. EXAMPLES

[0167] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein. It should be appreciated by those of skill in the art that the techniques disclosed in the following examples represent approaches that have been found to function well in the practice of the disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are described herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure. List of Abbreviations

[0168] In the accompanying procedures and schemes, abbreviations are used with the following meanings unless otherwise indicated: ACN = acetonitrile; AIBN = 2-[(1E)-2-(1- cyano-1-methylethyl)diazen-1-yl]-2-methylpropanenitrile; AlLiH4= lithium aluminum hydride; BINAP = 2,2'-bis(diphenylphosphaneyl)-1,1'-binaphthalene; Boc = tert-butyloxycarbonyl; BrettPhos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′- biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate methanesulfonate; cataCXium® A = di(1-adamantyl)-n-butylphosphine; cataCXium® A Pd G2 = chloro[(di(1- adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II); DAST = diethylaminosulfur trifluoride; DCM = dichloromethane; DCE = dichloroethane; Dess-Martin periodinane = 3-oxo- 1λ5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate; DIBAL = diisobutylaluminium hydride; DIPEA = ethylbis(propan-2-yl)amine; DMAc – N,N-dimethylacetamide; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EA = ethyl acetate; FA = formic acid; h, hr, hrs = hour(s); HATU = 1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HFP = 1,1,1,3,3,3-hexafluoropropan-2-ol; HPLC = high-performance liquid chromatography; [Ir[dF(CF3)ppy]2(dtbbpy)]PF6 = (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl]phenyl]iridium(III) hexafluorophosphate; LCMS = liquid chromatography-mass spectrometry; mCPBA = m-chloroperoxybenzoic acid; MeOH = methanol; min = minutes; MPLC = medium pressure liquid chromatography; MsCl = methanesulfonyl chloride; NaBH3CN = sodium cyanoborohydride; NBS = N-bromosuccinimide; NMR = nuclear magnetic resonance; Pd2(dba)3= tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 = 1,1'-bis(diphenylphosphino)ferrocene-palladium(II); Pd(dppf)Cl2·CH2Cl2 = 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex; Pd(TFA)2= trifluoroacetic acid palladium(II) salt; PE = petroleum ether; Prep-HPLC = preparative high- performance liquid chromatography; Ruphos = dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]- 2-yl)phosphane; RuPhos Pd G2 = chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); RuPhos Pd G3 = (2-dicyclohexylphosphino- 2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; SEM = 2-(trimethylsilyl)ethoxymethyl; S-Phos = 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl; (S)-segphos = (S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole; TBAB = tetrabutylammonium bromide; TBAF = tetrabutylammonium fluoride; TBDMS-Cl = tert-butyldimethylsilyl chloride; tBuXPhos Pd G3 = [(2-di-tert-butylphosphino-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TIPSCl = triisopropylsilyl chloride; TLC = thin layer chromatography; Xantphos = 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene; XPhos = dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane; and (4,4′-dtbbpy)NiCl2= [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine]nickel(II) dichloride. Example 1: Preparation of BET inhibitors.

[0169] The following example describes the preparation of compounds 1001-1492.

[0170] Compound names were generated using ChemDraw – version 22.2.0. To the extent that there are discrepancies between the name of a compound and its depicted structure, the depicted chemical structure is to be taken as the appropriate compound. The described general procedures may vary in duration and temperature of the reaction for the compounds described under that general procedure.General Procedure 1 Scheme 1. Synthesis of (R)-N-benzyl-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1001)

[0171] Step 1: Synthesis of methyl (R)-4-((1-methoxy-1-oxopropan-2-yl)amino)-3- nitrobenzoate.

[0172] To a mixture of methyl 4-fluoro-3-nitrobenzoate (5 g, 25.1 mmol) in ACN (70 mL) was added (R)-methyl 2-aminopropanoate hydrochloride (3.86 g, 27.6 mmol) and TEA (7.62 g, 75.3 mmol), then it was stirred at 80°C for 16 hours. Solvent of the reaction mixture was concentrated to get crude product which was purified by flash chromatography (PE / EA=10 / 1) to afford methyl (R)-4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate. LCMS (ESI) m / z = 283 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.69-8.59 (m, 2H), 7.99 (M, 1H), 7.12 (d, 1H), 4.78-4.70 (m, 1H), 3.84 (m, 3H), 3.74 (m, 3H), 1.51 (m, 3H).

[0173] Step 2: Synthesis of methyl (R)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate.

[0174] To a mixture of methyl (R)-4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate (6.2 g, 22 mmol) in MeOH (80 mL) was added palladium (1 g), then it was stirred at room temperature for 16 hours under H2atmosphere. The reaction mixture was filtered and the filter cake was washed with DCM (60 mL * 3). The filtrate was concentrated to afford methyl (R)-2- methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate. LCMS (ESI) m / z = 221 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.37 (m, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 6.83 (m, 1H), 6.68 (m, 1H), 3.95 (m, 1H), 3.75 (m, 3H), 1.28 (m, 3H).

[0175] Step 3: Synthesis of methyl (R)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate

[0176] To a solution of methyl (R)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate (3.4 g, 15.4 mmol) in DMF (15 mL) was added 60% sodium hydride (556 mg, 13.9 mmol). Then the mixture was stirred at 0oC for 30 min and added iodomethane (3.29 g, 23.2 mmol). After that, then the reaction mixture was stirred at 25oC for 1h. The mixture was added water and extracted with DCM, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to get crude product which was purified by flash chromatography (PE / EA=5 / 1) to afford methyl (R)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate. LCMS (ESI) m / z = 235 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 7.52 (m, 1H), 7.44 (m, 1H), 6.94 (m, 1H), 6.76 (m, 1H), 4.02 (m, 1H), 3.78 (m, 3H), 3.28 (m, 3H), 1.29 (m, 3H).

[0177] Step 4: Synthesis of methyl (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylate

[0178] To a mixture of methyl (R)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate (1.8 g, 7.68 mmol) in DMF (15 mL) was added 60% sodium hydride (461 mg, 11.5 mmol). Then the mixture was stirred at 0oC for 30 min and added 3-(bromomethyl)oxetane (1.74 g, 11.5 mmol). After that, then the reaction mixture was stirred at 25oC for 1h. To the mixture was added water and extracted with DCM, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to get crude product which was purified by flash chromatography (PE / EA=5 / 1) to afford methyl (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxylate. LCMS (ESI) m / z = 305 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 7.73 (m, 1H), 7.61 (m, 1H), 6.68 (m, 1H), 4.84 (m, 2H), 4.41 (m, 2H), 4.01 (m, 1H), 3.88 (m, 3H), 3.80 (m, 1H), 3.46 (m, 1H), 3.41 (m, 3H), 3.34 (m, 1H), 1.14 (m, 3H).

[0179] Step 5: Synthesis of (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid

[0180] To a solution of methyl (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylate (1.5 g, 4.93 mmol) in THF / MeOH / H2O (30 mL) was added lithium hydroxide (354 mg, 14.8 mmol). Then the reaction mixture was stirred at room temperature for 16h. The solvent was removed by vacuum to get crude, the crude was added 1N HCl solution adjusted pH=2-3 and extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to get (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid. LCMS (ESI) m / z = 291 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.48 (m, 1H), 7.60 (m, 1H), 7.50 (m, 1H), 6.87 (m, 1H), 4.63 (m, 2H), 4.35 (m, 1H), 4.34 (m, 1H), 4.11 (m, 1H), 3.76 (m, 1H), 3.48 (m, 1H), 3.34(m, 1H), 3.30 (m, 3H), 1.00 (m, 3H).

[0181] Step 6: Synthesis of (R)-N-benzyl-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1001)

[0182] To a solution of (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (0.6 g, 2.07 mmol) in DMF (10 mL) was added HATU (1.18 g, 3.1 mmol), DIPEA (534 mg, 4.13 mmol) and 1-phenylmethanamine (244 mg, 2.27 mmol). The reaction mixture was stirred at room temperature for 30 min. Then, the mixture was diluted with water and extracted with EA, the organic layer was dried over Na2SO4, filtered and isolated by flash chromatography (DCM / MeOH=50 / 1) to afford (R)-N-benzyl-2,4-dimethyl-1- (oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 380 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.88 (m, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.31 (m, 4H), 7.23 (m, 1H), 6.87 (m, 1H), 4.64 (m, 2H), 4.48 (m, 2H), 4.41 (m, 2H), 4.07 (m, 1H), 3.75 (m, 1H), 3.44 (m, 1H), 3.34 (m, 1H), 3.31 (m, 3H), 0.98 (m, 3H).

[0183] The following compounds were prepared according to general procedure and Scheme 1 provided above and using the appropriate intermediate(s) as starting materials and modifications described below. N-(2-fluorobenzyl)-2,4-dimethyl-1-(oxazol-4-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1002)

[0184] To prepare Compound 1002, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 4-(bromomethyl)-1,3-oxazole in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The productwas purified by a prep-HPLC. LCMS (ESI) m / z = 409.0 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 8.86 (t, J = 6.0 Hz, 1H), 8.42 - 8.33 (m, 1H), 8.13 (s, 1H), 7.62 - 7.56 (m, 2H), 7.33 - 7.27 (m, 1H), 7.33 - 7.27 (m, 1H), 7.21 - 7.14 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 4.58 - 4.49 (m, 3H), 4.33 - 4.27 (m, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.32 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H). N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1-(thiazol-4-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1003)

[0185] To prepare Compound 1003, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 4-(bromomethyl)-1,3-thiazole in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 425.0 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 9.10 (d, J = 2.0 Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.58 - 7.55 (m, 2H), 7.35 (dd, J = 8.4, 6.8 Hz, 1H), 7.29 (dd, J = 8.0, 5.6 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.16 - 7.13 (m, 1H), 6.94 - 6.91 (m, 1H), 4.81 - 4.75 (m, 1H), 4.55 - 4.49 (m, 3H), 4.10 (q, J = 6.8 Hz, 1H), 3.33 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H). N-(2-fluorobenzyl)-2,4-dimethyl-1-(oxazol-2-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1004)

[0186] To prepare Compound 1004, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 2-(bromomethyl)-1,3-oxazole in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The productwas purified by a prep-HPLC. LCMS (ESI) m / z = 409.2 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 8.87 (t, J = 6.0 Hz, 1H), 8.10 (d, J = 0.4 Hz, 1H), 7.61 – 7.55 (m, 2H), 7.37 – 7.27 (m, 2H), 7.21 – 7.14 (m, 3H), 6.93 (d, J = 9.2 Hz, 1H), 4.73 (dd, J = 52.0, 16.4 Hz, 2H), 4.51 (d, J = 6.0 Hz, 2H), 4.15 (q, J = 6.8 Hz, 1H), 3.34 (s, 3H), 1.04 (d, J = 6.8 Hz, 3H). 1-(4-methoxybenzyl)-N,2,4-trimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1005)

[0187] To prepare Compound 1005, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 1-(bromomethyl)-4-methoxybenzene in step 4; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 354 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.24 (q, J = 3.6 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 14.8 Hz, 1H), 4.22 (d, J = 14.8 Hz, 1H), 3.97 (q, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.33 (s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H). N-(2-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1006)

[0188] To prepare Compound 1006, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 1-bromo-2-methoxyethane in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product waspurified by a prep-HPLC. LCMS (ESI) m / z = 386.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.6 Hz, 1H), 7.65 – 7.53 (m, 2H), 7.38 – 7.26 (m, 2H), 7.20 - 7.18 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.51 (d, J = 3.6 Hz, 2H), 4.12 (q, J = 6.8 Hz, 1H), 3.67 – 3.58 (m, 1H), 3.56 – 3.48 (m, 2H), 3.35 (s, 1H), 3.32 (s, 3H), 3.26 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H). 1-benzyl-2,4-dimethyl-3-oxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1007)

[0189] To prepare Compound 1007, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with 1-(pyridin-4-yl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 401 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J = 6.0 Hz, 1H), 8.67 (d, J = 6.4 Hz, 2H), 7.63 (d, J = 5.2 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.29 – 7.25 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.67 (d, J = 15.2 Hz, 1H), 4.64 – 4.57 (m, 2H), 4.38 (d, J = 15.6 Hz, 1H), 4.11 – 4.05 (m, 1H), 3.36 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H). 1-benzyl-2,4-dimethyl-3-oxo-N-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1008)

[0190] To prepare Compound 1008, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with 1-(pyridin-3-yl)methanamine in step 6. The product waspurified by a prep-HPLC. LCMS (ESI) m / z = 401.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 5.6Hz, 1H), 8.59 (s, 1H), 8.51 (d, J = 3.2Hz, 1H), 7.83 (s, 1H), 7.56 (d, J = 1.6Hz, 1H), 7.53-7.48 (m, 1H), 7.46 (d, J = 4.8Hz, 1H), 7.34 (d, J = 4.4Hz, 4H), 7.27 (m, 1H), 6.77 (d, J = 8.8Hz, 1H), 4.66 (d, J = 15.6Hz, 1H), 4.49 (m, 1H), 4.36 (d, J = 15.6Hz, 1H), 4.06 (q, J = 6.8Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8Hz, 3H). 1-benzyl-2,4-dimethyl-3-oxo-N-(pyridazin-3-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1009)

[0191] To prepare Compound 1009, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with 1-(pyridazin-3-yl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 402.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.13 - 9.05 (m, 2H), 7.66 - 7.52 (m, 4H), 7.35 -7.24 (m, 5H), 6.78 (d, J = 8.4 Hz, 1H), 4.73 -4.70 (m, 2H), 4.66 (d, J = 15.6 Hz, 1H),4.36 (d, J = 15.2 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). 2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-N-(phenylmethyl-d2)-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1010)

[0192] To prepare Compound 1010, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with phenylmethan-d2-amine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 382.2 [M+H]+;1H NMR(400 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.61 (dd, J = 8.4, 1.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.35 -7.30 (m, 4H), 7.26 - 7.21 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.65 - 4.61 (m, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 13.6, 6.4 Hz, 1H), 3.44 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 4H), 0.98 (d, J = 6.8 Hz, 3H). 2-cyclopropyl-N-(2,4-difluorobenzyl)-4-methyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1011)

[0193] To prepare Compound 1011, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-amino-2- cyclopropylacetate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2,4- difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 442.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 5.6 Hz, 1H), 7.65 – 7.53 (m, 2H), 7.43 – 7.37 (m, 1H), 7.27 – 7.19 (m, 1H), 7.06 (td, J = 8.4, 2.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.65 – 4.56 (m, 2H), 4.48 (t, J = 7.6 Hz, 2H), 4.32 (t, J = 6.0 Hz, 1H), 4.26 (t, J = 6.0 Hz, 1H), 3.90 – 3.85 (m, 1H), 3.63 – 3.57 (m, 1H), 3.48 (d, J = 8.8 Hz, 1H), 3.32 (s, 3H), 3.32 – 3.25 (m, 1H), 0.72 – 0.65 (m, 1H), 0.58 – 0.52 (m, 1H), 0.47 – 0.37 (m, 1H), 0.36 – 0.26 (m, 2H). 1-benzyl-2,4-dimethyl-3-oxo-N-(pyrimidin-4-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1012)

[0194] To prepare Compound 1012, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with 1-(pyrimidin-4-yl)methanamine in step 6. The product waspurified by a prep-HPLC. LCMS (ESI) m / z = 402 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.2 Hz, 1H), 9.01 (t, J = 6.0 Hz, 1H), 8.71 (d, J = 5.2 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (dd, J = 5.2, 0.8 Hz, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.30 - 7.26 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 15.2 Hz, 1H), 4.52 (dd, J = 5.6, 2.4 Hz, 2H), 4.37 (d, J = 15.2 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.36 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H). 1-benzyl-2,4-dimethyl-3-oxo-N-(pyridazin-4-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1013)

[0195] To prepare Compound 1013, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with pyridazin-4-ylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 402 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.14 (d, J = 5.2Hz, 1H), 8.99 (t, J = 5.6Hz, 1H), 7.55 (m, 3H), 7.35 (d, J = 4.4Hz, 4H), 7.3-7.1 (m, 1H), 6.78 (d, J = 8.4Hz, 1H), 4.67 (d, J = 15.2Hz, 1H), 4.51 (d, J = 5.6Hz, 2H), 4.37 (d, J = 15.2Hz, 1H), 4.07 (q, J = 6.8Hz, 1H), 3.36 (s, 3H), 1.07 (d, J = 6.8Hz, 3H). N-((1,3,4-oxadiazol-2-yl)methyl)-1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1014)

[0196] To prepare Compound 1014, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with (1,3,4-oxadiazol-2-yl)methanamine in step 6. The productwas purified by a prep-HPLC. LCMS (ESI) m / z = 392.1 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 10.93 (s, 1H), 7.42-7.27 (m, 7H), 7.19 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.68 (d, J = 15.6 Hz, 1H), 4.40 (d, J = 15.2 Hz, 1H), 4.14-4.08 (m, 3H), 3.35 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H). 1-benzyl-N-(isoxazol-3-ylmethyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1015)

[0197] To prepare Compound 1015, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with isoxazol-3-ylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 391 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J = 6.0 Hz, 1H), 8.82 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.30 - 7.26 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 1.6 Hz, 1H), 4.66 (d, J = 15.2 Hz, 1H), 4.52 (dd, J = 6.0, 2.0 Hz, 2H), 4.36 (d, J = 15.2 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). 1-benzyl-2,4-dimethyl-N-(oxazol-5-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1016)

[0198] To prepare Compound 1016, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with oxazol-5-ylmethanamine in step 6. The product waspurified by a prep-HPLC. LCMS (ESI) m / z = 391 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.28 (s, 1H), 7.55 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.35-7.33 (m, 3H), 7.29-7.27 (m, 1H), 7.03 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.66 (s, J = 15.2 Hz, 1H), 4.52 (s, 2H), 4.35 (d, J = 15.2 Hz, 1H), 4.05 (q, J = 6.7 Hz, 1H), 3.38 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H). 1-benzyl-N-(cyclopropylmethyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1017)

[0199] To prepare Compound 1017, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with cyclopropylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 364.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.6Hz, 1H), 7.53 (d, J = 1.6Hz, 1H), 7.5-7.3 (m, 1H), 7.35 (d, J = 4.4Hz, 4H), 7.3- 7.1 (m, 1H), 6.75 (d, J = 8.6Hz, 1H), 4.65 (d, J = 15.2Hz, 1H), 4.35 (d, J = 15.2Hz, 1H), 4.04 (q, J = 6.8Hz, 1H), 3.36 (s, 3H), 3.25-3.0 (m, 2H), 1.05 (d, J = 6.8Hz, 3H),1.01 (m, 1H), 0.41 (m, 2H), 0.21 (m, 2H). 1-benzyl-2,4-dimethyl-N-(oxazol-2-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1018)

[0200] To prepare Compound 1018, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with oxazol-2-ylmethanamine in step 6. The product waspurified by a prep-HPLC. LCMS (ESI) m / z = 391 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 5.8 Hz, 1H), 8.03 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.51 (d, J =1.6Hz,8.4 Hz, 1H), 7.35-7.26 (m, 5H), 7.15 (s, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.67 (d, J = 15.2 Hz, 1H), 4.60 - 4.52 (m, 2H), 4.36 (d, J = 15.2 Hz, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). 1-benzyl-N-(isoxazol-5-ylmethyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1019)

[0201] To prepare Compound 1019, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with isoxazol-5-ylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 391.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.97 (t, J = 6.0 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.30 – 7.24 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.33 (d, J = 1.6 Hz, 1H), 4.67 (d, J = 15.2 Hz, 1H), 4.60 (dd, J = 5.6, 2.4 Hz, 2H), 4.36 (d, J = 15.2 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). 1-((1H-pyrazol-3-yl)methyl)-N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1020)

[0202] To prepare Compound 1020, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 3-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6; and a subsequent SEM deprotection step. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 408 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.84 (t, J = 5.6 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.39 – 7.27 (m, 2H), 7.17 (dd, J = 15.2, 7.6 Hz, 2H), 7.00 (d, J = 6.4 Hz, 1H), 6.23 (s, 1H), 4.59 (d, J = 13.6 Hz, 1H), 4.51 (d, J = 4.8 Hz, 2H), 4.30 (d, J = 14.6 Hz, 1H), 4.00 (q, J = 6.8 Hz, 1H), 3.32 (s, 3H), 1.01 (d, J = 6.8 Hz, 3H). N,2,4-trimethyl-3-oxo-1-(thiazol-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1021)

[0203] To prepare Compound 1021, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 2-(bromomethyl)thiazole (which was prepared by a bromination of thiazol-2-ylmethanol through a process described in the common literature) in step 4; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 331.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.26 (q, J = 4.8 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 3.6 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.97 (d, J = 16.4 Hz, 1H), 4.77 (d, J = 16.4 Hz, 1H), 4.25 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 2.76 (d, J = 4.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H). N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1-(1-phenylethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1022)

[0204] To prepare Compound 1022, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (1-bromoethyl)benzene in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 432.20 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J = 6.0 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 8.4, 1.6 Hz, 1H), 7.38 – 7.34 (m, 1H), 7.33 – 7.32 (m, 2H), 7.32 – 7.30 (m, 2H), 7.30 – 7.22 (m, 2H), 7.20 – 7.14 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 5.06 (q, J = 6.8 Hz, 1H), 4.53 – 4.48 (m, 2H), 3.98 (q, J = 6.4 Hz, 1H), 3.31 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H). N-(2,4-difluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1023)

[0205] To prepare Compound 1023, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2,4- difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 416 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 6.0 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.44-7.36 (m, 1H), 7.27-7.17 (m, 1H), 7.10-7.02 (m, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.68-4.60 (m, 2H), 4.51-4.42 (m, 2H), 4.37-4.32 (m, 1H), 4.31-4.25 (m, 1H), 4.07 (q, J = 6.4 Hz, 1H), 3.81-3.70 (m, 1H), 3.48-3.41 (m, 1H), 3.31 (s, 3H), 3.30-3.27 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). N,2,4-trimethyl-3-oxo-1-(1-phenylethyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1024)

[0206] To prepare Compound 1024, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (1-bromoethyl)benzene in step 4; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 338.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.24 (dd, J = 8.4, 4.0 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 8.4, 1.6 Hz, 1H), 7.33 – 7.22 (m, 5H), 6.94 (d, J = 8.8 Hz, 1H), 5.03 (q, J = 7.2 Hz, 1H), 3.97 (q, J = 6.8 Hz, 1H), 3.30 (s, 3H), 2.76 (d, J = 4.8 Hz, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H). 1-((1H-pyrazol-3-yl)methyl)-N-(2,4-difluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1025)

[0207] To prepare Compound 1025, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 3-(bromomethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole in step 4; and replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6; and a subsequent SEM deprotection step. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 426 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.84 (t, J = 5.6 Hz, 1H), 7.69 (s, 1H), 7.59 – 7.53 (m, 2H), 7.40 (dd, J = 15.6, 8.8 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.04- 6.98 (m, 2H), 6.24 (d, J = 16.0 Hz, 1H), 4.62 (dd, J = 31.2, 16.4 Hz, 1H), 4.46 (d, J = 4.0 Hz, 2H), 4.29 (d, J = 14.4 Hz, 1H), 4.00 (q, J = 6.8 Hz, 1H), 3.32 (s, 3H), 1.01 (d, J = 6.8 Hz, 3H).1-((1H-pyrazol-3-yl)methyl)-N,2,4-trimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1026)

[0208] To prepare Compound 1026, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 3-(bromomethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole in step 4; and replacing 1-phenylmethanamine with methanamine in step 6; and a subsequent SEM deprotection step. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 314 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.25 (d, J = 4.4Hz, 1H), 7.68 (s, 1H), 7.49 (d, J = 6.0Hz, 2H), 6.97 (s, 1H), 6.23 (s, 1H), 4.58 (d, J = 14.4Hz, 1H), 4.28 (d, J = 14.8Hz, 1H), 3.98 (q, J = 6.8Hz, 1H), 3.31 (s, 3H), 2.77 (d, J = 4.4Hz, 3H), 1.00 (d, J = 6.8Hz, 3H). (R)-N-(2-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1027)

[0209] To prepare Compound 1027, the general procedure 1 of Scheme 1 was modified by replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was isolated by isolated by flash chromatography (DCM / MeOH=50 / 1) and purified by SFC. LCMS (ESI) m / z = 398 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 6.0 Hz, 1H), 7.61 (dd, J = 8.4, 1.2 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.38-7.27 (m, 2H), 7.21-7.13 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.68-4.60 (m, 2H), 4.51 (d, J = 5.6 Hz, 2H), 4.37-4.26 (m, 2H), 4.09-4.03 (m, 1H), 3.79-3.71 (m, 1H), 3.48-3.41 (m, 1H), 3.36-3.33 (m, 1H), 3.31 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H).N-((2-fluoropyridin-3-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1028)

[0210] To prepare Compound 1028, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-fluoropyridin-3- yl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 399 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 5.6 Hz, 1H), 8.13 (d, J = 4.4Hz, 1H), 7.86 - 7.77 (m, 1H), 7.61 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.33 - 7.26 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.64 - 4.58 (m, 2H), 4.48 (d, J = 5.6 Hz, 2H), 4.32 - 4.26 (m, 2H), 4.07 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.45 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 3H), 3.28 (dd, J = 9.2, 4.0 Hz, 1H), 0.98 (d, J = 6.8 Hz, 3H). N-(2-chloro-6-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1029)

[0211] To prepare Compound 1029, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-chloro-6- fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 432 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.59 (t, J = 4.8 Hz, 1H), 7.57 (dd, J = 8.4, 1.6 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.36 (dt, J = 14.8, 6.8 Hz, 2H), 7.27 – 7.19 (m, 1H), 4.68 – 4.54 (m, 4H), 4.31 - 4.23 (m, 2H), 4.09 – 4.01 (m, 1H), 3.78 – 3.69 (m, 1H), 3.43 (dd, J = 13.9, 8.4 Hz, 1H), 3.29 (s, 3H), 3.27 (s, 1H), 0.97 (d, J = 6.8 Hz, 3H).N-((3,5-difluoropyridin-2-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1030)

[0212] To prepare Compound 1030, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3,5-difluoropyridin-2- yl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 417 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 5.6 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.96 – 7.87 (m, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.68 – 4.57 (m, 4H), 4.31 - 4.23 (m, 2H), 4.06 (q, J = 6.8 Hz, 1H), 3.74 (dd, J = 13.6, 6.4 Hz, 1H), 3.44 (dd, J = 14.0, 8.4 Hz, 1H), 3.30 (s, 3H), 3.28 (s, 1H), 0.98 (d, J = 6.8 Hz, 3H). N-(2,6-difluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1031)

[0213] To prepare Compound 1031, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2,6- difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 416 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 5.2Hz, 1H), 7.56 (dd, J = 8.4, 1.6Hz, 1H), 7.50 (d, J = 1.6Hz, 1H), 7.39 - 7.33 (m, 1H), 7.08 (t, J = 8.0Hz, 2H), 6.83 (d, J = 8.4Hz, 1H), 4.67 – 4.59 (m, 2H), 4.51 (t, J = 4.8Hz, 2H), 4.31 - 4.26 (m, 2H), 4.05 (q, J = 6.8Hz, 1H), 3.77 – 3.65 (m, 1H), 3.43 (dd, J = 14.0, 8.4Hz, 1H), 3.29 (s, 3H), 3.28 – 3.25 (m, 1H), 0.96 (d, J = 6.8Hz, 3H).N-(2,5-difluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1032)

[0214] To prepare Compound 1032, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2,5- difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 416 [M+H]+;1H NMR (400 MHz, DMSO-d6) 8.90 (t, J = 6.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.30 – 7.22 (m, 1H), 7.14 - 7.06 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.64 - 6.58 (m, 2H), 4.49 (d, J = 5.6 Hz, 2H), 4.32 - 4.26 (m, 2H), 4.07 (q, J = 6.4 Hz, 1H), 3.76 (dd, J = 14.0, 6.0 Hz, 1H), 3.45 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 3H), 3.30 – 3.26 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). N-((3-fluoropyridin-2-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1033)

[0215] To prepare Compound 1033, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3-fluoropyridin-2- yl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 399.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.8 Hz, 1H), 8.37-7.36 (m,1H), 7.71 -7.66 (m, 1H), 7.61 -7.55 (m, 2H), 7.41 - 7.37 (m, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.66 - 4.59 (m, 4H), 4.35 -4.27 (m, 2H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 14.0, 6.0 Hz, 1H), 3.44 (dd, J = 13.6, 8.4 Hz, 1H), 3.30 -3.28 (m, 4H), 0.98 (d, J = 6.4 Hz, 3H).(R)-1-(4-methoxybenzyl)-N,2,4-trimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1034)

[0216] To prepare Compound 1034, the general procedure 1 of Scheme 1 was modified by replacing 3-(bromomethyl)oxetane with 1-(bromomethyl)-4-methoxybenzene in step 4; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC, followed by SFC separation [IH-30%D-2.5 column: DAICEL IH 4.6mmI.D.*250mmL 5µm; mobile Phase: CO2 / MEOH 0.1% NH3 (7M Solution in MeOH)]=70 / 30; oven: 400C; flow rate: 2.5ml / min]. LCMS (ESI) m / z = 354.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.23 (q, J = 3.6 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 14.8 Hz, 1H), 4.22 (d, J = 14.8 Hz, 1H), 3.97 (q, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.33 (s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H). N-(2-fluorobenzyl)-1-(3-methoxybenzyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1035)

[0217] To prepare Compound 1035, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 1-(bromomethyl)-3-methoxybenzene in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 448.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.83 (t, J = 6.0 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.37 –7.23 (m, 3H), 7.19 - 7.13 (m, 2H), 6.91 (d, J = 6.8 Hz, 2H), 6.87 – 6.82 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 15.6 Hz, 1H), 4.54 – 4.43 (m, 2H), 4.32 (d, J = 15.2 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.72 (s, 3H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). N-(2-fluorobenzyl)-1-(2-(hydroxymethyl)benzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1036)

[0218] To prepare Compound 1036, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with ((2-(bromomethyl)benzyl)oxy)(tert- butyl)dimethylsilane in step 4, followed by TBDMS deprotection in the subsequent step; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 448.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.83 (t, J = 5.6Hz, 1H), 7.59 (d, J = 2.0Hz, 1H), 7.53 (dd, J = 8.4, 1.6Hz, 1H), 7.46 – 7.43 (m, 1H), 7.37 – 7.33 (m, 1H), 7.31 – 7.26 (m, 3H), 7.22 – 7.15 (m, 3H), 6.78 (d, J = 8.4Hz, 1H), 5.11 (s, 1H), 4.77 (d, J = 15.6Hz, 1H), 4.58 – 4.55 (m, 2H), 4.50 (d, J = 5.2Hz, 2H), 4.32 (d, J = 15.6 Hz, 1H), 3.96 (q, J = 6.8Hz, 1H), 3.36 (s, 3H), 1.08 (d, J = 6.8Hz, 3H). N-(2,4-difluorobenzyl)-1-(2-(hydroxymethyl)benzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1037)

[0219] To prepare Compound 1037, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with ((2-(bromomethyl)benzyl)oxy)(tert- butyl)dimethylsilane in step 4, followed by TBDMS deprotection in the subsequent step; andreplacing 1-phenylmethanamine with (2.4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 466.0 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 8.83 (t, J = 5.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H), 7.46 – 7.43 (m, 1H), 7.41 – 7.36 (m, 1H), 7.29 – 7.25 (m, 2H), 7.24 – 7.19 (m, 2H), 7.07 – 7.02 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.56 (d, J = 0.8 Hz, 2H), 4.46 (d, J = 5.2 Hz, 2H), 4.32 (d, J = 15.6 Hz, 1H), 3.96 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H). 1-(2-(hydroxymethyl)benzyl)-N,2,4-trimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1038)

[0220] To prepare Compound 1038, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with ((2-(bromomethyl)benzyl)oxy)(tert- butyl)dimethylsilane in step 4, followed by TBDMS deprotection in the subsequent step; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 353.95 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 4.8Hz, 1H), 7.51 (d, J = 1.6Hz, 1H), 7.46 – 7.43 (m, 2H), 7.29 – 7.25 (m, 2H), 7.22 – 7.20 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.18 (s, 1H), 4.75 (d, J = 15.2Hz, 1H), 4.56 (s, 2H), 4.30 (d, J = 15.2Hz, 1H), 3.94 (q, J = 6.8Hz, 1H), 3.35 (s, 3H), 2.76 (d, J = 4.8Hz, 3H), 1.06 (d, J = 6.8Hz, 3H).N-(2-fluorobenzyl)-1-(3-(hydroxymethyl)benzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1039)

[0221] To prepare Compound 1039, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 1-(bromomethyl)-3-methoxybenzene in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 448.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J = 5.6 Hz, 1H), 7.60 – 7.51 (m, 2H), 7.37 – 7.27 (m, 4H), 7.23 – 7.13 (m, 4H), 6.78 (d, J = 8.4 Hz, 1H), 5.18 (t, J = 5.6 Hz, 1H), 4.65 (d, J = 15.2 Hz, 1H), 4.52 – 4.42 (m, 4H), 4.33 (d, J = 15.2 Hz, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). N-(2,4-difluorobenzyl)-1-(3-(hydroxymethyl)benzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1040)

[0222] To prepare Compound 1040, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 1-(bromomethyl)-3-methoxybenzene in step 4; and replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 466.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 7.57 – 7.49 (m, 2H), 7.40 - 7.31 (m, 1H), 7.31 - 7.28 (m, 2H), 7.22 (t, J = 7.2 Hz, 3H), 7.04 (t, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.18 (t, J = 5.6 Hz,1H), 4.64 (d, J = 15.2 Hz, 1H), 4.47 (d, J = 5.6 Hz, 4H), 4.33 (d, J = 15.2 Hz, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). 1-(3-(hydroxymethyl)benzyl)-N,2,4-trimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1041)

[0223] To prepare Compound 1041, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 1-(bromomethyl)-3-methoxybenzene in step 4; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 354.1[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 4.0 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.31 - 7.28 (m, 2H), 7.21 (d, J = 7.6 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 15.2 Hz, 1H), 4.47 (s, 2H), 4.31 (d, J = 15.2 Hz, 1H), 4.05 – 4.00 (m, 1H), 3.34 (s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H). 1-(benzo[d]oxazol-4-ylmethyl)-N,2,4-trimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1042)

[0224] To prepare Compound 1042, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 4-(bromomethyl)benzo[d]oxazole (which was synthesized according to the synthetic procedure described in Scheme 1a) in step 4; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by aprep-HPLC. LCMS (ESI) m / z = 365.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.21 (d, J = 4.4 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.49 (s, 1H), 7.43-7.34 (m, 3H), 6.82 (d, J = 8.4 Hz, 1H), 5.04-4.94 (m, 1H), 4.73-4.63 (m, 1H), 4.17 (q, J = 6.8 Hz, 1H), 3.33 (s, 3H), 2.75 (d, J = 4.4 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H). Scheme 1a. Synthesis of 4-(bromomethyl)benzo[d]oxazole

[0225] Step 1: Synthesis of 4-methylbenzo[d]oxazole

[0226] To a solution of 2-amino-3-methylphenol (2 g, 16.2 mmol) in triethyl orthoformate (20 mL) was stirred at 150℃ for 2 hours. Then the mixture was concentrated to get crude product which was purified by flash chromatography (PE / EA = 8 / 1, v / v) to afford 4- (bromomethyl)benzo[d]oxazole.1H NMR (400 MHz, Chloroform-D) δ 8.08 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 2.64 (s, 3H).

[0227] Step 2: Synthesis of 4-(bromomethyl)benzo[d]oxazole

[0228] To a solution of 4-(bromomethyl)benzo[d]oxazole (0.6 g, 4.51 mmol) in DCM (30 mL) was added NBS (882 mg, 4.96 mmol) and AIBN (74 mg, 0.451 mmol). After that, the reaction mixture was stirred at 65℃ for 10 hours under N2. The mixture was concentrated to get crude product which was purified by flash chromatography (PE / DCM = 5 / 1, v / v) to 4- (bromomethyl)benzo[d]oxazole.1H NMR (400 MHz, Chloroform-D) δ 8.16 (s, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.44-7.37 (m, 2H), 4.89 (s, 2H). 1-(benzo[d]oxazol-4-ylmethyl)-N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1043)

[0229] To prepare Compound 1043, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 4-(bromomethyl)benzo[d]oxazole (which was synthesized according to the synthetic procedure described in Scheme 1a) in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 459.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.97-8.71 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.4, 1.6 Hz, 1H), 7.41- 7.27 (m, 4H), 7.19-7.12 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.69 (d, J = 15.6 Hz, 1H), 4.54-4.44 (m, 2H), 4.20 (q, J = 6.8 Hz, 1H), 3.34 (s, 3H), 1.13 (d, J = 6.8 Hz, 3H). N-(2,4-difluorobenzyl)-2-ethyl-4-methyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1044)

[0230] To prepare Compound 1044, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminobutanoate in step 1; and replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 430.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.62 – 7.56 (m, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.25 – 7.19 (m, 1H), 7.08 – 7.03 (m, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.66 – 4.58 (m, 2H), 4.50 – 4.42 (m, 2H), 4.35 – 4.25 (m, 2H), 3.99 – 3.93 (m, 1H), 3.90 – 3.81 (m, 1H), 3.58 – 3.38 (m, 1H), 3.32 – 3.31 (m, 4H), 1.52 – 1.40 (m, 2H), 0.76 (t, J = 7.6 Hz, 3H). 2-ethyl-N-(2-fluorobenzyl)-4-methyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1045)

[0231] To prepare Compound 1045, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminobutanoate in step 1; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine amine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 412.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J = 6.0 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.37 – 7.28 (m, 2H), 7.20 – 7.15 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 4.66 – 4.58 (m, 2H), 4.51 (d, J = 4.4Hz, 2H), 4.36 – 4.24 (m, 2H), 3.99 – 3.83 (m, 2H), 3.58 – 3.48 (m, 1H), 3.32 (s, 3H), 3.30 – 3.27 (m, 1H), 1.55 – 1.47 (m, 1H), 1.43 – 1.35 (m, 1H), 0.76 (t, J = 7.2 Hz, 3H). N-(2,4-difluorobenzyl)-2,4-dimethyl-1-((3-methyloxetan-3-yl)methyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1046)

[0232] To prepare Compound 1046, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 3-(bromomethyl)-3-methyloxetanein in step 4; and replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 430.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.6 Hz, 1H), 7.60-7.55 (m, 2H), 7.44-7.38 (m, 1H), 7.25-7.18 (m, 1H), 7.08-7.02 (m, 1H), 6.93 (d, J = 9.2 Hz, 1H), 4.50-4.44 (m, 3H), 4.41-4.37 (m, 1H), 4.16- 4.11 (m, 2H), 3.90 (q, J = 6.8 Hz, 1H), 3.72-3.66 (m, 1H), 3.34 (s, 3H), 3.26-3.21 (m, 1H), 1.30 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H). N-(2-fluorobenzyl)-2,4-dimethyl-1-((3-methyloxetan-3-yl)methyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1047)

[0233] To prepare Compound 1047, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 3-(bromomethyl)-3-methyloxetanein in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 412.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 6.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.40-7.34 (m, 1H), 7.33-7.27 (m, 1H), 7.21-7.13 (m, 2H), 6.94 (d, J = 9.2 Hz, 1H), 4.56-4.49 (m, 2H), 4.49-4.46 (m, 1H), 4.42-4.37 (m, 1H), 4.17-4.11 (m, 2H), 3.90 (q, J = 6.8 Hz, 1H), 3.72-3.65 (m, 1H), 3.35 (s, 3H), 3.27-3.21 (m, 1H), 1.31 (s, 3H), 1.01 (d, J = 6.8 Hz, 3H). 1-((1H-indazol-4-yl)methyl)-N,2,4-trimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1048)

[0234] To prepare Compound 1048, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 4-(bromomethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indazole (which was synthesized according to the synthetic procedure described in Scheme 1b) in step 4, followed by the subsequent SEM deprotection stage; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 364.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.06 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.00 (d, J = 15.6 Hz, 1H), 4.63 (d, J = 15.6 Hz, 1H), 4.09 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 2.75 (d, J = 4.4 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H).Scheme 1b. Synthesis of 4-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0235] Step 1: Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0236] To methyl 1H-imidazole-4-carboxylate (2.0 g, 15.9 mmol) in DMF (10 mL) at 0 °C was added NaH (0.73 g, 30.5 mmol) dropwise. The reaction was warmed to 25 °C. After 30 mins, SEM-Cl (6.35 g, 38.1 mmol) was added to the mixture. The reaction was stirred overnight. Water (30 mL) was added to the solution. And then extract the mixture with EA (30 x 4). The organic layers were washed with brine (50 x 3) and were dried over Na2SO4, filtered and concentrated in vacuo to afford 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole.1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.57 – 7.43 (m, 2H), 7.56 – 7.46 (m, 2H), 5.90 (s, 2H), 3.64 (t, J = 8.0 Hz, 2H), 0.93 (d, J = 8.0 Hz, 2H), -0.00 (s, 9H).

[0237] Step 2: Synthesis of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4- carboxylate

[0238] To a solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.0 g, 6.11 mmol) in MeOH (24 mL) was added triethylamine (3 mL), and Pd(dppf)Cl2(0.671 g,0.917 mmol). Then the reaction mixture was stirred at 65oC for 16h under CO. To the reaction mixture was added water and extracted with DCM, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to get crude product which was purified by flash chromatography (EA:PE= 1;1) to afford 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4- carboxylate. LCMS (ESI) m / z = 307 [M+H]+.

[0239] Step 3: Synthesis of methyl (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4- yl)methanol

[0240] To mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylate (1.5 g, 4.89 mmol) in THF (20 mL) was added AlLiH4 (279 mg, 7.34 mmol) at 0oC. Upon the reaction completion, the mixture was diluted with water and extracted with EA (3 x 50 mL). The combined organic layers was washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by column chromatography toafford the desired product methyl (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4- yl)methanol.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.51 – 7.45 (m, 1H), 7.24 (d, J = 7.2 Hz, 1H), 5.85 (s, 2H), 5.46 (t, J = 5.6 Hz, 1H), 4.93 (d, J = 5.6 Hz, 2H), 3.66 – 3.58 (m, 2H), 0.93 – 0.85 (m, 2H), -0.00 (s, 9H).

[0241] Step 4: Synthesis of 4-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazole

[0242] To a solution of methyl (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4- yl)methanol (0.8 g, 2.87 mmol) in DCM (10 mL) was added tetrabromomethane (1.91 g, 5.75 mmol) at 0oC. Then the mixture was stirred at 0℃ for 10 min. To the reaction mixture was added triphenylphosphane (1.51 g, 5.75 mmol) at 0℃ and stirred at room temperature for 1 hours. The mixture was concentrated to get crude product which was purified by flash chromatography (PE / EA= 10 / 1, v / v) to afford 4-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazole.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.71 (dd, J = 8.4, 7.6 Hz, 1H), 5.96 (s, 2H), 4.08 (s, 2H), 3.66 – 3.62 (m, 2H), 0.94 – 0.90 (m, 2H), -0.00 (s, 9H). 1-((1H-indazol-4-yl)methyl)-N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1049)

[0243] To prepare Compound 1049, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 4-(bromomethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indazole (which was synthesized according to the synthetic procedure described in Scheme 1b) in step 4, followed by the subsequent SEM deprotection stage; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 458.1 [M+H]+;1H NMR (400 MHz,DMSO-d6) δ 13.14 (s, 1H), 8.82 (d, J = 5.6 Hz, 1H), 8.06 (s, 1H), 7.59 (s, 1H), 7.51 - 7.44 (m, 2H), 7.36 – 7.25 (m, 3H), 7.20 – 7.08 (m, 3H), 6.82 (d, J = 8.4 Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.65 (d, J = 15.2 Hz, 1H), 4.49 (s, 2H), 4.11 (d, J = 6.4 Hz, 1H), 3.36 (s, 3H), 1.10 (d, J = 6.4 Hz, 3H). 1-((1H-indazol-4-yl)methyl)-N-(2,4-difluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1050)

[0244] To prepare Compound 1050, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with 4-(bromomethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indazole (which was synthesized according to the synthetic procedure described in Scheme 1b) in step 4, followed by the subsequent SEM deprotection stage; and replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 476.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.82 (t, J = 5.6 Hz, 1H), 8.06 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.52 – 7.43 (m, 2H), 7.41 - 7.35 (m, 1H), 7.31 – 7.27 (m, 1H), 7.20 - 7.18 (m, 1H), 7.10 - 7.08 (m, 1H), 7.06 - 7.01 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.65 (d, J = 15.6 Hz, 1H), 4.49 – 4.40 (m, 2H), 4.10 (t, J = 6.8 Hz, 1H), 3.36 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H). N-((1H-indazol-5-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1051)

[0245] To prepare Compound 1051, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoatehydrochloride in step 1; and replacing 1-phenylmethanamine with (1H-indazol-5- yl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 420.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.02 (s, 1H), 7.63 (m, 2H), 7.57 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.64 (m, 2H), 4.57 (d, J = 5.6 Hz, 2H), 4.32 (m, 2H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 13.6, 6.0 Hz, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 3.31 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). 4-ethyl-N-(2-fluorobenzyl)-2-methyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1052)

[0246] To prepare Compound 1052, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; iodomethane with iodoethane in step 3; and replacing 1- phenylmethanamine with (2,fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 412 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J = 5.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.38-7.27 (m, 2H), 7.20-7.14 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.68-4.60 (m, 2H), 4.51 (d, J = 6.0 Hz, 2H), 4.36-4.27 (m, 2H), 4.07-3.97 (m, 2H), 3.91-3.82 (m, 1H), 3.77-3.70 (m, 1H), 3.48-3.41 (m, 1H), 3.37-3.32 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). (R)-N-(2-fluorobenzyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1053)

[0247] To prepare Compound 1053, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (2,fluorophenyl)methanamine in step 6. The product was isolated by flash chromatography(DCM / MeOH=50 / 1) and purified by SFC [instrument: SHIMADZU LC-30AD SFC; SFC Method: IC-40%D-2.5; column: DAICEL IC 4.6mm I.D.*250mmL 5µm; mobile Phase: CO2 / MEOH [0.1% NH3(7M Solution in MeOH)] = 60 / 40; flow rate:2.5ml / min]. LCMS (ESI) m / z = 401 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.37-7.29 (m, 2H), 7.20-7.15 (m, 2H), 6.87 (dd, J = 8.8, 3.2 Hz, 1H), 4.68-4.61 (m, 2H), 4.52 (s, 2H), 4.36-4.33 (m, 1H), 4.32-4.27 (m, 1H), 4.09-4.04 (m, 1H), 3.78-3.72 (m, 1H), 3.48- 3.42 (m, 1H), 3.32 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H). N-(3-hydroxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1054)

[0248] To prepare Compound 1054, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 3-(aminomethyl)phenol in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 396.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.83 (t, J = 6.0 Hz, 1H), 7.60 (m, 2H), 7.10 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.71 (m, 2H), 6.61 (d, J = 8.8 Hz, 1H), 4.64 (m, 2H), 4.34 (m, 4H), 4.07 (q, J = 6.4 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.45 (m, 1H), 3.31 (s, 3H), 2.68 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H). N-(4-hydroxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1055)

[0249] To prepare Compound 1055, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 4-(aminomethyl)phenol instep 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 396 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.76 (t, J = 6.0 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 4.68-4.60 (m, 2H), 4.37-4.27 (m, 4H), 4.06 (q, J = 6.8 Hz, 1H), 3.78-3.70 (m, 1H), 3.48- 3.41 (m, 1H), 3.35-3.32 (m, 1H), 3.30 (s, 3H), 0.97 (d, J = 6.8 Hz, 3H). N-(2-hydroxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1056)

[0250] To prepare Compound 1056, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 2-(aminomethyl)phenol in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 396.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.85 (s, 1H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.13 – 7.04 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 4.67 - 4.61 (m, 2H), 4.41 (d, J = 3.2 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.77 - 3.73 (m, 1H), 3.49 – 3.42 (m, 1H), 3.31 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). N-(3-cyanobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1057)

[0251] To prepare Compound 1057, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 3-(aminomethyl)benzonitrile in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 405.1 [M+H]+;1HNMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 6.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.59 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 4.64 (m, 2H), 4.52 (d, J = 5.6 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.4 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.45 (m, 1H), 3.34 (m, 1H), 3.31 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H). N-(4-methoxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1058)

[0252] To prepare Compound 1058, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (4- methoxyphenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 410.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.81 (t, J = 5.6Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.55 (s, 1H), 7.23 (d, J = 8.4Hz, 2H), 6.89 – 6.84 (m, 3H), 4.67 – 4.60 (m, 2H), 4.40 (d, J = 6.0Hz, 2H), 4.31 (dt, J = 22.4, 6.0Hz, 2H), 4.06 (q, J = 6.8Hz, 1H), 3.78 – 3.71 (m, 4H), 3.47 – 3.40 (m, 1H), 3.31 – 3.22 (m, 4H), 0.98 (d, J = 6.8 Hz, 3H). N-(3-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1059)

[0253] To prepare Compound 1059, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 398.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.92 (t, J = 6.0 Hz, 1H), 7.59 (m, 2H), 7.37 (dd, J = 14.0, 8.0 Hz, 1H), 7.10 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 4.64 (m, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.32 (m, 2H),4.07 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 14.0, 6.0 Hz, 1H), 3.45 (m, 1H), 3.34 (m, 1H), 3.31 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H). N-(4-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1060)

[0254] To prepare Compound 1060, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (4-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 398.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J = 6.0 Hz, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 8.4, 5.6 Hz, 2H), 7.18 – 7.11 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.67 - 4.61 (m, 2H), 4.45 (d, J = 6.0 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 13.6, 6.0 Hz, 1H), 3.44 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 3H), 0.97 (t, J = 7.6 Hz, 3H). 2,4-dimethyl-N-(2-methylbenzyl)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1061)

[0255] To prepare Compound 1061, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with o-tolylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 394 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.73 (t, J = 5.2Hz, 1H), 7.62 (d, J = 8.4Hz, 2H), 7.57 (s, 1H), 7.22 (d, J = 3.6Hz, 1H), 7.17 – 7.12 (m, 3H), 6.86 (d, J = 8.4Hz, 1H), 4.67 – 4.60 (m, 2H), 4.45 (d, J =5.6Hz, 2H), 4.32 (dt, J = 22.4, 5.2Hz, 2H), 4.06 (q, J = 6.4Hz, 1H), 3.78 – 3.70 (m, 1H), 3.48 – 3.41 (m, 1H), 3.31 – 3.25 (m, 4H), 2.32 (s, 3H), 0.98 (d, J = 6.4Hz, 3H). 2,4-dimethyl-N-(3-methylbenzyl)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1062)

[0256] To prepare Compound 1062, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with m-tolylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 394.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J = 6.0 Hz, 1H), 7.59 (m, 2H), 7.20 (m, 1H), 7.08 (m, 3H), 6.86 (d, J = 8.4 Hz, 1H), 4.64 (m, 2H), 4.44 (d, J = 5.6 Hz, 2H), 4.32 (m, 2H), 4.06 (q, J = 6.4 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.44 (dd, J = 13.6, 8.4 Hz, 1H), 3.35 (m, 1H), 3.31 (s, 3H), 2.28 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). 2,4-dimethyl-N-(4-methylbenzyl)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1063)

[0257] To prepare Compound 1063, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with p-tolylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 394.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.83 (t, J = 6.0 Hz, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.67 - 4.61 (m, 2H), 4.43 (d, J = 6.0 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8Hz, 1H), 3.74 (dd, J = 13.6, 6.0 Hz, 1H), 3.44 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 3H), 2.27 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). 2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-N-(3-(trifluoromethyl)benzyl)-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1064)

[0258] To prepare Compound 1064, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3- (trifluoromethyl)phenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 448.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 6.0Hz, 1H), 7.66 – 7.55 (m, 6H), 6.88 (d, J = 8.4Hz, 1H), 4.68 – 4.61 (m, 2H), 4.56 (d, J = 5.6Hz, 2H), 4.32 (dt, J = 22.4, 6.0Hz, 2H), 4.07 (q, J = 6.8Hz, 1H), 3.79 – 3.72 (m, 1H), 3.49 – 3.42 (m, 1H), 3.32 – 3.26 (m, 4H), 0.99 (d, J = 6.8Hz, 3H). N-(4-chlorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1065)

[0259] To prepare Compound 1065, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (4-chlorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 414.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J = 6.0 Hz, 1H), 7.58 (m, 2H), 7.36 (dd, J = 23.2, 8.4 Hz, 4H), 6.87 (d, J = 8.8 Hz, 1H), 4.64 (m, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.32 (m, 2H), 4.07 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.45 (m, 1H), 3.35 (m, 1H), 3.31 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H).N-(3-chlorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1066)

[0260] To prepare Compound 1066, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3-chlorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 414.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 6.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.29 (t, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.67 - 4.61 (m, 2H), 4.47 (d, J = 6.0 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.78 - 3.73 m, 1H), 3.48 - 3.42 (m, 1H), 3.31 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H). N-(2-chlorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1067)

[0261] To prepare Compound 1067, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-chlorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 414 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J = 5.6 Hz, 1H), 7.63 (dd, J = 8.4, 1.6 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.35-7.27 (m, 3H), 6.88 (d, J = 8.4 Hz, 1H), 4.69-4.61 (m, 2H), 4.57-4.51 (m, 2H), 4.37-4.27 (m, 2H), 4.08 (q, J = 6.8 Hz, 1H), 3.80-3.72 (m, 1H), 3.50-3.42 (m, 1H), 3.34-3.32 (m, 1H), 3.31 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H).N-(2-bromobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1068)

[0262] To prepare Compound 1068, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-bromophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 459.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J = 6.0 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 10.8, 4.0 Hz, 1H), 7.31 (dd, J = 7.6, 1.6 Hz, 1H), 7.21 (td, J = 7.6, 1.6 Hz, 1H), 4.67 - 4.61 (m, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.30 (t, J = 6.0 Hz, 1H), 4.08 (q, J = 6.8 Hz, 1H), 3.76 (dd, J = 13.6, 6.0 Hz, 1H), 3.49 - 3.43 (m, 1H), 3.32 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H). N-(4-bromobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1069)

[0263] To prepare Compound 1069, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (4-bromophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 460.05 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J = 6.0Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 8.4Hz, 2H), 7.27 (d, J = 8.4Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.67 – 4.61 (m, 2H), 4.44 (d, J = 6.0Hz, 2H), 4.32 (dt, J = 22.4, 6.0Hz, 2H), 4.07 (q, J = 6.8Hz, 1H), 3.78 – 3.72 (m, 1H), 3.48 – 3.42 (m, 1H), 3.31 – 3.27 (m, 4H), 0.98 (d, J = 6.8Hz, 3H).N-(3-bromobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1070)

[0264] To prepare Compound 1070, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3-bromophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 458 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.92 (t, J = 6.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.49 (s, 1H), 7.46-7.42 (m, 1H), 7.33-7.27 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.68-4.60 (m, 2H), 4.49-4.43 (m, 2H), 4.36-4.27 (m, 2H), 4.07 (q, J = 6.8 Hz, 1H), 3.80-3.72 (m, 1H), 3.49-3.41 (m, 1H), 3.34-3.32 (m, 1H), 3.31 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H). N-(3-isopropylbenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1071)

[0265] To prepare Compound 1071, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3- isopropylphenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 422 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.26-7.21 (m, 1H), 7.18 (s, 1H), 7.13-7.08 (d, J = 7.6 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.67-4.60 (m, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.36-4.27 (m, 2H), 4.06 (q, J = 6.8 Hz, 1H), 3.78-3.71 (m, 1H), 3.48-3.41 (m, 1H), 3.35-3.32 (m, 1H), 3.31 (s, 3H), 2.89-2.83 (m, 1H), 1.19 (d, J = 7.2 Hz, 6H), 0.98 (d, J = 6.8 Hz, 3H).N-(3-aminobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1072)

[0266] To prepare Compound 1072, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 3-(aminomethyl)aniline in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 395.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.76 (t, J = 6.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 6.46 – 6.40 (m, 2H), 5.01 (s, 2H), 4.65 - 4.61 (m, 2H), 4.39 – 4.31 (m, 3H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.47 - 3.41 (m, 1H), 3.31 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). N-(2-aminobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1073)

[0267] To prepare Compound 1073, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 2-(aminomethyl)aniline in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 395.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.75 (t, J = 6.0 Hz, 1H), 7.58 (m, 2H), 7.03 (d, J = 6.4 Hz, 1H), 6.95 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.50 (t, J = 7.6 Hz, 1H), 5.17 (s, 2H), 4.64 (m, 2H), 4.31 (m, 4H), 4.06 (q, J = 6.4 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 3.31 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H).(R)-N-(2-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl-d2)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1074)

[0268] To prepare Compound 1074, the general procedure 1 of Scheme 1 was modified by replacing 3-(bromomethyl)oxetane with oxetan-3-ylmethyl-d24-methylbenzenesulfonate (which was synthesized according to the synthetic procedure described in Scheme 1c) in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was isolated by flash chromatography (DCM / MeOH=50 / 1) and purified by a SFC. LCMS (ESI) m / z = 400 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.6 Hz, 1H), 7.61 (dd, J = 8.4, 1.2 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.38-7.27 (m, 2H), 7.21-7.14 (m, 2H), 6.87 (d, J = 8.8 Hz, 1H), 4.67-4.60 (m, 2H), 4.54-4.47 (m, 2H), 4.37-4.32 (m, 1H), 4.30-4.27 (m, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.31 (s, 3H), 3.30-3.27 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). Scheme 1c. Synthesis of oxetan-3-ylmethyl-d24-methylbenzenesulfonate

[0269] Step 1: Synthesis of oxetan-3-ylmethan-d2-ol

[0270] To a solution of oxetane-3-carboxylic acid (7 g, 68.6 mmol) in THF (50 mL) was added AlLiD4 (5.76 g, 137 mmol) at 0oC. Then the reaction mixture was stirred at 25oC for 2h. The mixture was quenched with D2O, concentrated to get crude product which was purified by flash chromatography (DCM / MeOH=30 / 1) to afford (oxetan-3-ylmethan-d2-ol.1H NMR (400 MHz, Chloroform-D) δ 4.84-4.77 (m, 2H), 4.51-4.44 (m, 2H), 3.19-3.10 (m, 1H).

[0271] Step 2: Synthesis of oxetan-3-ylmethyl-d24-methylbenzenesulfonate

[0272] To a solution of oxetan-3-ylmethan-d2-ol (0.3 g, 3.33 mmol) in DCM (9 mL) was added DMAP (40.7 mg, 0.333 mmol) and TEA (371 mg, 3.66 mmol) and p- (chlorosulfonyl)toluene (1.27 g, 6.66 mmol). The reaction mixture was stirred at 25oC for 3h,concentrated to get crude product which was purified by flash chromatography (PE / EA=3 / 1) to afford oxetan-3-ylmethyl-d2-4-methylbenzenesulfonate. LCMS (ESI) m / z = 245 [M+H]+;1H NMR (400 MHz, Chloroform-D) δ 7.80 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.76-4.71 (m, 2H), 4.35-4.30 (m, 2H), 3.32-3.24 (m, 1H), 2.46 (s, 3H). (R)-N-((1H-indol-7-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1075)

[0273] To prepare Compound 1075, step 6 of general procedure 1 of Scheme 1, was modified as follows: To a solution of (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (99.29 mg, 342.02 μmol) in DMF (1 mL) was added HATU (195.07 mg, 513.04 μmol) and 1H-indol-7-ylmethanamine (50 mg, 342.02 μm), DIPEA (132.61 mg, 1.03 mmol, 178.72 μL).The mixture was stirred at 0°C for 1h. The mixture was filtrated, and the residue was purified by prep-HPLC [instrument: CAS-CD-SEMI-PFEP-C; column: CD01-Phenomenex luna C18150×25×10um; mobile phase: A: water (0.1% FA), B: ACN; gradient: 30-60%; oven: 15 min; flow rate: 25 ml / min]. LCMS (ESI) m / z = 419.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.96 (br s, 1H), 8.97 (br t, J = 5.9 Hz, 1H), 7.68 - 7.55 (m, 2H), 7.48 - 7.36 (m, 2H), 7.04 - 6.92 (m, 2H), 6.87 (d, J = 8.5 Hz, 1H), 6.46 (dd, J = 1.9, 3.0 Hz, 1H), 4.74 (d, J = 6.0 Hz, 2H), 4.67 - 4.59 (m, 2H), 4.38 - 4.25 (m, 2H), 4.10 - 4.01 (m, 1H), 3.75 (dd, J = 6.3, 13.9 Hz, 1H), 3.44 (dd, J = 8.4, 13.9 Hz, 1H), 3.31 (s, 4H), 0.98 (d, J = 6.8 Hz, 3H). (R)-N-((1H-indol-5-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1076)

[0274] To prepare Compound 1076, step 6 of the general procedure 1 of Scheme 1, was modified as follows: A solution of (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (0.1 g, 344 µmol) and HATU (196 mg, 517 µmol) in DMF (1 mL, 12.9 mmol) stirred at 25°C for 0.5 h, then was added DIPEA (89 mg, 689 µmol) and (1H-indol-5-yl)methanamine (50.4 mg, 344 µmol) in one portion. Then the reaction mixture was stirred at room temperature for 16 h. The reaction was filtered and was purified prep-HPLC [instrument: CAS-CD-SEMI-PFEP-C; column: Waters xbridge 150×25mm×10um; mobile phase: A: water (0.1% NH4CO3), B: ACN; gradient: 19-49%; oven: 10 min; flow rate: 25 ml / min] to afford (R)-N-((1H-indol-5-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 411 [M+H]+;1H NMR (400 MHz, DMSO) δ 11.01 (br s, 1H), 8.83 (br t, J = 6.0 Hz, 1H), 7.62 (dd, J = 1.6, 8.4 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.46 (s, 1H), 7.37 - 7.26 (m, 2H), 7.07 (dd, J = 1.6, 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 4.68 - 4.60 (m, 2H), 4.54 (br dd, J = 2.0, 5.7 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.74 (dd, J = 6.4, 13.8 Hz, 1H), 3.44 (dd, J = 8.4, 13.8 Hz, 1H), 3.31 (s, 4H), 0.98 (d, J = 6.6 Hz, 3H). (R)-N-((1H-indazol-5-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1077)

[0275] To prepare Compound 1077, step 6 of the general procedure 1 of Scheme 1, was modified as follows: A solution of (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (0.1 g, 344 µmol), DIPEA (44.5 mg, 344 µmol), HATU (196 mg, 517 µmol) in DMF (1 mL) was stirred for 0.5 h at 25 °C. Then, (1H-indazol-5- yl)methanamine (50.7 mg, 344 µmol) was added. The mixture was stirred for 16 hr at room temperature. The mixture was filtered, and purified prep-HPLC [instrument: CAS-CD-SEMI- PFEP-C; column: Phenomenex luna C18150×25mm×10um; mobile phase: A: water (0.1% NH4CO3), B: ACN; gradient: 25-54%; oven: 10 min; flow rate: 25 ml / min], to afford (R)-N- ((1H-indazol-5-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 420.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.99 (br s, 1H), 8.90 (br t, J = 6.0 Hz, 1H), 8.02 (s, 1H), 7.69 - 7.60 (m, 2H), 7.57 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 0.8, 8.6 Hz, 1H), 6.86 (d, J = 8.4 Hz,1H), 4.68 - 4.60 (m, 2H), 4.60 - 4.52 (m, 2H), 4.39 - 4.24 (m, 2H), 4.06 (q, J = 6.4 Hz, 1H), 3.75 (dd, J = 6.4, 14.0 Hz, 1H), 3.44 (dd, J = 8.4, 14.0 Hz, 1H), 3.31 (s, 4H), 0.98 (d, J = 6.4 Hz, 3H). (R)-N-((1H-indol-4-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1078)

[0276] To prepare Compound 1078, step 6 of the general procedure 1 of Scheme 1, was modified as follows: A solution of (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (0.3 g, 1.03 mmol), DIPEA (360 µl, 2.07 mmol), HATU (589 mg, 1.55 mmol) in DMF (3 mL) was stirred for 10 min at 25 °C. Then, (1H-indol-4- yl)methanamine (151 mg, 1.03 mmol) was added. The mixture was stirred for 0.5 hr at room temperature. The mixture was filtered, and purified by prep-HPLC [instrument: CAS-CD-SEMI- PFEP-C; column: Waters xbridge 150×25mm×10um; mobile phase: A: water (0.1% NH4CO3), B: ACN; gradient: 19-49%; oven: 10 min; flow rate: 25 ml / min], to afford (R)-N-((1H-indol-4- yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide. LCMS (ESI) m / z = 419.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.10 (br s, 1H), 8.81 (t, J = 5.6 Hz, 1H), 7.63 (dd, J = 1.6, 8.4 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.57 (br s, 1H), 4.74 (br d, J = 5.6 Hz, 2H), 4.67 - 4.61 (m, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.74 (dd, J = 6.0, 14.0 Hz, 1H), 3.44 (dd, J = 8.4, 14.0 Hz, 1H), 3.36 (br s, 1H), 3.30 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H). (R)-N-(benzofuran-6-ylmethyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1079)

[0277] To prepare Compound 1079, the general procedure 1 of Scheme 1 was modified by replacing 1-phenylmethanamine with benzofuran-6-ylmethanamine in step 6. The product was purified by reverse MPLC [column: Waters xbridge 150*25mm 10um;vmobile phase: water (NH4HCO3)-ACN; gradient: 23%-43% B over 10 min. LCMS (ESI) m / z = 420.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.92 (t, J = 6.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.64-7.55 (m, 3H), 7.51 (s, 1H), 7.23 (dd, J = 1.2, 8.0 Hz, 1H), 6.92 (dd, J = 0.8, 2.0 Hz, 1H), 6.89-6.84 (m, 1H), 4.67-4.61 (m, 2H), 4.59 (br d, J = 6.0 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 6.4, 14.0 Hz, 1H), 3.44 (dd, J = 8.4, 14.0 Hz, 1H), 3.31 (s, 4H), 0.98 (d, J = 6.8 Hz, 3H). (R)-N-(2-aminobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1080)

[0278] To prepare Compound 1080, the general procedure 1 of Scheme 1 was modified by replacing 1-phenylmethanamine with 2-(aminomethyl)aniline in step 6. The product was purified by prep-HPLC [instrument: SemiPre-HPLC-C(0.1%FA); column: CD04-Welch Utimate C18 150×25×7um; mobile phase: water (0.1%FA)-ACN; B%: 10%-40%; flow rate: 30 ml / min]. LCMS (ESI) m / z = 411 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 6.0 Hz, 1H), 7.60 (dd, J = 1.8, 8.4 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.07 - 7.00 (m, 1H), 6.95 (dt, J = 1.4, 7.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.64 - 6.57 (m, 1H), 6.50 (dt, J = 0.9, 7.3 Hz, 1H), 5.17 (s, 2H), 4.70 - 4.56 (m, 2H), 4.36 - 4.25 (m, 4H), 4.06 (q, J = 6.7 Hz, 1H), 3.74 (dd, J = 6.3, 13.9 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.31 (s, 4H), 0.98 (d, J = 6.8 Hz, 3H). (R)-N-(2-amino-3-chlorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1081)

[0279] To prepare Compound 1081, the general procedure 1 of Scheme 1 was modified by replacing 1-phenylmethanamine with 2-(aminomethyl)-6-chloroaniline in step 6. The product was purified by reverse MPLC [instrument: Biotage Isolera Prime; column: Welch Xtimate C18 150×25mm×5um; mobile phase: water (0.1%FA)-ACN; B%: 20%-40%; flow rate: 40 ml / min]. LCMS (ESI) m / z = 429.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (br t, J = 6.0 Hz, 1H), 8.41 (br s, 1H), 7.60 (br d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.55 (t, J = 7.6 Hz, 1H), 5.41 (s, 2H), 4.68 - 4.60 (m, 2H), 4.39 (br d, J = 6.0 Hz, 2H), 4.36 - 4.32 (m, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.4 Hz, 1H), 3.75 (dd, J = 6.4, 13.6 Hz, 1H), 3.44 (br d, J = 5.6 Hz, 1H), 3.31 (s, 3H), 3.29 - 3.27 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H). (R)-N-(2,4-difluorobenzyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1082)

[0280] To prepare Compound 1082, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and step 6 was modified as follows:

[0281] To a solution of (R)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (60 mg, 205 µmol) and HATU (93.3 mg, 245 µmol) in DMF (1 mL) was added DIPEA (79.3 mg, 614 µmol). The mixture was stirred at 25 °C for 30 min, then (2,4-difluorophenyl)methanamine (35.1 mg, 245 µmol) was added. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was filtered and poured into EA (50 mL) and H2O (50 mL), then the mixture was separated. The organic phase was washed with H2O (30 mL*2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to give a residue. The crude product was purified by reversed-phase HPLC (Biotage Isolera Prime,column: Phenomenex luna C18150*25mm* 10um ; mobile phase: water (0.1% FA)-ACN; B%: 30%-50%, 10 min, 60 mL / min] to afford (R)-N-(2,4- difluorobenzyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 419.1 [M+H]+;1H NMR (400 MHz,DMSO-d6) δ 8.86 (br t, J = 5.6 Hz, 1H), 7.60 (dd, J = 1.6, 8.4 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.26 - 7.18 (m, 1H), 7.05 (dt, J = 2.4, 8.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.69 - 4.59 (m, 2H), 4.47 (br d, J = 5.2 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 6.4, 14.0 Hz, 1H), 3.44 (br dd, J = 8.4, 13.6 Hz, 2H), 0.98 (d, J = 6.8 Hz, 3H). (R)-N-(4-fluoro-2-methylbenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1083)

[0282] To prepare Compound 1083, step 6 of the general procedure 1 of Scheme 1, was modified as follows:

[0283] A solution of (R)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (0.2 g, 689 µmol) and HATU (314 mg, 827 µmol) in DMF (4 mL) was added DIPEA (360 µl, 2.07 mmol) dropwise, and stirred for 0.5 hr at 25 °C. Then, (4-fluoro-2-methylphenyl)methanamine (115 mg, 827 µmol) was added. The mixture was stirred for 2 hr at room temperature. The mixture was filtered, and purified by prep-HPLC (instrument: CAS-CD-SEMI-PREP-z; column: Waters Xbridge BEH C18150×25mm×5um; mobile phase:A: water (0.1% NH4HCO3), B: ACN; gradient: 23-53%; oven: 10 min; flow rate: 25 ml / min] to afford (R)-N-(4-fluoro-2-methylbenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3- oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 412.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.74 (br t, J = 5.6 Hz, 1H), 7.61 (dd, J = 1.6, 8.4 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 6.4, 8.4 Hz, 1H), 7.03 (dd, J = 2.4, 10.0 Hz, 1H), 6.97 (dt, J = 2.8, 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.64 (ddd, J = 6.0, 7.6, 10.0 Hz, 2H), 4.41 (br d, J = 5.6 Hz, 2H), 4.37 - 4.32 (m, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (br dd, J = 6.0, 14.0 Hz, 1H), 3.46 (br d, J = 8.4 Hz, 1H), 3.42 (br s, 1H), 3.31 (br s, 3H), 2.33 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H).(R)-N-((7-fluoro-1H-indol-4-yl)methyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1084)

[0284] To prepare Compound 1084, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (7-fluoro-1H-indol-4-yl)methanamine (which was synthesized according to the procedure described in Scheme 1d below) in step 6. The product was purified by prep-HPLC reverse MPLC [instrument: Biotage Isolera Prime; column: CD02-Waters Xbidge BEH C18; 150×25×10um; mobile phase: A: water (0.1%NH4HCO3), B: ACN; gradient: 19-49%; oven: 10 min; flow rate: 60 ml / min]. LCMS (ESI) m / z = 437.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.72 - 11.42 (m, 1H), 8.80 ( t, J = 5.6 Hz, 1H), 7.61 (dd, J = 1.6, 8.4 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.39 (t, J = 2.8 Hz, 1H), 6.87 (d, J = 4.0 Hz, 1H), 6.85 - 6.82 (m, 1H), 6.66 (br d, J = 2.0 Hz, 1H), 4.73 - 4.60 (m, 4H), 4.36 - 4.25 (m, 2H), 4.05 (q, J = 6.4 Hz, 1H), 3.74 (dd, J = 6.0, 14.0 Hz, 1H), 3.44 (dd, J = 8.4, 14.0 Hz, 1H), 3.28 - 3.25 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). Scheme 1d. Synthesis of 7-fluoro-1H-indol-4-yl)methanamine

[0285] Step 1: Synthesis of tert-butyl ((7-fluoro-1H-indol-4-yl)methyl)carbamate

[0286] The mixture of 4-bromo-7-fluoro-1H-indole (0.3 g, 1.4 mmol) , potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (498 mg, 2.1 mmol) in1,4-dioxane (3 mL) and water (1 mL), was added cataCXium® A (50.3 mg, 140 µmol), dicaesium carbonate (1.37 g, 4.2 mmol) and BrettPhos Pd G3 (127 mg, 140 µmol) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 4 hour under N2 atmosphere. On completion, the mixture filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE: EA=10 / 1 to 3 / 1) to give the product tert-butyl ((7-fluoro-1H-indol-4-yl)methyl)carbamate. LCMS (ESI) m / z = 208.8 [M+H]+;1H NMR (400MHz, DMSO-d6) δ 11.59 ( s, 1H), 7.39 (t, J = 2.8 Hz, 1H), 7.33 ( t, J = 6.0 Hz, 1H), 6.89 - 6.76 (m, 2H), 6.62 ( d, J = 1.6 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2H), 1.43 - 1.37 (m, 9H).

[0287] Step 2: Synthesis of 7-fluoro-1H-indol-4-yl)methanamine

[0288] To a solution of tert-butyl ((7-fluoro-1H-indol-4-yl)methyl)carbamate (310 mg, 1.17 mmol) in DCM (6 mL) was added hydrogen chloride (3 mL, 1.17 mmol) .The mixture was stirred at 25 °C for 1 hours. On completion, the reaction mixture was filtered and the filter cake was concentrated in vacuo to give the title compound 7-fluoro-1H-indol-4-yl)methanamine, which was used in the next step without further purification. (R)-N-((1H-benzo[d]imidazol-4-yl)methyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3- oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1085)

[0289] To prepare Compound 1085, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3in step 3; and replacing 1-phenylmethanamine with (1H-benzo[d]imidazol-4-yl)methanamine in step 6. The product was purified by reverse MPLC [instrument: Biotage Isolera Prime; column: CD07-Daisogel SP-100-8-ODS-PK 150×25×10um; 150×25×10um; mobile phase: A: water (0.1% NH4HCO3), B: ACN; gradient: 8- 38%; oven: 10 min; flow rate: 60 ml / min]. LCMS (ESI) m / z = 423.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.46 (br d, J = 8.4 Hz, 1H), 7.31 (s, 2H), 7.26 - 7.20 (m, 2H), 6.73 - 6.66 (m, 1H), 5.00 - 4.90 (m, 2H), 4.86 (t, J = 6.8 Hz, 2H), 4.43 (td, J = 5.6, 11.2 Hz, 2H), 4.06 - 3.99 (m, 1H), 3.81 (dd, J = 6.4, 13.6 Hz, 1H), 3.48 - 3.33 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H).(R)-N-((6-fluoro-1H-indol-4-yl)methyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1086)

[0290] To prepare Compound 1086, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (6-fluoro-1H-indol-4-yl)methanamine (which was synthesized according to the procedure described in Scheme 1d, by replacing 4-bromo-7-fluoro-1H-indole with 4-bromo-6-fluoro-1H- indole in step 1) in step 6. The product was purified by reverse MPLC [instrument: Biotage Isolera Prime; column: Phenomenex luna C18150×25mm×10um; 150×25×10um; mobile phase: A: water (0.1% FA), B: ACN; gradient: 22-52%; oven: 10 min; flow rate: 60 ml / min]. LCMS (ESI) m / z = 440.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 8.88 (br t, J = 5.6 Hz, 1H), 7.63 (dd, J = 1.6, 8.4 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.33 (t, J = 2.4 Hz, 1H), 7.09 - 7.01 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.75 (dd, J = 2.0, 10.8 Hz, 1H), 6.58 (br s, 1H), 4.72 (br d, J = 6.0 Hz, 2H), 4.67 - 4.59 (m, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.4 Hz, 1H), 3.75 (br dd, J = 6.4, 13.8 Hz, 1H), 3.35 - 3.25 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H). (R)-N-((5-fluoro-1H-indol-4-yl)methyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1087)

[0291] To prepare Compound 1087, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3in step 3; and replacing 1-phenylmethanamine with (5-fluoro-1H-indol-4-yl)methanamine (which was synthesized according to the procedure described in Scheme 1d, by replacing 4-bromo-7-fluoro-1H-indole with 4-bromo-5-fluoro-1H- indole in step 1) in step 6. The product was purified by reverse MPLC [instrument: Biotage Isolera Prime; column: CD07-Daisogel SP-100-8-ODS-PK 150×25×10um; 150×25×10um;mobile phase: A: water (0.1% NH4HCO3), B: ACN; gradient: 18-48%; oven: 10 min; flow rate: 15 ml / min]. LCMS (ESI) m / z = 440.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 8.69 (br t, J = 5.6 Hz, 1H), 7.59 (dd, J = 1.6, 8.4 Hz, 1H), 7.52 (s, 1H), 7.35 (t, J = 2.8 Hz, 1H), 7.30 (dd, J = 4.2, 8.8 Hz, 1H), 6.95 - 6.88 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.59 (br s, 1H), 4.76 (br d, J = 2.8 Hz, 2H), 4.66 - 4.59 (m, 2H), 4.33 (t, J = 6.0 Hz, 1H), 4.27 (t, J = 6.0 Hz, 1H), 4.04 (q, J = 6.8 Hz, 1H), 3.72 (dd, J = 6.0, 13.2 Hz, 1H), 3.42 (br dd, J = 8.4, 13.6 Hz, 2H), 0.96 (d, J = 6.8 Hz, 3H). (R)-N-((1H-indol-4-yl)methyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1088)

[0292] To prepare Compound 1088, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (1H-indol-4-yl)methanamine in step 6. The product was purified by reverse MPLC [instrument: Biotage Isolera Prime; column: CD07-Daisogel SP-100-8-ODS-PK 150×25×10um; 150×25×10um; mobile phase: A: water (0.1% NH4HCO3), B: ACN; gradient: 18-48%; oven: 10 min; flow rate: 15 ml / min]. LCMS (ESI) m / z = 422.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.10 ( s, 1H), 8.80 (t, J = 6.0 Hz, 1H), 7.63 (dd, J = 2.0, 8.4 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 6.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 4.74 (d, J = 5.2 Hz, 2H), 4.68 - 4.59 (m, 2H), 4.36 - 4.26 (m, 2H), 4.05 (q, J = 6.8 Hz, 1H), 3.74 (dd, J = 6.4, 13.6 Hz, 1H), 3.44 (dd, J = 8.4, 13.6 Hz, 1H), 3.36 - 3.32 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). (R)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-N-((2-oxo-1,2,3,4-tetrahydroquinolin- 7-yl)methyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1089)

[0293] To prepare Compound 1089, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with 7-(aminomethyl)-3,4-dihydroquinolin-2(1H)-one in step 6. The product was purified by prep-HPLC [instrument: CAS-CD-SEMI-PFEP-C; column: CD04-Welch Utimate C18 150×25×7um; mobile phase: A: water (0.1%FA), B: ACN; gradient: 13-43%; oven: 10 min; flow rate: 35 ml / min]. LCMS (ESI) m / z = 452.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.84 (t, J = 6.0 Hz, 1H), 7.60 (dd, J = 2.0, 8.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.90 - 6.78 (m, 3H), 4.72 - 4.55 (m, 2H), 4.45 - 4.26 (m, 4H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 6.4, 14.0 Hz, 1H), 3.44 (dd, J = 8.4, 14.0 Hz, 1H), 3.31 - 3.23 (m, 1H), 2.82 (t, J = 7.6 Hz, 2H), 2.41 (dd, J = 6.8, 8.4 Hz, 2H), 0.98 (d, J = 6.8 Hz, 3H). (R)-N-((1H-indazol-4-yl)methyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1090)

[0294] To prepare Compound 1090, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (1H-indazol-4-yl)methanamine in step 6. The product was purified by prep-HPLC [instrument: CAS-CD-SEMI-PFEP-C; column: CD07-Daisogel SP-100-8-ODS-PK 150×25×10um; mobile phase: A: water (0.1% NH4HCO3), B: ACN; gradient: 10-40%; oven: 10 min; flow rate: 30 ml / min]. LCMS (ESI) m / z = 423.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 13.08 (br s, 1H), 8.95 (br t, J = 5.6 Hz, 1H), 8.19 (s, 1H), 7.63 (dd, J = 1.6, 8.4 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.80 (br d, J = 5.6 Hz, 2H), 4.67 - 4.60 (m, 2H), 4.36 - 4.27 (m, 2H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 6.0, 14.0 Hz, 1H), 3.44 (dd, J = 8.4, 14.0 Hz, 1H), 3.31 - 3.24 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H).(R)-N-((6-fluoro-1H-indazol-5-yl)methyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1091)

[0295] To prepare Compound 1091, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (6-fluoro-1H-indazol-5-yl)methanamine (which was synthesized by 6-fluoro-1H-indazole- 5-carbonitrile hydrolysis) in step 6. The product was purified by reverse MPLC [instrument: Biotage Isolera Prime; column: Welch Xtimate C18150×25mm×5um; 150×25×10um; mobile phase: A: water (0.1% FA), B: ACN; gradient: 40-50%; oven: 10 min; flow rate: 60 ml / min]. LCMS (ESI) m / z = 441.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.86 (t, J = 5.6 Hz, 1H), 8.06 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.63 (dd, J = 2.0, 8.4 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 10.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.69 - 4.60 (m, 2H), 4.57 (br d, J = 3.6 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 6.2, 13.6 Hz, 1H), 3.45 (dd, J = 8.4, 13.8 Hz, 1H), 3.31 - 3.27 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). (R)-1-(benzo[d]oxazol-4-ylmethyl)-N-(2,4-difluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1092)

[0296] To prepare Compound 1092, the general procedure 1 of Scheme 1 was modified by replacing 3-(bromomethyl)oxetane with 4-(bromomethyl)benzo[d]oxazole (which was synthesized according to the procedure described in Scheme 1a) in step 4; and replacing 1- phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 477 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.84-8.77(m, 2H), 7.69 (dd, J = 7.6, 1.2 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 8.4, 1.6 Hz, 1H), 7.41-7.35 (m, 3H), 7.23-7.17 (m, 1H), 7.06-7.01 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.04-4.97 (m, 1H), 4.72-4.66 (m, 1H), 4.47-4.41 (m, 2H), 4.19 (t, J = 6.8 Hz, 1H), 3.33 (s, 3H), 1.12 (d, J = 6.8 Hz, 3H). 1-benzyl-2-ethyl-N-(4-fluorobenzyl)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1093)

[0297] To prepare Compound 1093, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminobutanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with (4-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 432.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.83 (t, J = 6.0 Hz, 1H), 7.51 (dd, J = 20.8, 4.8 Hz, 2H), 7.37 – 7.30 (m, 6H), 7.29 – 7.22 (m, 1H), 7.13 (t, J = 8.9 Hz, 2H), 6.75 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 15.6 Hz, 1H), 4.52 – 4.39 (m, 3H), 3.99 (dd, J = 7.6, 5.6 Hz, 1H), 3.36 (s, 3H), 1.67 – 1.44 (m, 2H), 0.77 (t, J = 7.6 Hz, 3H). 7-chloro-1-cyclopropyl-N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1094)

[0298] To prepare Compound 1094, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; methyl 4-fluoro-3-nitrobenzoate with methyl 2-chloro-4-fluoro-5- nitrobenzoate in step 1 (which was synthesized according to the procedure described in Scheme 1e below); and step 4 was modified as follows:

[0299] A mixture of methyl 7-chloro-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate (2.0 g, 7.44 mmol), cyclopropyboronic acid (1.28 g, 14.9 mmol), copper acetate (1.35 g, 7.44 mmol), disodium carbonate (1.58 g, 14.9 mmol) and dipyridine (1.3 g, 7.44 mmol) was prepared in a round bottom flask. Then DCE (10 mL) was added, and the solution was stirred at 70oC for 6 h under O2. The resulting solution was concentrated under reduced pressure and purified by column chromatography (silica, PE / EA = 5: 1) to afford methyl 7-chloro-1- cyclopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate. LCMS (ESI) m / z = 309.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.13 (s, 1H), 4.13-4.07 (q, J = 5.2 Hz, 1H), 3.82 (s, 3H), 2.98 (s, 3H), 3.17 (d, J = 5.2 Hz, 3H), 2.63-2.56 (m, 1H), 1.04-1.03 (m, 1H), 0.85-0.76 (m, 1H), 0.74-0.67 (m, 1H), 0.49-0.42 (m, 1H).

[0300] Finally, methyl 7-chloro-1-cyclopropyl-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylate was subjected to steps 5 and 6 of general procedure 1 of Scheme 1 by replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 402.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.81 (t, J = 5.4 Hz, 1H), 7.46 (t, J = 7.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.22-7.17 (m, 2H), 7.14 (s, 1H), 7.08 (s, 1H), 4.48 (d, J = 5.2 Hz, 2H), 4.09-4.02 (m, 1H), 3.27 (s, 3H), 2.54- 2.52 (m,1H), 1.11 (d, J = 2.8 Hz, 3H), 1.05-0.98 (m, 1H), 0.82-0.75 (m, 1H), 0.71-0.61 (m, 1H), 0.45-0.35 (m, 1H). Scheme 1e. Synthesis of methyl 2-chloro-4-fluoro-5-nitrobenzoate

[0301] To a stirred solution of 2-chloro-4-fluoro-5-nitrobenzoic acid (1.0 g, 4.55 mmol) in MeOH (10 mL) was added sulfuric acid (0.3 ml, 4.55 mmol). The reaction mixture was stirred at 65°C for 4 h. Then the reaction mixture was cooled to rt, washed with water, and extracted with DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford methyl 2-chloro-4-fluoro-5-nitrobenzoate.1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 11.2 Hz, 2H), 3.91 (s, 3H).1-cyclopropyl-N-(2,4-difluorobenzyl)-7-fluoro-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1095)

[0302] To prepare Compound 1095, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; methyl 4-fluoro-3-nitrobenzoate with methyl 2,4-difluoro-5- nitrobenzoatein in step 1; and step 4 was modified as follows:

[0303] Bipyridine (61.9 mg,0.40 mmol) was added to the solution of methyl 7-fluoro-2,4- dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.1 g, 0.40 mmol) in DCE. Then cyclopropylboronic acid (68.1 mg, 0.40 mmol), copper diacetate hydrate (79.1 mg, 0.40 mmol) and Na2CO3 (84 mg, 0.79 mmol were added to the solution and the mixture was stirred at 70 °C for 16 hrs under O2. Then, the mixture was concentrated and purified by column chromatography to afford methyl 1-cyclopropyl-7-fluoro-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate.1H NMR (400 MHz, Chloroform-D) δ 77.45 (d, J = 6.8Hz, 1H), 6.82 (d, J = 12.8Hz, 1H), 4.14 (m, 1H), 3.91 (s, 3H), 3.37 (s, 3H), 2.47 (m, 1H), 1.25 (d, J = 6.8Hz, 3H), 1.03 (m, 1H), 0.86 (m, 1H), 0.68 (m, 1H), 0.59 (m, 1H).

[0304] Finally, methyl 1-cyclopropyl-7-fluoro-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylate was subjected to steps 5 and 6 of general procedure 1 of Scheme 1 by replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 404.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 4.8Hz, 1H), 7.5-7.4 (m, 1H), 7.30 (d, J = 7.2Hz, 1H), 7.23 (m, 1H), 7.08 (m, 1H), 6.91 (d, J = 12.8Hz, 1H), 4.47 (d, J = 5.6Hz, 2H), 4.06 (q, J = 6.8Hz, 1H), 3.26 (s, 3H), 1.13 (d, J = 6.8Hz, 3H), 1.04 (m, 1H), 0.80 (m, 1H), 0.70 (m, 1H), 0.43 (m, 1H).1-cyclopropyl-7-fluoro-N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1096)

[0305] To prepare Compound 1096, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; methyl 4-fluoro-3-nitrobenzoate with methyl 2,4-difluoro-5- nitrobenzoatein in step 1; and step 4 was modified as follows:

[0306] Bipyridine (61.9 mg,0.40 mmol) was added to the solution of methyl 7-fluoro-2,4- dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.1 g, 0.40 mmol) in DCE. Then cyclopropylboronic acid (68.1 mg, 0.40 mmol), copper diacetate hydrate (79.1 mg, 0.40 mmol) and Na2CO3 (84 mg, 0.79 mmol were added to the solution and the mixture was stirred at 70 °C for 16 hrs under O2. Then, the mixture was concentrated and purified by column chromatography to afford methyl 1-cyclopropyl-7-fluoro-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate.1H NMR (400 MHz, Chloroform-D) δ 7.45 (d, J = 6.8Hz, 1H), 6.82 (d, J = 12.8Hz, 1H), 4.14 (m, 1H), 3.91 (s, 3H), 3.37 (s, 3H), 2.47 (m, 1H), 1.25 (d, J = 6.8Hz, 3H), 1.03 (m, 1H), 0.86 (m, 1H), 0.68 (m, 1H), 0.59 (m, 1H).

[0307] Finally, methyl 1-cyclopropyl-7-fluoro-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylate was subjected to steps 5, and 6 of general procedure 1 of Scheme 1 by replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC (ACN / H2O(0.5%FA)). LCMS (ESI) m / z = 386.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.8Hz, 1H), 7.4-7.35 (m, 1H), 7.30 (t, J = 6.8Hz, 1H), 7.22 -7.15 (m, 1H), 6.92 (d, J = 12.8 Hz, 1H), 4.51 (d, J = 6.0Hz, 2H), 4.06 (q, J = 6.8Hz, 1H), 3.27 (s, 1H), 1.11 (t, J =6.8Hz, 3H), 1.08-1.0 (m, 1H), 0.85-0.75 (m, 1H), 0.75-0.65 (m, 1H), 0.45-0.35 (m, 1H).7-chloro-1-cyclopropyl-N-(2,4-difluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1097)

[0308] To prepare Compound 1097, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; methyl 4-fluoro-3-nitrobenzoate with methyl 2-chloro-4-fluoro-5- nitrobenzoate in step 1 (which was synthesized according to the procedure described in Scheme 1e); and step 4 was modified as follows:

[0309] A mixture of methyl 7-chloro-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxylate (2.0 g, 7.44 mmol), cyclopropyboronic acid (1.28 g, 14.9 mmol), copper acetate (1.35 g, 7.44 mmol), disodium carbonate (1.58 g, 14.9 mmol) and dipyridine (1.3 g, 7.44 mmol) was prepared in a round bottom flask. Then DCE (10 mL) was added, and the solution was stirred at 70oC for 6 h under O2. The resulting solution was concentrated under reduced pressure and purified by column chromatography (silica, PE / EA = 5 : 1) to afford methyl 7-chloro-1- cyclopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate. LCMS (ESI) m / z = 309.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.13 (s, 1H), 4.13-4.07 (q, J = 5.2 Hz, 1H), 3.82 (s, 3H), 2.98 (s, 3H), 3.17 (d, J = 5.2 Hz, 3H), 2.63-2.56 (m, 1H), 1.04-1.03 (m, 1H), 0.85-0.76 (m, 1H), 0.74-0.67 (m, 1H), 0.49-0.42 (m, 1H).

[0310] Finally, methyl 7-chloro-1-cyclopropyl-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylate was subjected to steps 5 and 6 of general procedure 1 of Scheme 1 by replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 420.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.82 (t, J = 5.8 Hz, 1H), 7.49 (q, J = 8.0 Hz, 1H), 7.27-7.21 (m, 1H), 7.12 (s, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.07 (s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 4.11-4.02 (m, 1H), 3.26 (s, 3H), 2.56-2.52 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 1.05-1.00 (m, 1H), 0.80-0.75 (m, 1H), 0.69- 0.60 (m, 1H), 0.43-0.56 (m, 1H).1-benzyl-2,4-dimethyl-3-oxo-N-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1098)

[0311] To prepare Compound 1098, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with pyridin-2-ylmethanamine in step 6. The product was purified by a prep-HPLC (Gemini 5um C18150*21.2mm, mobile phase : ACN - H2O (0.1% FA); gradient : 5 - 95). LCMS (ESI) m / z = 401.9 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J = 6.0 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 7.93 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.4, 1.6 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.35 (d, J = 4.4 Hz, 4H), 7.30 – 7.25 (m, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.67 (d, J = 15.2 Hz, 1H), 4.60 (dd, J = 5.6, 2.8 Hz, 2H), 4.37 (d, J = 15.2 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.36 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H). (S)-N-(2-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1099)

[0312] To prepare Compound 1099, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with (S)-methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.05% FA)-ACN]; B%: 40%-70%, 10 min), followed SFC separation (Column: Chiralpak AS-350×4.6mm I.D., 3um; Mobile phase: Phase A - CO2, and Phase B - MeOH (0.05% DEA); Gradient: B in A from 5% to 40%; Flow rate: 3mL / min; Detector: PDA; Column Temp: 35oC; Back Pressure: 100Bar). LCMS (ESI) m / z = 398.2[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.6 Hz, 1H), 7.61 (dd, J = 1.6, 8.4 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.22 - 7.12 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.64 (ddd, J = 6.0, 7.6, 10.0 Hz, 2H), 4.51 (br d, J = 5.6 Hz, 2H), 4.39 - 4.23 (m, 2H), 4.07 (d, J = 6.8 Hz, 1H), 3.75 (dd, J = 6.4, 13.9 Hz, 1H), 3.48 - 3.41 (m, 1H), 3.31 (s, 3H), 3.30 - 3.22 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H). 2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-N-((1R,2S)-2-phenylcyclopropyl)-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1100)

[0313] To prepare Compound 1100, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1;1-phenylmethanamine with (1R,2S)-2-phenylcyclopropan-1-amine in step 6. The product was purified by prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 406.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 3.6 Hz, 1H), 7.55 (dd, J = 8.4, 1.6 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.30 - 7.26 (m, 2H), 7.19 - 7.15 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 4.67 - 4.61(m, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 13.6, 6.4 Hz, 1H), 3.44 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 4H), 3.01 - 2.97 (m, 1H), 2.08 - 2.02 (m, 1H), 1.36 - 1.30 (m, 1H), 1.23 (dd, J = 13.6, 6.0 Hz, 1H), 0.98 (d, J = 6.8 Hz, 3H). 2-cyclopropyl-N-(2-fluorobenzyl)-4-methyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1101)

[0314] To prepare Compound 1101, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-amino-2- cyclopropylacetate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by column chromatography (DCM: MeOH=10 :1).1H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 5.6 Hz, 1H), 7.66 – 7.55 (m, 2H), 7.38 – 7.27 (m, 2H), 7.17 (dt, J = 7.6, 4.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1H), 4.68 - 4.56 (m, 2H), 4.52 - 4.47 (m, 2H), 4.32 (t, J = 6.0 Hz, 1H), 4.26 (t, J = 6.0 Hz, 1H), 3.90 - 3.85 (m, 1H), 3.63 - 3.58(m, 1H), 3.48 (d, J = 8.8 Hz, 1H), 3.33 (s, 3H), 3.32 – 3.25 (m, 1H), 0.73 - 0.65 (m, 1H), 0.58 - 0.52(m, 1H), 0.46 – 0.37 (m, 1H), 0.36 – 0.23 (m, 2H). 1-benzyl-2,4-dimethyl-3-oxo-N-(pyrimidin-4-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1102)

[0315] To prepare Compound 1102, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with pyrazin-2-ylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 402.15 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J = 5.6 Hz, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.59 – 8.57 (m, 1H), 8.53 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.29 - 7.25 (m, 1H), 6.78 (d, J = 8.6 Hz, 1H), 4.67 (d, J = 15.2 Hz, 1H), 4.59 (dd, J = 5.6, 2.0 Hz, 2H), 4.36 (d, J = 15.3 Hz, 1H), 4.06 (q, J = 6.8 Hz, 1H), 3.35 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H). 1-benzyl-2,4-dimethyl-3-oxo-N-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1103)

[0316] To prepare Compound 1103, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoatehydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with (tetrahydro-2H-pyran-4-yl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% FA)]. LCMS (ESI) m / z = 408.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (t, J = 5.8Hz, 1H), 7.51 (d, J = 1.6Hz,1H), 7.46 (dd, J = 8.4, 1.8Hz, 1H), 7.34 (t, J = 6.8Hz, 4H), 7.3-7.25 (m, 1H), 6.74 (d, J = 8.8Hz, 1H), 4.65 (d, J = 15.2Hz, 1H), 4.35 (d, J = 15.2Hz, 1H), 4.05 (q, J = 6.8Hz, 1H), 3.86-3.79 (m, 2H), 3.35 (s, 3H), 3.24 (t, J = 10.8Hz, 2H), 3.15-3.10 (m, 2H), 1.76 (m, 1H), 1.57 (d, J = 12.4Hz, 2H), 1.2- 1.1 (m, 2H), 1.05 (d, J = 6.8Hz, 3H). 1-benzyl-2,4-dimethyl-N-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1104)

[0317] To prepare Compound 1104, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (bromomethyl)benzene in step 4; and replacing 1-phenylmethanamine with oxetan-3-ylmethanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.1% NH3*H2O)]. LCMS (ESI) m / z = 380.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.6 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 7.36(d, J = 4.8 Hz, 4H),7.29-7.7.24(m, 1H), 6.75 (d, J = 8.4Hz, 1H), 4.66-4.59 (m, 3H), 4.36-4.31 (m,, 3H), 4.05 (q, J = 6.8 Hz, 1H), 3.52- 3.47(m, 2H), 3.35 (s, 3H), 3.16-3.09 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H).N-(5-chloro-2-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1105)

[0318] To prepare Compound 1105, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (5-chloro-2- fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 432 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.90 (t, J = 6.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.26 (t, J = 9.2 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.64 - 4.56 (m, 2H), 4.49 (d, J = 5.6 Hz, 2H), 4.32 - 4.25 (m, 2H), 4.08 (q, J = 6.8 Hz, 1H), 3.76 (dd, J = 13.6, 6.4 Hz, 1H), 3.45 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 3H), 3.31 – 3.27 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). 1-((1H-imidazol-4-yl)methyl)-N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1106)

[0319] To prepare Compound 1106, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; (bromomethyl)oxetane with 4-(bromomethyl)-1H-imidazole in step 4; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 408.1 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 12.00 (s, 1H), 8.84 (t, J = 5.2 Hz, 1H), 7.63 – 7.56 (m, 3H), 7.38 – 7.34 (m, 1H), 7.32 – 7.27 (m, 1H), 7.20 – 7.14 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 4.53 – 4.45 (m, 3H), 4.19 (d, J = 14.4 Hz, 1H), 4.01 (q, J = 6.4 Hz, 1H), 3.31 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H).1-(2-amino-2-oxoethyl)-N-(2,4-difluorobenzyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1107)

[0320] To prepare Compound 1107, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; (bromomethyl)oxetane with 2-bromoacetamide in step 4; and replacing 1-phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 403 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.6Hz, 1H), 7.60 – 7.49 (m, 3H), 7.40 (dd, J = 15.6, 8.8Hz, 1H), 7.22 - 7.12 (m, 1H), 7.15 (s, 1H), 7.09 – 7.02 (m, 1H), 6.56 (d, J = 8.4Hz, 1H), 4.47 (d, J = 5.6Hz, 2H), 4.14 (q, J = 6.8Hz, 1H), 3.91 – 3.80 (m, 2H), 3.32 (s, 3H), 1.08 (d, J = 6.8Hz, 3H). N-benzyl-2-cyclopropyl-4-methyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1108)

[0321] To prepare Compound 1108, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-amino-2- cyclopropylacetate hydrochloride in step 1. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 406.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J = 6.0 Hz, 1H), 7.65 – 7.55 (m, 2H), 7.36 – 7.29 (m, 4H), 7.27 - 7.21 (m, 1H), 6.91 (d, J = 8.8Hz, 1H), 4.65 - 4.56 (m, 2H), 4.54 – 4.41 (m, 2H), 4.32 (t, J = 6.0 Hz, 1H), 4.26 (t, J = 6.0 Hz, 1H), 3.90 - 3.85 (m, 1H), 3.63 - 3.57 (m, 1H), 3.47 (d, J = 8.8 Hz, 1H), 3.33 (s, 3H), 3.28 (d, J = 6.4 Hz, 1H), 0.73 - 0.67 (m, 1H), 0.56 - 0.52(m, 1H), 0.46 – 0.38 (m, 1H), 0.36 – 0.26 (m, 2H).N-(isoxazol-5-ylmethyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1109)

[0322] To prepare Compound 1109, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (isoxazol-5-ylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 371.05 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.00 (t, J = 5.6 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H), 4.67 – 4.60 (m, 4H), 4.37 – 4.27 (m, 2H), 4.08 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.45 (dd, J = 13.6, 8.4 Hz, 1H), 3.32 – 3.28 (m, 4H), 0.98 (d, J = 6.8 Hz, 3H). 2,4-dimethyl-N-(oxazol-5-ylmethyl)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1110)

[0323] To prepare Compound 1110, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with oxazol-5-ylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 371 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.6Hz, 1H), 8.29 (s, 1H), 7.58 (dd, J = 8.4, 1.6Hz, 1H), 7.53 (d, J = 1.6Hz, 1H), 7.04 (s, 1H), 6.86 (d, J = 8.8Hz, 1H), 4.67 – 4.61 (m, 2H), 4.53 (d, J = 6.0Hz, 2H), 4.34 (t, J = 6.0Hz, 1H), 4.28 (t, J = 6.0Hz, 1H), 4.07 (q, J = 6.8Hz, 1H), 3.75 (dd, J = 14.0, 6.4Hz, 1H), 3.44 (dd, J = 14.0, 8.4Hz, 1H), 3.31 – 3.27 (m, 4H), 0.98 (d, J = 6.8Hz, 3H).2,4-dimethyl-N-(oxazol-2-ylmethyl)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1111)

[0324] To prepare Compound 1111, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with oxazol-2-ylmethanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 371.05 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.99 (t, J = 6.0 Hz, 1H), 8.04 (d, J = 0.4 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 0.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.67 – 4.64 (m, 1H), 4.64 – 4.61 (m, 1H), 4.57 (dd, J = 6.0, 2.4 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 14.0, 6.4 Hz, 1H), 3.45 (dd, J = 14.0, 8.4 Hz, 1H), 3.32 – 3.22 (m, 4H), 0.99 (d, J = 6.8 Hz, 3H). N-(2,4-difluorobenzyl)-2,4-dimethyl-3-oxo-1-(thiazol-2-ylmethyl)-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1112)

[0325] To prepare Compound 1112, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; (bromomethyl)oxetane with 2-(bromomethyl)thiazole in step 4 [2- (bromomethyl)thiazole was synthesized according to the procedure described in step 4 of Scheme1c, by replacing (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methanol with thiazol-2-ylmethanol]; and replacing 1-phenylmethanamine with (2,4- difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 443.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 3.6 Hz, 1H), 7.66 – 7.49 (m, 3H), 7.39 (dd, J = 15.6, 8.8 Hz, 1H), 7.25 – 7.17 (m, 1H), 7.08 – 7.01(m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 16.4 Hz, 1H), 4.78 (d, J = 16.4 Hz, 1H), 4.46 (d, J = 3.6 Hz, 2H), 4.27 (q, J = 6.8 Hz, 1H), 3.36 (s, 3H), 1.08 (d, J = 6.8 Hz, 3H). N,2,4-trimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1113)

[0326] To prepare Compound 1113, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 304.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 4.4 Hz, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.67 - 4.61 (m, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.28 (t, J = 6.0 Hz, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.73 (dd, J = 13.6, 6.0 Hz, 1H), 3.43 (dd, J = 14.0, 8.4 Hz, 1H), 3.30 (s, 4H), 2.77 (d, J = 4.4 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H). N-(2-fluorobenzyl)-2,4-dimethyl-3-oxo-1-(thiazol-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1114)

[0327] To prepare Compound 1114, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; (bromomethyl)oxetane with 2-(bromomethyl)thiazole in step 4 [2- (bromomethyl)thiazole was synthesized according to the procedure described in step 4 of Scheme1c, by replacing (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methanol with thiazol-2-ylmethanol]; and replacing 1-phenylmethanamine with (2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 425.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.6Hz, 1H), 7.78 (d, J = 3.2Hz, 1H), 7.65 – 7.52 (m,3H), 7.37 – 7.27 (m, 2H), 7.20 – 7.13 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 4.99 (d, J = 16.4Hz, 1H), 4.78 (d, J = 16.4Hz, 1H), 4.50 (d, J = 4.8Hz, 2H), 4.27 (q, J = 6.8Hz, 1H), 3.36 (s, 3H), 1.09 (d, J = 6.8Hz, 3H). N,2,4-trimethyl-3-oxo-1-(thiazol-4-ylmethyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1115)

[0328] To prepare Compound 1115, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; (bromomethyl)oxetane with 4-(bromomethyl)thiazole in step 4 [4- (bromomethyl)thiazole was synthesized according to the procedure described in step 2 of Scheme1b, by replacing 4-methylbenzo[d]oxazole with 4-methylthiazole; and replacing 1- phenylmethanamine with methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 331 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.6 Hz, 1H), 8.28-8.20 (m, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.51-7.44 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 4.80- 4.70 (m, 1H), 4.55-4.47 (m 1H), 4.08 (q, J = 6.4 Hz, 1H), 3.32 (s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H). N-(2,4-difluorobenzyl)-2,4-dimethyl-3-oxo-1-(thiazol-4-ylmethyl)-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1116)

[0329] To prepare Compound 1116, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; (bromomethyl)oxetane with 4-(bromomethyl)thiazole in step 4. [4- (bromomethyl)thiazole was synthesized according to the procedure described in step 2 ofScheme1b, by replacing 4-methylbenzo[d]oxazole with 4-methylthiazole; and replacing 1- phenylmethanamine with (2,4-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC [Column: Gemini, ACN-H2O (0.1% FA)]. LCMS (ESI) m / z = 443 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 2.0 Hz, 1H), 8.84 (t, J = 5.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.58-7.53 (m, 2H), 7.43-7.36 (m, 1H), 7.25-7.18 (m, 1H), 7.08-7.02 (m, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.81-4.73 (m 1H), 4.55-4.50 (m, 1H), 4.49-4.41 (m, 2H), 4.10 (q, J = 6.8 Hz, 1H), 3.33 (s, 3H), 1.04 (d, J = 6.8 Hz, 3H). N-((3-fluoropyridin-4-yl)methyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1117)

[0330] To prepare Compound 1117, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3-fluoropyridin-4- yl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 399 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ δ 8.98 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.38 (dd, J = 4.8, 0.8 Hz, 1H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.38 – 7.31 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.64 - 4.58 (m, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.32 - 4.26 (m, 2H), 4.08 (q, J = 6.8 Hz, 1H), 3.76 (dd, J = 14.0, 6.0 Hz, 1H), 3.46 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 3H), 3.31 – 3.25 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). N-(5-chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1118)

[0331] To prepare Compound 1118, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoatehydrochloride in step 1; (bromomethyl)oxetane with (2-bromoethoxy)(tert-butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection; and replacing 1-phenylmethanamine with (5-chloro-2-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% FA)]. LCMS (ESI) m / z = 406.1 [-d6) δ .87 (t, J = 5.6Hz, 1H), 7.60 (dd, J = 8.4, 2.0Hz, 1H), 7.55 (d, J = 2.0Hz, 1H), 7.36 (d, J = 5.2Hz, 2H), 7.27 (m, 1H), 6.85 (d, J = 8.4Hz, 1H), 4.49 (d, J = 5.6Hz, 2H), 4.15 (q, J = 6.8Hz, 1H), 3.54 (m, 4H), 3.32 (s, 3H), 3.21 (m, 1H), 1.05 (d, J = 6.8Hz, 3H). N-(2,4-difluoro-3-methoxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1119)

[0332] To prepare Compound 1119, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2,4-difluoro-3- methoxyphenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 446 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.6 Hz, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.15 – 7.02 (m, 2H), 6.87 (d, J = 8.8 Hz, 1H), 4.64 - 4.56 (m, 2H), 4.47 (d, J = 5.6 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.75 (dd, J = 14.0, 6..0 Hz, 1H), 3.45 - 3.38 (m, 1H), 3.31 (s, 3H), 3.29 (s, 1H), 0.98 (d, J = 6.8 Hz, 3H). N-(2-fluoro-4-(trifluoromethoxy)benzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1120)

[0333] To prepare Compound 1120, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoatehydrochloride in step 1; 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert- butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection; and replacing 1- phenylmethanamine with (2-fluoro-4-(trifluoromethoxy)phenyl)methanamine in step 6.2-fluoro- 4-(trifluoromethoxy)phenyl)methanamine was synthesized according to the modified procedure described in Scheme 1d, by replacing 4-bromo-7-fluoro-1H-indole with 1-bromo-2-fluoro-4- (trifluoromethoxy)benzene. The product was purified by prep-HPLC [Gemini 5um C18 150*21.2mm; mobile phase: ACN - H2O (0.1% FA); gradient : 5 – 95]. LCMS (ESI) m / z = 456.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.88 (t, J = 5.6 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.38 (dd, J = 10.0, 1.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.81 (s, 1H), 4.51 (d, J = 4.8 Hz, 2H), 4.15 (q, J = 6.8 Hz, 1H), 3.63 – 3.48 (m, 3H) , 3.32 (s, 3H), 3.25 – 3.16 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H). N-(2-fluoro-4-methoxybenzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1121)

[0334] To prepare Compound 1121, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert- butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection; and replacing 1- phenylmethanamine with (2-fluoro-4-methoxyphenyl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% FA)]. LCMS (ESI) m / z = 402.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.75 (t, J = 5.6Hz, 1H), 7.57 (m, 2H), 7.27 (t, J = 8.8Hz, 1H), 6.78 (m, 3H), 4.80 (t, J = 5.2Hz, 1H), 4.42 (d, J = 3.6Hz, 2H), 4.14 (q, J = 6.8Hz, 1H), 3.74 (s, 3H), 3.55 (m, 3H), 3.31 (s, 3H), 3.21 (dd, J = 13.6, 6.0Hz, 1H), 1.03 (d, J = 6.8Hz, 3H).N-(2-chloro-6-fluorobenzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1122)

[0335] To prepare Compound 1122, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert- butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection; and replacing 1- phenylmethanamine with (2-chloro-6-fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% FA)]. LCMS (ESI) m / z = 406 [(400 MHz, DMSO-d6) δ 8.55 (t, J = 4.8 Hz, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.45-7.3 (m, 2H), 7.23 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.57 (m, 2H), 4.13 (q, J = 6.8 Hz, 1H), 3.57 (t, J = 5.6 Hz, 2H), 3.55-3.45 (m, 2H), 3.29 (s, 3H), 3.19 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H). N-(2-(difluoromethoxy)-6-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1123)

[0336] To prepare Compound 1123, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-(difluoromethoxy)-6- fluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 464 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.56 (t, J = 4.8 Hz, 1H), 7.54 (dd, J = 8.4, 1.6 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.25 – 7.04 (m, 3H), 6.83 (d, J = 8.8 Hz, 1H), 4.63 - 4.56 (m, 2H), 4.49 (d, J = 4.9 Hz, 2H), 4.31 - 4.24 (m, 2H), 4.05 (q, J = 6.4 Hz,1H), 3.73 (dd, J = 14.0, 6.4 Hz, 1H), 3.43 (dd, J = 14.0, 8.4 Hz, 1H), 3.29 (s, 3H), 3.28 – 3.23 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H) N-(2-fluoro-4-methoxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1124)

[0337] To prepare Compound 1124, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-fluoro-4- methoxyphenyl)methanaminein step 6. The product was purified by a prep-HPLC. LCMS (ESI) m / z = 428 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 6.0 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.27 (t, J = 8.8 Hz, 1H), 6.87 – 6.73 (m, 3H), 4.64 - 4.56 (m, 2H), 4.43 (d, J = 5.6 Hz, 2H), 4.31 - 4.23 (m, 2H), 4.06 (q, J = 6.4 Hz, 1H), 3.78 – 3.71 (m, 4H), 3.44 (dd, J = 14.0, 8.4 Hz, 1H), 3.31 (s, 3H), 3.30 – 3.24 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). N-(2,5-difluorobenzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1125)

[0338] To prepare Compound 1125, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert- butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection; and replacing 1- phenylmethanamine with (2,5-difluorophenyl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% FA)]. LCMS (ESI) m / z = 390.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 5.6Hz, 1H), 7.60 (dd, J = 8.4, 1.6Hz, 1H), 7.55 (d, J = 1.6Hz,1H), 7.25 (m, 1H), 7.14 (m, 2H), 6.85 (d, J = 8.4Hz, 1H), 4.49 (d, J = 5.6Hz, 2H), 4.15 (q, J = 6.8Hz, 1H), 3.57 (m, 3H), 3.51 (m, 1H), 3.32 (s, 3H), 3.21 (m, 1H), 1.04 (d, J = 6.8Hz, 3H). N-(2-fluoro-4-(trifluoromethoxy)benzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1126)

[0339] To prepare Compound 1126, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-fluoro-4- (trifluoromethoxy)phenyl)methanamine in step 6.2-fluoro-4- (trifluoromethoxy)phenyl)methanamine was synthesized by a Boc deprotection of 1-bromo-2- fluoro-4-(trifluoromethoxy)benzene. The product was purified by prep-HPLC [Gemini 5um C18 150*21.2mm; mobile phase: ACN - H2O (0.1% FA); gradient : 5 – 95]. LCMS (ESI) m / z = 482.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.92 (t, J = 5.6 Hz, 1H), 7.61 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.38 (dd, J = 10.4, 1.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.69 – 4.60 (m, 2H), 4.51 (d, J = 5.6 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.80 – 3.41 (m, 2H), 3.31 (s, 3H), 3.30 – 3.26 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). N-(2-fluoro-6-methoxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1127)

[0340] To prepare Compound 1127, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-fluoro-6- methoxyphenyl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O(0.5% NH3*H2O)]. LCMS (ESI) m / z = 428.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.35 (t, J = 4.8 Hz, 1H), 7.56 (dd, J = 8.4, 1.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 15.2, 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.82 -6.77 (m, 2H), 4.66 -4.60 (m, 2H), 4.46 (t, J = 3.6 Hz ,2H), 4.35 - 4.26 (m, 2H), 4.04 (q, J = 6.6 Hz, 1H), 3.83 (s, 3H), 3.73 (dd, J = 14.0, 6.4 Hz, 1H), 3.42 (dd, J = 13.6, 8.0 Hz, 1H), 3.29 -3.27 (m,4H), 0.96 (d, J = 6.8 Hz, 3H). N-benzyl-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1128)

[0341] To prepare Compound 1128, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert- butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection. The product was purified by a prep-HPLC [ACN / H2O (0.5% FA)]. LCMS (ESI) m / z = 354.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 6.0Hz, 1H), 7.60 (dd, J = 8.4, 1.8Hz, 1H), 7.55 (d, J =2.0Hz, 1H), 7.31 (m, 4H), 7.24 (dd, J = 6.0, 2.4Hz, 1H), 6.84 (d, J = 8.4Hz, 1H), 4.48 (dd, J = 6.0, 2.0Hz, 2H), 4.14 (q, J = 6.8Hz, 1H), 3.59 (t, J = 5.6Hz, 2H), 3.52 (m, 2H), 3.32 (s, 3H), 3.20 (m, 1H), 1.04 (d, J = 6.8Hz, 3H). N-(2-fluoro-5-(trifluoromethoxy)benzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1129)

[0342] To prepare Compound 1129, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (2-fluoro-5- (trifluoromethoxy)phenyl)methanamine in step 6. The product was purified by a prep-HPLC[ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 482.4 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 8.93 (t, J = 5.8 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.37 -7.32 (m, 3H), 6.88 (d, J = 8.4 Hz, 1H), 4.67 - 4.61 (m,2H), 4.52 (d, J = 5.6 Hz, 2H), 4.36 -4.27 (m, 2H), 4.08 (q, J = 6.8 Hz, 1H), 3.76 (dd, J = 13.6, 6.0 Hz, 1H), 3.45 (dd, J = 13.6, 8.4 Hz, 1H), 3.31 -3.29 (m, 4H), 0.99 (d, J = 6.8 Hz, 3H). N-(2,4-difluoro-3-methoxybenzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1130)

[0343] To prepare Compound 1130, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert- butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection; and replacing 1- phenylmethanamine with (2,4-difluoro-3-methoxyphenyl)methanamine in step 6 The product was purified by a prep-HPLC [ACN / H2O (0.5% FA)]. LCMS (ESI) m / z = 420.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 7.58 (dd, J = 8.4, 1.6Hz, 1H), 7.54 (d, J = 1.6Hz, 1H), 7.15-7.0 (m, 2H), 6.84 (d, J = 8.4Hz, 1H), 4.46 (d, J = 5.2Hz, 2H), 4.14 (q, J = 6.8Hz, 1H), 3.92 (s, 3H), 3.58 (t, J = 5.6Hz, 2H), 3.60-3.50 (m, 2H), 3.31 (s, 3H), 3.20-3.15 (m, 1H), 1.04 (d, J = 6.8Hz, 3H). (R)-N-(2,4-difluorobenzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1131)

[0344] To prepare Compound 1131, the general procedure 1 of Scheme 1 was modified by replacing 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert-butyl)dimethylsilane in step 4,followed by a subsequent TBDMS deprotection; and replacing 1-phenylmethanamine with (2,4- difluorophenyl)methanamine in step 6. The product was purified by column chromatography (DCM: MeOH=10 :1), followed by SFC separation [instrument: SHIMADZU LC-30AD SFC; method: IC-30%D-2.5; column: DAICEL IC 4.6mmI.D.*250mmL 5µm; mobilephase: CO2 / MEOH [0.1% NH3 (7M Solution in MeOH)] = 70 / 30; flow rate: 2.5 ml / min. LCMS (ESI) m / z = 390.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) .83 (t, J = 5.6 Hz, 1H), 7.62 – 7.52 (m, 2H), 7.43 - 7.37(m, 1H), 7.25 - 7.20 (m, 1H), 7.10 – 7.02 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.80 (t, J = 5.6 Hz, 1H), 4.47 (d, J = 5.2 Hz, 2H), 4.14 (q, J = 6.8 Hz, 1H), 3.62 – 3.48 (m, 3H), 3.31 (s, 3H), 3.24 - 3.18 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H). (R)-N-(2-fluorobenzyl)-1-(2-hydroxyethyl)-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1132)

[0345] To prepare Compound 1132, the general procedure 1 of Scheme 1 was modified by replacing 3-(bromomethyl)oxetane with (2-bromoethoxy)(tert-butyl)dimethylsilane in step 4, followed by a subsequent TBDMS deprotection; and replacing 1-phenylmethanamine with (2- fluorophenyl)methanamine in step 6 The product was purified by column chromatography (DCM: MeOH=10 :1), followed by SFC separation [instrument: SHIMADZU LC-30AD SFC; SFC Method: IC-35%D-2.5; column: DAICEL IC 4.6mmI.D.*250mmL 5µm; mobile Phase: CO2 / MEOH [0.1% NH3 (7M Solution in MeOH)] = 65 / 35; flow rate:2.5ml / min. LCMS (ESI) m / z = 372 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (t, J = 6.0 Hz, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.39 – 7.26 (m, 2H), 7.22 – 7.13 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 4.81 (t, J = 5.6 Hz, 1H), 4.52 (d, J = 5.2 Hz, 2H), 4.14 (q, J = 6.8 Hz, 1H), 3.62 – 3.48 (m, 3H), 3.31 (d, J = 9.2 Hz, 3H), 3.25 – 3.16 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H).N-(2-fluoro-4-(methylsulfonamido)benzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1133)

[0346] To prepare Compound 1133, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 4-(aminomethyl)-3- fluoroaniline in step 6, to afford N-(4-amino-2-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3- ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide. Then, N-(4-amino-2- fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide was modified according to the procedure described in Scheme 1f below. Scheme 1f. Synthesis of N-(2-fluoro-4-(methylsulfonamido)benzyl)-2,4-dimethyl-1-(oxetan-3- ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1133)

[0347] To a solution of N-[(4-amino-2-fluorophenyl)methyl]-2-methyl-4-methyl-1-[(3- oxetanyl)methyl]-3-oxo-1,2,3,4-tetrahydro-6-quinoxalinecarboxamide (150 mg, 0.36 mmol) in DCM (5 mL) was added to methanesulfonyl chloride (41.7 mg, 0.36 mmol) and pyridine (158 mg, 2 mmol). Then the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EA, the organic layer was dried over Na2SO4, filtered and purified by prep-HPLC to afford 2,4-dimethyl-N-(4-(methylsulfonamido)benzyl)-1-(oxetan- 3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 491.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.81 (t, J = 5.6 Hz, 1H), 7.58 (m, 2H), 7.31 (t, J = 8.8 Hz, 1H), 6.98 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 4.64 (m, 2H), 4.44 (d, J = 4.4 Hz, 2H), 4.32 (m, 2H), 4.06 (q, J = 6.4 Hz, 1H), 3.75 (m, 1H), 3.44 (m, 1H), 3.33 (m, 1H), 3.31 (s, 3H), 3.01 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H).N-(4-cyanobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1134)

[0348] To prepare Compound 1134, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 4-(aminomethyl)benzonitrile in step 6. The product was purified by column chromatography (DCM: MeOH=10 :1). LCMS (ESI) m / z = 405.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.99 (t, J = 6.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 4.67 - 4.61 (m, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.08 (q, J = 6.8 Hz, 1H), 3.78 - 3.73 (m, 1H), 3.48 - 3.43 (m, 1H), 3.31 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H). N-(4-acetylbenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1135)

[0349] To prepare Compound 1135, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 1-(4- (aminomethyl)phenyl)ethan-1-one in step 6. (1-(4-(aminomethyl)phenyl)ethan-1-one was synthesized by a Boc group deprotection from tert-butyl (4-acetylbenzyl)carbamate). The product was purified by a prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 422 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 6.0Hz, 1H), 7.92 (d, J = 8.4Hz, 2H), 7.64 – 7.55 (m, 2H), 7.44 (d, J = 8.4Hz, 2H), 6.88 (d, J = 8.4Hz, 1H), 4.68 – 4.60 (m, 2H), 4.54 (d, J= 5.6Hz, 2H), 4.32 (dt, J = 22.4, 6.0Hz, 2H), 4.07 (q, J = 6.8Hz, 1H), 3.79 – 3.71 (m, 1H), 3.49 – 3.42 (m, 1H), 3.37 – 3.31 (m, 4H), 2.56 (s, 3H), 0.99 (d, J = 6.8Hz, 3H). N-(3-acetylbenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamide (Compound 1136)

[0350] To prepare Compound 1136, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with 1-(3- (aminomethyl)phenyl)ethan-1-one in step 6. (1-(3-(aminomethyl)phenyl)ethan-1-one was synthesized by a Boc group deprotection from tert-butyl (3-acetylbenzyl)carbamate). The product was purified by a prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 422.15 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 6.0 Hz, 1H), 7.90 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.63 – 7.55 (m, 3H), 7.51 – 7.46 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.67 – 4.61 (m, 2H), 4.54 (d, J = 6.0 Hz, 2H), 4.32 (dt, J = 22.4, 6.0 Hz, 2H), 4.07 (q, J = 6.8 Hz, 1H), 3.78 – 3.72 (m, 1H), 3.48 – 3.41 (m, 1H), 3.32 – 3.26 (m, 4H), 2.57 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H). N-(4-acetamidobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1137)

[0351] To prepare Compound 1137, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with N-(4- (aminomethyl)phenyl)acetamide in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 437 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.81 (t, J = 5.6 Hz, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.51 (d, J =8.4 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.67-4.60 (m, 2H), 4.45-4.38 (m, 2H), 4.36-4.27 (m, 2H), 4.06 (q, J = 6.8 Hz, 1H), 3.78-3.71 (m, 1H), 3.48-3.41 (m, 1H), 3.34- 3.32 (m, 1H), 3.31 (s, 3H), 2.01 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). N-(3-acetamidobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1138)

[0352] To prepare Compound 1138, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with N-(3- (aminomethyl)phenyl)acetamide in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 437.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.88 (t, J = 6.0 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 11.6 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.67 - 4.61(m, 2H), 4.44 (d, J = 6.0 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.78- 3.73 (m, 1H), 3.48 - 3.42 (m, 1H), 3.31 (s, 3H), 2.01 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). Scheme 1g. Synthesis of N-(2-acetamidobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1139)

[0353] To a solution of N-(2-aminobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1073; 140 mg, 0.355 mmol) in DMF (2 mL) was added to AcOH (21.3 mg, 0.355 mmol) and HATU (270 mg, 0.71 mmol), DIPEA (91.7 mg, 0.71 mmol). Then the reaction mixture was stirred at room temperature for 30 min.Then, the mixture was diluted with water and extracted with EA, the organic layer was dried over Na2SO4, filtered and isolated by prep-HPLC to afford N-(2-acetamidobenzyl)-2,4-dimethyl- 1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 437.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.96 (t, J = 6.0 Hz, 1H), 7.62 (m, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.26 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.64 (m, 2H), 4.45 (d, J = 6.0 Hz, 2H), 4.32 (m, 2H), 4.07 (q, J = 6.4 Hz, 1H), 3.75 (dd, J = 14.4, 6.4 Hz, 1H), 3.40 (m, 2H), 3.31 (s, 3H), 2.12 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). N-(3-methoxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1140)

[0354] To prepare Compound 1140, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoate hydrochloride in step 1; and replacing 1-phenylmethanamine with (3- methoxyphenyl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 410.15 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 6.0Hz, 1H), 7.61 (dd, J = 8.4, 2.0Hz, 1H), 7.56 (d, J = 1.6Hz, 1H), 7.22 (t, J = 8.0Hz, 1H), 6.89 – 6.85 (m, 3H), 6.82 – 6.79 (m, 1H), 4.67 – 4.61 (m, 2H), 4.45 (d, J = 6.0Hz, 2H), 4.32 (dt, J = 22.4, 6.0Hz, 2H), 4.07 (q, J = 6.8Hz, 1H), 3.78 – 3.72 (m, 4H), 3.48 – 3.41 (m, 1H), 3.31 – 3.27 (m, 4H), 0.98 (d, J = 6.8Hz, 3H). N-(2-methoxybenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-carboxamide (Compound 1141)

[0355] To prepare Compound 1141, the general procedure 1 of Scheme 1 was modified by replacing (R)-methyl 2-aminopropanoate hydrochloride with methyl 2-aminopropanoatehydrochloride in step 1; and replacing 1-phenylmethanamine with (2- methoxyphenyl)methanamine in step 6. The product was purified by a prep-HPLC [ACN / H2O (0.5% NH3*H2O)]. LCMS (ESI) m / z = 410.15 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 5.6Hz, 1H), 7.65 – 7.61 (m, 1H), 7.58 (s, 1H), 7.23 (t, J = 7.6Hz, 1H), 7.16 (d, J = 7.6Hz, 1H), 6.99 (d, J = 8.0Hz, 1H), 6.92 – 6.85 (m, 2H), 4.68 – 4.61 (m, 2H), 4.44 (d, J = 6.0Hz, 2H), 4.32 (dt, J = 22.8, 6.0Hz, 2H), 4.07 (q, J = 6.8Hz, 1H), 3.83 (s, 3H), 3.78 – 3.72 (m, 1H), 3.48 – 3.41 (m, 1H), 3.32 – 3.26 (m, 4H), 0.99 (d, J = 6.8Hz, 3H). (R)-N-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)methyl)-2-methyl-4-(methyl-d3)-1- (oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1142)

[0356] To prepare Compound 1142, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (6-(aminomethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide in step 6.6-(aminomethyl)- 2,3-dihydrobenzo[b]thiophene 1,1-dioxide was synthesized according to the procedure described in Scheme 1h below. The product was purified by prep-HPLC [column: CD07-Daisogel SP-100- 8-ODS-PK 150*25*10um; mobile phase: water (NH4HCO3)-ACN; gradient:12%-42% B over 15 min]. LCMS (ESI) m / z = 473.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 6.0 Hz, 1H), 7.77 - 7.38 (m, 5H), 6.88 (d, J = 8.4 Hz, 1H), 4.69 - 4.58 (m, 2H), 4.54 (d, J = 5.6 Hz, 2H), 4.39 - 4.24 (m, 2H), 4.07 (q, J = 6.8 Hz, 1H), 3.75 (dd, J = 6.0, 14.0 Hz, 1H), 3.62 - 3.52 (m, 2H), 3.45 (dd, J = 8.4, 14.0 Hz, 2H), 3.30 - 3.13 (m, 2H), 0.99 (d, J = 6.8 Hz, 3H). Scheme 1h. Synthesis of 6-(aminomethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

[0357] Step 1: Synthesis of benzo[b]thiophene-6-carbonitrile 1,1-dioxide

[0358] To a solution of benzo[b]thiophene-6-carbonitrile (0.2 g, 1.26 mmol) in DCM (6 mL) was added MCPBA (650 mg, 3.77 mmol). The mixture was stirred at 40 °C for 12 h. The solidwas removed by filtration through a pad of Celite and washed with DCM. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (PE / EA = 3 / 1) to afford benzo[b]thiophene-6-carbonitrile 1,1-dioxide.1H NMR (400 MHz, DMSO-d6) δ = 8.20 - 7.99 (m, 3H), 7.67 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H).

[0359] Step 2: Synthesis of 6-(aminomethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

[0360] To a solution of benzo[b]thiophene-6-carbonitrile 1,1-dioxide (110 mg, 575 µmol) in EtOH (5 mL) was added Pd(OH)2(50 mg, 94 µmol) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (40 Psi) at 25 °C for 12 h. The reaction solution was filtered and the filtrate was collected. The crude product was used into next step without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.70 - 7.57 (m, 1H), 7.51 - 7.43 (m, 1H), 7.39 - 7.25 (m, 1H), 3.82 - 3.71 (m, 1H), 3.61 - 3.48 (m, 2H), 3.32 - 3.27 (m, 2H), 3.19 - 3.06 (m, 1H). (R)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-N-((2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-8-yl)methyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1143)

[0361] To prepare Compound 1143, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and replacing 1-phenylmethanamine with (2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)methanamine in step 6. (2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-8-yl)methanamine was synthesized according to the step 2 of the procedure described in Scheme 1h, by replacing benzo[b]thiophene-6-carbonitrile 1,1- dioxide with 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carbonitrile . The product was purified by prep-HPLC [column: CD04-Welch Utimate C18150*25*7um; mobile phase: water (FA)- ACN); B%: 13%-43%, 15 min]. LCMS (ESI) m / z = 454.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.75 (br t, J = 5.6 Hz, 1H), 7.60 (dd, J = 2.0, 8.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 - 6.68 (m, 2H), 6.56 (dd, J = 2.0, 8.0 Hz, 1H), 5.37 (br s, 1H), 4.73 - 4.54 (m, 2H), 4.37 - 4.26 (m, 4H), 4.06 (q, J = 6.8 Hz, 1H), 3.93 (t, J = 5.2 Hz, 2H), 3.74 (dd, J= 6.0, 14.0 Hz, 1H), 3.44 (dd, J = 8.4, 14.0 Hz, 1H), 3.30 - 3.24 (m, 1H), 3.09 - 2.99 (m, 2H), 1.88 - 1.79 (m, 2H), 0.98 (d, J = 6.8 Hz, 3H). (R)-N-(isoindolin-4-ylmethyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1144)

[0362] To prepare Compound 1144, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3in step 3; and replacing 1-phenylmethanamine with tert-butyl 4-(aminomethyl)isoindoline-2-carboxylate in step 6 to afford tert-butyl (R)-4-((2- methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6- carboxamido)methyl)isoindoline-2-carboxylate that was subjected to a Boc deprotection stage to afford the final product. The product was purified by prep-HPLC [column: aters xbridge 150*25mm 10um; mobile phase: water (NH4HCO3)-ACN); 30%-70%, 20 min]. LCMS (ESI) m / z = 424.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.86 - 8.75 (m, 1H), 7.63 - 7.58 (m, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.27 - 7.17 (m, 1H), 7.16 - 7.09 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.68 - 4.59 (m, 3H), 4.42 ( d, J = 5.2 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 4.14 - 4.05 (m, 4H), 3.77 - 3.72 (m, 1H), 3.48 - 3.40 (m, 2H), 0.98 (d, J = 6.8 Hz, 3H). (R)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-N-((3-(trifluoromethyl)-1H-indazol-6- yl)methyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1145)

[0363] To prepare Compound 1145, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3in step 3; and step 6 was modified as follows:

[0364] To a solution of (R)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (50 mg, 170 µmol) in DMF (1 mL) was added HATU (77.8 mg, 205 µmol). The mixture was stirred at 20 °C for 0.5 h before DIPEA (66.1 mg, 511µmol) and (3-(trifluoromethyl)-1H-indazol-6-yl)methanamine (44 mg, 205 µmol) in 1 mL DMF was added [(3-(trifluoromethyl)-1H-indazol-6-yl)methanamine was synthesized according to the synthetic procedure described in Scheme 1b by replacing 4-bromo-7-fluoro-1H-indole with 5- bromo-3-(trifluoromethyl)-1H-indazole]. The reaction mixture was stirred at 250C for 2 hours. The reaction mixture was diluted with EA (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(0.05%FA)-ACN];B%: 24%-54%,10min) to afford (R)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-N-((3- (trifluoromethyl)-1H-indazol-6-yl)methyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 491.0 [M+H]+;1H NMR (400 MHz, Chloroform-D) δ 11.76 - 9.96 (m, 1H), 8.04 (s, 1H), 7.80 (s, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.52 (s, 2H), 7.38 (dd, J = 1.6, 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.50 (br t, J = 5.6 Hz, 1H), 4.86 - 4.78 (m, 4H), 4.41 (td, J = 5.8, 11.1 Hz, 2H), 4.00 (q, J = 6.8 Hz, 1H), 3.79 (dd, J = 6.3, 13.4 Hz, 1H), 3.45 - 3.31 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H). (R)-2-methyl-4-(methyl-d3)-N-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-1- (oxetan-3-ylmethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide (Compound 1146)

[0365] To prepare Compound 1146, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d3 in step 3; and step 6 was modified as follows:

[0366] To a solution of (R)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxylic acid (50 mg, 170 µmol) in DMF (1 mL) was added HATU (84.3 mg, 222 µmol). The mixture was stirred at 20 °C for 0.5 h before DIPEA (66.1 mg, 511 µmol) and (4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methanamine (60.8 mg, 341 µmol) was added [(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methanamine was synthesized according to the synthetic procedure described in Scheme 1h, by replacing benzo[b]thiophene-6-carbonitrile 1,1-dioxide with 4-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbonitrile]. The mixture was stirred for additional 2 h. The mixturewas diluted with 5 mL water and extracted by EA (3 × 5 mL). The combine organic layer was washed by brine (2 × 5 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by pre- HPLC (Column: Phenomenex Gemini 150*25mm*10um, water(0.1% NH3•H2O )-ACN, 48-55% ACN, 10 min) to afford (R)-2-methyl-4-(methyl-d3)-N-((4-methyl- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide. LCMS (ESI) m / z = 454.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.71 (br t, J = 5.6 Hz, 1H), 7.58 (br d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.72 (br d, J = 8.4 Hz, 1H), 6.67 - 6.57 (m, 2H), 4.69 - 4.59 (m, 2H), 4.34 (t, J = 5.6 Hz, 1H), 4.32 - 4.24 (m, 3H), 4.22 - 4.16 (m, 2H), 4.05 (q, J = 6.8 Hz, 1H), 3.74 (br dd, J = 6.0, 13.6 Hz, 1H), 3.44 (br dd, J = 8.4, 13.6 Hz, 1H), 3.27 (br s, 1H), 3.20 - 3.12 (m, 2H), 2.78 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H). (R)-N-(3-fluoro-2-methylbenzyl)-2-methyl-4-(methyl-d3)-1-(oxetan-3-ylmethyl)-3-oxo-1,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 1147)

[0367] To prepare Compound 1147, the general procedure 1 of Scheme 1 was modified by replacing iodomethane with 1-iodoethane-2,2,2-d...

Claims

CLAIMS 1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:(I), wherein in formula (I): X is a moiety comprising one or more groups selected from -NRa-, -S-, -S(O)-, -S(O)2-, -O-, C(O), -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)S-, -SC(O)-, -OC(O)S-, -SC(O)O-, -C(O)NRa-, -NRaC(O)-, -CRa=N-NRa-, -C(O)NRaSO2-, -SO2NRaC(O)-, -OC(O)NRa-, -NRaC(O)O-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; A1is N or CR5; A2is N or CR6; A3is N or CR8; R1is selected from optionally substituted C1-C6alkyl and optionally substituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C3-C6cycloalkyl, and optionally substituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety comprising one or more groups selected from C(O), -C(O)O-, -C(O)S-, -C(O)NRa-,-S(O)-, -S(O)2-, -C(O)NRaSO2-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; R4is selected from -C(O)Ra, C(O)ORa, C(O)N(Ra)2, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl,optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; R5, R6, and R8are each independently selected from H, deuterium, halide, -CN, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, -OH, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; t is 1 or 2; R7is selected from -ORa, -C(O)Ra, C(O)ORa, C(O)N(Ra)2, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; and Rais independently at each occurrence selected from H, deuterium, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein X is a moiety comprising one or more groups selected from -NRa-, -S-, -S(O)-, -S(O)2-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NRa-, -NRaC(O)-, -OC(O)NRa-, -NRaC(O)O-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R5, R6, and R8are each independently selected from H, deuterium, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, trimethylsilanyl, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -S(O)tN(Ra)2,-S(O)tORa, -P(O)(ORa)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted C1-C6alkoxy, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and t is 1 or 2.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, deuterium, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein A1is N or CR5; A2 is N or CR6; and A3is CR8.

6. The compound of any one of claims 1 to 5, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (II):, wherein in formula (II): X is a moiety comprising one or more groups selected from -NRa-, -S-, -S(O)-, -S(O)2-, -O-, C(O), -C(O)NRa-, -NRaC(O)-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heterocycloalkylene; A1is N or CR5;A2 is N or CR6; R1is selected from optionally substituted C1-C4alkyl and unsubstituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety selected from -C(O)-, -C(O)NRa-, -S(O)-, -S(O)2-, optionally substituted alkylene, optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and optionally substituted heteroalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; R5, R6, and R8are each independently selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -S(O)tORa, -P(O)(ORa)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted C1-C6alkoxy, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; t is 1 or 2; R7is selected from -ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, deuterium, optionally substituted C1-C4alkyl, optionally substituted C1-C4haloalkyl, optionally substituted phenyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein X is a moiety comprising one or more groups selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted alkylene,optionally substituted haloalkylene, optionally substituted arylene, optionally substituted cycloalkylene, and unsubstituted heterocycloalkylene.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein X is a moiety comprising one or more groups selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted C1-C10alkylene, optionally substituted C1-C10haloalkylene, optionally substituted C6-C10arylene, optionally substituted C3-C6cycloalkylene, and unsubstituted 3- to 10-membered heterocycloalkylene.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein L is a bond or a moiety selected from C(O), -S(O)2-, optionally substituted C1-C10alkylene, optionally substituted C1-C10haloalkylene, optionally substituted C6-C10arylene, and optionally substituted C3-C6cycloalkylene.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R5, R6, and R8are each independently selected from H, halide, -CN, -OH, -NO2, -ORa, -N(Ra)2, -S(O)tORa, optionally substituted C1-C6alkyl, unsubstituted C1-C6haloalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C6alkoxy, unsubstituted 3- to 6-membered heteroalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; and t is 1 or 2.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein: R5and R6are each independently selected from H, halide, -OH, -NO2, -ORa, -N(Ra)2, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl; andR8is selected from H, halide, -CN, -OH, -NO2, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, unsubstituted C3-C5 cycloalkyl, unsubstituted C1-C3alkoxy, and unsubstituted 3- to 5-membered heterocycloalkyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, optionally substituted phenyl, optionally substituted benzyl, unsubstituted C3-C6cycloalkyl, unsubstituted 3- to 6-membered heteroalkyl, unsubstituted 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocycloalkyl.

13. The compound of any one of claims 1 to 12, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (III):(III), wherein in formula (III): W is a bond or a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted C1-C6alkylene, optionally substituted C1-C6haloalkylene, optionally substituted C6-C10arylene, optionally substituted C3-C6cycloalkylene, and unsubstituted 3- to 6-membered heterocycloalkylene; X1is a moiety selected from -C(O)-, -C(O)NRa-, -NRaC(O)-, and optionally substituted C1-C4alkylene; R1is selected from optionally substituted C1-C4alkyl and unsubstituted C3-C6cycloalkyl; R3is selected from H, optionally substituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 6-membered heterocycloalkyl; L is a bond or a moiety selected from -C(O)-, optionally substituted C1-C6alkylene, optionally substituted C1-C6haloalkylene, and optionally substituted C3-C6cycloalkylene;R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; R5and R6are each independently selected from H, halide, -OH, -ORa, -N(Ra)2, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, optionally substituted C6-C10aryl, unsubstituted C3-C6cycloalkyl, and unsubstituted C1-C4alkoxy; R8is selected from H, halide, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, unsubstituted C3-C5cycloalkyl, and unsubstituted C1-C3alkoxy; R7is selected from-ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 10-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, optionally substituted phenyl, optionally substituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein X1is a moiety selected from -C(O)-, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)-, -N(CH3)C(O)-, and unsubstituted C1-C4alkylene.

15. The compound of claim 13 or claim 14, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein X1is a moiety selected from -C(O)-, -C(O)NH-, -NHC(O)-, -N(CH3)C(O)-, and -CH2-.

16. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein W is a bond or a moiety selected from -C(O)NH-, optionally substituted C1-C4alkylene, optionally substituted C1- C4haloalkylene, optionally substituted phenylene, and unsubstituted C3-C6cycloalkylene.

17. The compound of any one of claims 1 to 16, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (IVa) or formula (IVb):

18. The compound of any one of claims 1 to 17, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R3is selected from H, optionally substituted C1-C4alkyl, unsubstituted C1-C4fluoroalkyl, unsubstituted C3-C5cycloalkyl, and unsubstituted 4- to 6-membered heterocycloalkyl.

19. The compound of any one of claims 1 to 18, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein: R5and R6are each independently selected from H, halide, -ORa, -NHRa, unsubstituted C1-C4alkyl, optionally substituted phenyl, unsubstituted C1-C4alkoxy, and unsubstituted 3- to 6-membered heterocycloalkyl; and R8is selected from H, halide, unsubstituted C1-C3alkyl, unsubstituted C1-C3fluoroalkyl, and unsubstituted C1-C3alkoxy.

20. The compound of any one of claims 1 to 19, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, -CH3, -CH2CH3, -CH2CH2CH3, optionally substituted phenyl, optionally substituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl.

21. The compound of any one of claims 1 to 20, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (V):, wherein in formula (V): W is a bond or a moiety selected from optionally substituted C1-C4alkylene, optionally substituted C1-C3haloalkylene, optionally substituted phenylene, and unsubstituted C3-C6cycloalkylene; R1is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, deuterated methyl (-CD3), -CH2CH2OH, unsubstituted cyclopropyl, and unsubstituted cyclobutyl; R3is selected from H, optionally substituted C1-C3alkyl, unsubstituted C1-C4fluoroalkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted oxetane, unsubstituted azetidine, unsubstituted tetrahydrofuran, unsubstituted pyrrolidine, unsubstituted tetrahydropyran, and unsubstituted piperidine; L is a bond or a moiety selected from C(O), optionally substituted C1-C3alkylene, and unsubstituted C1-C3haloalkylene; R4is selected from -C(O)N(Ra)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; R5and R6are each independently selected from H, halide, -ORa, -NHRa, unsubstituted C1-C4alkyl, optionally substituted phenyl, and unsubstituted C1-C3alkoxy; and R8is selected from H, halide, and unsubstituted C1-C3alkyl; R7is selected from -ORa, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6cycloalkyl, optionallysubstituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; and Rais independently at each occurrence selected from H, -CH3, optionally substituted phenyl, optionally substituted benzyl, and unsubstituted C3-C6cycloalkyl.

22. The compound of any one of claims 13 to 21, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein W is a bond or a moiety selected from optionally substituted C1-C3alkylene, unsubstituted C1-C3haloalkylene, optionally substituted phenylene, and unsubstituted C3-C5cycloalkylene.

23. The compound of any one of claims 13 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein W is a bond or a moiety selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CD2-, -CD2CD2-, -CH2CD2-, -CD2CH2-, -CF2-, -CF2CF2-, -CH2CF2-, -CF2CH2-, optionally substituted phenylene, unsubstituted cyclopropylene, and unsubstituted cyclobutylene.

24. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, unsubstituted C1-C4haloalkyl, unsubstituted phenyl, unsubstituted benzyl, unsubstituted C3-C6cycloalkyl, unsubstituted 3- to 6-membered heteroalkyl, unsubstituted 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocycloalkyl.

25. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, unsubstituted C1-C4alkyl, unsubstituted phenyl, unsubstituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl.

26. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, -CH3, -CH2CH3, -CH2CH2CH3, unsubstituted phenyl,unsubstituted benzyl, unsubstituted C3-C6cycloalkyl, and unsubstituted 3- to 5-membered heterocycloalkyl.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, -CH3, unsubstituted phenyl, unsubstituted benzyl, and unsubstituted C3-C6cycloalkyl.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R5is selected from H, Cl, F, Br, optionally substituted -O-phenyl, optionally substituted -NH-phenyl, -CH3, -CH2CH3, -CH2CH2CH3, optionally substituted phenyl, -OCH3, -OCH2CH3, and -OCH2CH2CH3.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R5is selected from H, Cl, F, Br, unsubstituted -O-phenyl, unsubstituted -NH-phenyl, -CH3, -CH2CH3, -CH2CH2CH3, unsubstituted phenyl, -OCH3, -OCH2CH3, and -OCH2CH2CH3.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R6is selected from H, Cl, F, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, and -OCH2CH3.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R8is H or halide.

32. The compound of any one of claims 1 to 31, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (VIa) or formula (VIb):formula (VIa) formula (VIb).

33. The compound of any one of claims 13 to 32, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein W is a bond or a moiety selected from -CH2-, -CH2CH2-, -CD2-, -CF2CH2-, unsubstituted -CH2-phenylene, and unsubstituted cyclopropylene.

34. The compound of any one of claims 13 to 33, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein W is a bond or a moiety selected from.

35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R1is selected from -CH3, -CH2CH3, -CH(CH3)2, deuterated methyl (-CD3), -CH2CH2OH, and unsubstituted cyclopropyl.

36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R3is selected from H, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CFH2, -CF3, -CH2CHF2, unsubstituted benzyl, unsubstituted cyclopropyl, and unsubstituted oxetane.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R3is selected from -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CFH2, -CF3, -CH2CHF2, unsubstituted cyclopropyl, and unsubstituted oxetane.

38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein L is a bond or a moiety selected from -C(O)-, -CD2-, -CH2-, -CH2CH2-, and -CH(CH3)-.

39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R4is selected from -C(O)NH2, optionally substituted C1-C4alkyl, optionally substituted C1-C3haloalkyl, optionally substituted phenyl, optionally substituted C3-C4cycloalkyl, optionally substituted 5- to 9-membered heteroaryl, and optionally substituted 4- to 7-membered heterocycloalkyl.

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R5is selected from H, unsubstituted phenyl, unsubstituted -O-phenyl, unsubstituted -NH-phenyl, -OCH3, and F.

41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R6is selected from H, -CH3, -OCH3, F, and Cl.

42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R8is selected from H and F.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R7is selected from -OH, unsubstituted C1-C6alkyl, unsubstituted C1-C6haloalkyl, optionally substituted C6-C10aryl,optionally substituted C3-C5 cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 11-membered heterocycloalkyl.

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R7is selected from -CH3, -CH2CF3, optionally substituted C6-C10aryl, optionally substituted C3-C5cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 11-membered heterocycloalkyl.

45. The compound of claim 1, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to any one of formula 1001-1595.

46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

47. A method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

48. A method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 46.

49. The method of claim 47 or claim 48, wherein the disease or disorder is an inflammatory disease or an autoimmune disease.

50. The method of any one of claims 47 to 49, wherein the disease or disorder is selected from chronic or acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis (RA),cardiovascular disease, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, reactive arthritis, Reiter’s syndrome, gouty arthritis, psoriasis, erythrodermic psoriasis, pustular psoriasis, dermatitis, scleroderma, Raynaud’s syndrome, Sjögren’s syndrome, inflammatory bowel disease, intestinal fibrosis, Crohn’s disease, enteropathic arthritis, ulcerative colitis, colitis, diverticulitis, nephritis, urethritis, salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupus erythematosus, multiple sclerosis (MS), meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis, thrombophlebitis, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), inflammatory lung disease, allergic rhinitis, endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valve disease, rheumatic aortic valve disease, prostatitis, prostatocystitis, spondyloarthritis, ankylosing spondylitis, synovitis, tenosynovotis, myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis, bursitis, gout, pseudogout, vasculitides, granulomatous thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis, acute thyroiditis, Hashimoto’s disease, Kawasaki’s disease, neuroinflammatory disease, sepsis, conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis, lymphadenitis, nasopharyngitis, sinusitis, pharyngitis, tonsillitis, laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis, esophagitis, gastritis, peritonitis, hepatitis, cholelithiasis, cholecystitis, glomerulonephritis, Goodpasture syndrome, crescentic glomerulonephritis, pancreatitis, endometritis, myometritis, metritis, cervicitis, endocervicitis, exocervicitis, parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis, pneumoconiosis, hidradenitis suppurativa (HS), obesity, obesity-related inflammation, Still’s disease, systemic juvenile idiopathic arthritis (SJIA), adult-onset Still’s disease (AOSD), macrophage activation syndrome, and inflammatory polyarthritis.

51. The method of any one of claims 47 to 50, wherein the disease or disorder is selected from rheumatoid arthritis (RA), cardiovascular disease, multiple sclerosis (MS), osteoarthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa (HS), obesity-related inflammation, Still’s disease, systemic juvenile idiopathic arthritis (SJIA), adult-onset Still’s disease (AOSD), and macrophage activation syndrome.

52. The method of any one of claims 47 to 51, wherein the disease or disorder is alleviated by inhibiting bromodomain and extra-terminal domain (BET) protein activity in the patient.

53. The method of any one of claims 47 to 52, wherein the disease or disorder is alleviated by inhibiting BRD4 protein activity in the patient.

54. The compound of any one of claims 1 to 45, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a cellular activity of at least about 10 μM as measured by an in vitro cellular assay.

55. The compound of any one of claims 1 to 45, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has an IC50 of about 1 μM or less.

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