Tricyclic 5-HT2ar agonists and uses thereof

Abstract

The present disclosure relates to compounds useful for activating 5-hydroxytryptamine 2A receptor (5-HT2AR), pharmaceutically acceptable compositions thereof, and methods of using said compounds and compositions. Formula (I).

Description

TRICYCLIC 5-HT2AR AGONISTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 693.439, filed September 11, 2024: U.S. Provisional Application No. 63 / 755,598, filed February 7, 2025; and U.S. Provisional Application No. 63 / 872,477, filed August 29, 2025; the contents of each of which are herein incorporated by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods useful for activating the 5- hydroxytryptamine 2A receptor (5-HT2AR). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION

[0003] Agonists of the 5-HT2AR may have potential as pharmacals for a variety of neurological diseases and disorders including, but not limited to, depression, anxiety, substance abuse, migraine headaches, and / or cluster headaches, and various somatic illnesses including, but not limited to, various inflammatory cardiovascular, and / or pain disorders. As such, 5-HT2AR agonists hold promise as therapeutic agents.SUMMARY OF THE INVENTION

[0004] The present application relates to compounds as agonists of 5-HT2AR, and methods of preparation and uses thereof. 5-HT2AR is a target of interest, owing to its role in psychiatric disorders including psychosis, depression, dyskinesia, and hallucination (Slocum et al., 2021). Although 5-HT2AR agonists have been developed, few are selective for this receptor over related subtypes, for example, the 5- HT2B receptor, a toxicology anti-target strongly implicated in serious side effects including drug-induced valvular heart disease.

[0005] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, arc effective as agonists of 5-HT2AR. In some embodiments, the present disclosure provides a compound of formula I:1BUSINESS.33510111.1T or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0006] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of 5-HT2AR. Such diseases, disorders, or conditions include those described herein.

[0007] Compounds provided by this invention are also useful for the study of 5-HT2AR in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new 5-HT2AR modulators, in vitro or in vivo.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Invention:

[0008] Compounds of the present invention, and pharmaceutical compositions thereof, are useful as agonists of 5-HT2AR. In some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, is an agonist of 5-HT2AR.

[0009] In some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0010] In another aspect, the present disclosure provides methods of treating and / or preventing a 5- HT2AR-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0011] In another aspect, the present disclosure provides methods of treating and / or preventing a neurological disease, disorder, or condition in a patient in need thereof, comprising administering to the2BUSINESS.33510111.1patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0012] In another aspect, the present disclosure provides methods of activating the 5- hydroxy try plain inc 2A receptor (5-HT2AR) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmacally acceptable composition thereof.

[0013] In another aspect, the present disclosure provides methods of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a |3-arrestin signaling pathway associated with 5- HT2AR in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmacally acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0014] In another aspect, the present disclosure provides methods of selectively activating the 5- hydroxytryptamine 2A receptor (5-HT2AR) (e.g., over the 5-HT2B and / or 5-HT2C receptors) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0015] In another aspect, the present disclosure provides methods of treating and / or preventing a 5- HT2AR-mediated disorder in a patient in need thereof, and / or methods of activating the 5- hydroxy tryptamine 2A receptor (5-HT2AR) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmacally acceptable salt thereof, or a pharmaceutically acceptable composition thereof, wherein the patient does not experience a hallucinogenic effect as a result of the activating or treating.2. Compounds and Definitions:

[0016] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of th is invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which arc hereby incorporated by reference.

[0017] The tenn “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also3BUSINESS.33510111.1referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic Cs-Ce hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0018] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:4BUSINESS.33510111.1

[0019] The term “lower alkyl” refers to a CM straight or branched alkyl group. Exemplar}’ lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized fonn of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-277-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)).

[0021] The tenn "unsaturated." as used herein, means that a moiety has one or more units of unsaturation.

[0022] As used herein, the term “bivalent Ci-s (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkcnylcnc, and alkynylcnc chains that arc straight or branched as defined herein.

[0023] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0024] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0025] As used herein, the term “cyclopropylcnyl” refers to a bivalent cyclopropyl group of the following structure:

[0026] Tire tenn “halogen” means F, Cl, Br, or I.

[0027] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy.” or5BUSINESS.33510111.1“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to. phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and tire like. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl).

[0028] Tire terms “heteroaryl” and “hctcroar-,” used alone or as part of a larger moiety, c.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms: having 6, 10, or 14 % electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tctrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / 7 quinol iziny I. carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl. tetraliydroquinolinyl, tetrahydroisoquinolinyl. and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. The temr “heteroarylenyl” refers to bivalent heteroaryl groups (e.g.. pyridylenyl).

[0029] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical.” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3.4-dihydro-2 / / pyrrolyl). NH (as in pyrrolidinyl), or+NR (as in6BUSINESS.33510111.1' substituted pyrrolidinyl).

[0030] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyL dioxanyl, dioxolanyL diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms ’‘heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H- indolyl. chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0031] As used herein, the temi “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. Hie term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties. as herein defined.

[0032] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety of compounds are replaced with a suitable substituent. “Substituted”). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the fonnation of stable or chemically feasible compounds. Hie term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or7BUSINESS.33510111.1410095-001WG (221124) more of the purposes disclosed herein.

[0033] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; (CI [?) >4F<OI -(CB I2)u4OR°: -0(CBl2)o 4R0, -0-(CBB2)OMC(0)OR°; - (CH2)CMCH(OR°)2; -(CH;)„ 4SR0; -(Cffrfr 4 Ph. which may be substituted with R°; -(CH2)N40(CBl2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CBI2)OMO(C1-I2)O 1- pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o^N(R°)2; -(CH2)0^N(R°)C(O)R°; - N(R°)C(S)R°; -(CH2)O4N(R°)C(0)NRO2; -N(RO)C(S)NR°2; -(CH2)OMN(R°)C(0)OR0;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)„4C(O)R°; -C(S)R°; - (CH2)(I 4C(O)OR°; -(CH2)OMC(0)SR°; -(CH2)NJZ’(O)OSIR°3: -(CH2)0MOC(O)R°; -OC(O)(CH2)„4S R°; - (CH2)CMSC(O)R°; -(CH2)OMC(0)NR02; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)OMSSR°; -(CH2)O 4S(O)2R°; -(CH2)„4S(0)20RO; -(CH2)OMOS(0)2R°; -S(O)2NRO2; -(CH2)OMS(0)R°; -N(R°)S(O)2NRO2; - N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CI I2)o4P(0)2R°; -(CH2)OMP(0)R02; -(CH2)OMOP(0)R02; - (CH2)CMOP(O)(OR°)2; SiR0?,; -(CM straight or branched alkylene)O-N(R°)2; or -(CIM straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-e aliphatic, -CH2Ph, 0(CB42)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0034] Suitable monovalent substituents on R° (or the ring fonned by taking two independent occurrences of R° together with their intervening atoms), are independently halogen. -(C142)o 2R*. -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(CIM straight or branched alkylene)C(O)OR*, or - SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CIM aliphatic. -CH2PI1. -0(CBl2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0035] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0. =S. =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*. =NOR*, - O(C(R*2))2-3O-, or-S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen,8BUSINESS.33510111.1Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-e aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR’, -O(haloR*), -CN, -C(O)OH, -C(O)OR’, -NH2, -NHR*. -NR\ or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Cu aliphatic, -CH2PI1. -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include - R:. -NR'2. -C(O)Rt, -C(O)OR\ -C(O)C(O)Rf, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NR*2, -C(S)NRf2, - C(NH)NR12, or -N(R:)S(O)2R:; wherein each R' is independently hydrogen, Ci , aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or and ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R'. taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or ary l mono- or bicyclic ring having 0-4 hctcroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on the aliphatic group of R;are independently halogen, -R*, -(haloR*), - OH. -OR*, -O(haloR’). -CN. -C(O)OH, -C(O)OR*. -NH2, -NHR*. -NR’2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Cw aliphatic, -CH2Ph, -O(CH2)0-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] As used herein, the term "pharmacally acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmacally acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacal Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C’i 4alkyl)4 salts. In some embodiments, the provided compounds are purified in salt form for9BUSINESS.33510111.1410095-001WG (221124) convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention

[0042] As used herein, the term about" refers to within 20% of a given value. In some embodiments, the term '‘about” refers to within 20%, 19%. 18%. 17%. 16%. 15%. 14%. 13%. 12%. 11%, 10%, 9%. 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.3. Description of Exemplary Embodiments:

[0043] In some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X is N or CR4; each of R1, R2, R3, or R4is independently selected from hydrogen, halogen, -CN, -OR’, -NR2, -C(O)R -10BUSINESS.33510111.1C(0)NR.2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; orR1and R2. R2and R3, or R3and R4may be taken together to fonn an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R5is hydrogen or an optionally substituted group selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;Rbis hydrogen or optionally substituted Ci-6 aliphatic; each R7is independently selected from halogen, -CN, -OR, -NR:, or an optionally substituted Ci-e aliphatic; or two R7groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R7groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged carbocyclyl or bridged heterocyclyl having 1 - 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently hydrogen or optionally substituted Ci-e aliphatic; and n is 0, 1, 2, 3, 4, 5. 6, 7, or 8.

[0044] As defined above and described herein, X1is N or CR1. In some embodiments. X1is N. In some embodiments, X1is CR1.

[0045] As defined above and described herein, X2is N or CR2. In some embodiments, X2is N. In some embodiments, X2is CR2.

[0046] As defined above and described herein, X3is N or CR3. In some embodiments, X3is N. In some embodiments. X3is CR3.

[0047] As defined above and described herein, X4is N or CR4. In some embodiments, X4is N. In some embodiments, X4is CR4.

[0048] In some embodiments, at least one of X1. X2. X3. or X4is N. In some embodiments, at least one of R1, R2, R3, or R4is not hydrogen.

[0049] As defined above and described herein, each of R1, R2, R3, or R4is independently selected from hydrogen, halogen, -CN, -OR5, -NR:, -C(O)R, -C(O)NR:, -C(O)OR, or an optionally substituted group11BUSINESS.33510111.1selected from Ci.6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R1and R2, R2and R3, or R3and R4may be taken together to form an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] In some embodiments, R1is selected from hydrogen, fluoro, chloro, -CN, -OR’, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5 - to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] In some embodiments, R1is selected from fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is selected from hydrogen, fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is selected from fluoro, chloro, -CN, -OR5, - NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5 - to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is fluoro. In some embodiments, R1is chloro. In some embodiments, R1is bromo. In some embodiments, R1is -CN.

[0053] In some embodiments, R1is -OR’. In some embodiments, R1is -OH. In some embodiments, R1is -OCH3. In some embodiments, R1is -OCH2CH3. In some embodiments, R1is -OCH(CH3)2. In some embodiments, R1is -OCF3.

[0054] In some embodiments, R1is -NR2. In some embodiments, R1is -NH2. In some embodiments, R1is -NR2, wherein each R is independently C1-6 aliphatic.

[0055] In some embodiments, R1is -C(O)NR2. In some embodiments, R1is -C(O)NH2. In some embodiments, R1is -C(O)NR2, wherein each R is independently C1.6 aliphatic.

[0056] In some embodiments, R1is -C(O)OR. In some embodiments, R1is -C(O)OH. In some12BUSINESS.33510111.1embodiments, R1is -C(O)OR, wherein R is Ci .6 aliphatic.

[0057] In some embodiments, R1is -NRC(O)R. In some embodiments, R1is -NHC(O)R. In some embodiments, R1is -NHC(O)R, wherein R is Ci-6 aliphatic.

[0058] In some embodiments, R1is -OC(O)R. In some embodiments. R1is -OC(O)R, wherein R is Ci-6 aliphatic.

[0059] In some embodiments, R1is optionally substituted Ci-e aliphatic. In some embodiments, R1is Ci-6 aliphatic. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is n-propyl. In some embodiments, R1is isopropyl. In some embodiments, R1is n-butyl. In some embodiments, R1is s-butyl. In some embodiments. R1is t-butyl.

[0060] In some embodiments, R1is. In some embodiments. R1is ' . In some embodiments, R1is '

[0061] In some embodiments, R1is C1.6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R1is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R1is -CH2F. In some embodiments, R1is -CHF2. In some embodiments, R1is -CF3. In some embodiments, R1is -CH2CF3. In some embodiments, R1is Ci-e aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R1is - CH2OH.

[0062] In some embodiments, R1is -CF2CH3. In some embodiments, R1is -CH(CH3)CF3. In some embodiments, R1. ,

[0063] In some embodiments, R1is -CH(CH3)OH. In some embodiments, R1. In some embodiments, R1. In some embodiments, R1is -CfCFfehOH. In some embodiments, R1is - C(CH3)2OCH3.

[0064] In some embodiments, R1is an optionally substituted 3- to 8-mcmbcrcd saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted13BUSINESS.33510111.1cyclopropyl. In some embodiments, R1is an optionally substituted cyclobutyl . In some embodiments, R1is an optionally substituted cyclopentyl . In some embodiments, R1is an optionally substituted cyclohexyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is cyclobutyl. In some embodiments, R1is cyclopentyl. In some embodiments, R1is cyclohexyl.

[0065] In some embodiments,

[0066] In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted oxetanyl. In some embodiments, R1is an optionally substituted tetrahydrofuranyl. In some embodiments, R1is an optionally substituted tetrahydropyranyl. In some embodiments,.

[0067] In some embodiments, R1is an optionally substituted phenyl. In some embodiments, R1is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted oxazolyl. In some embodiments. R1is an optionally substituted isooxazolyl. In some embodiments, R1is an oxazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments, R1is isoxazolyl optionally substituted with -R°, wherein -R° is Ci.e aliphatic. In some embodiments,

[0068] In some embodiments, R1is optionally substituted pyrazolyl. In some embodiments, R1is optionally substituted imidazolyl. In some embodiments, R1is pyrazolyl optionally substituted with -R°, wherein -R° is Ci-e aliphatic. In some embodiments, R1is imidazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments, R1is

[0069] In some embodiments, R1is hydrogen, fluoro, chloro, bromo. -CN. -OH. -OCHs. -OCH2CH3,-NH2, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2OH, -CH2CF3, cyclopropyl, cyclobutyl. cyclohexyl,14BUSINESS.33510111.1

[0070] In some embodiments, R1is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -NH?, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2OH, -CH2CF3, cyclopropyl, cyclobutyl,

[0071] In some embodiments, R1is hydrogen, fluoro, chloro, bromo. -CN. -OH. -OCH3. -OCH2CH3,

[0072] In some embodiments, R2is selected from hydrogen, fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5 - to 6-membered hctcroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0073] In some embodiments, R2is selected from fluoro, chloro, -CN, -OR5. -NR2, -C(O)R, -C(O)NR2, -C(O)OR. or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is selected from hydrogen, fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is selected from fluoro, chloro, -CN, -OR5, - NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered hctcroary l having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0074] In some embodiments, R2is hydrogen. In some embodiments, R2is halogen. In some15BUSINESS.33510111.1embodiments, R2is fluoro. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is -CN.

[0075] In some embodiments, R2is -OR5. In some embodiments, R2is -OH. In some embodiments, R is -OCHs In some embodiments, R2is -OCH2CH3. In some embodiments, R2is -OCH(CH3)2. In some embodiments, R2is -OCF3.

[0076] In some embodiments, R2is -NR2. In some embodiments, R2is -NH2. In some embodiments, R2is -NR2, wherein each R is independently C1-6 aliphatic.

[0077] In some embodiments, R2is -C(O)NR2. In some embodiments, R2is -C(O)NH2. In some embodiments, R2is -C(O)NR2, wherein each R is independently C1-6 aliphatic.

[0078] In some embodiments, R2is -C(O)OR. In some embodiments, R2is -C(O)OH. In some embodiments, R2is -C(O)OR, wherein R is C1-6 aliphatic.

[0079] In some embodiments, R2is -NRC(O)R. In some embodiments, R2is -NHC(O)R. In some embodiments, R2is -NHC(O)R, wherein R is C1-6 aliphatic.

[0080] In some embodiments, R2is -OC(O)R. In some embodiments. R2is -OC(O)R, wherein R is Cue aliphatic.

[0081] In some embodiments, R2is optionally substituted Ci-e aliphatic. In some embodiments, R2is C1-6 aliphatic. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is n-propyl. In some embodiments, R2is isopropyl. In some embodiments, R2is n-butyl. In some embodiments, R2is s-butyl. In some embodiments. R2is t-butyl.

[0082] In some embodiments, R2isIn some embodiments, R2isIn some embodiments.

[0083] In some embodiments, R2is C1-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R2is Ci-e aliphatic, optionally substituted with halogen. In some embodiments, R2is -CHF2. In some embodiments, R2is -CF3. In some embodiments, R2is -CH2CF3. In some embodiments, R2is C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R2is -CH2OH.

[0084] In some embodiments, R2is -CF2CH3. In some embodiments, R2is -CH(CH3)CF3. In some embodiments, R2is. In some embodiments, R2is16BUSINESS.33510111.1

[0085] In some embodiments, R2is -CH(CH3)OH. In some embodiments, R2is. In some embodiments, R2is. In some embodiments, R2is -C(CH3)3OH. In some embodiments, R2is -C(CH3)2OCH3.

[0086] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R2is an optionally substituted cyclopropyl. In some embodiments, R2is an optionally substituted cyclobutyl. In some embodiments, R2is an optionally substituted cyclopentyl. In some embodiments, R2is an optionally substituted cyclohexyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is cyclobutyl. In some embodiments, R2is cyclopentyl. In some embodiments, R2is cyclohexyl.

[0087] In some embodiments,

[0088] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted oxetanyl. In some embodiments, R2is an optionally substituted tctrahydrofuranyl. In some embodiments, R2is an optionally substituted tctrahydropyranyl. In some embodiments,

[0089] In some embodiments, R2is an optionally substituted phenyl. In some embodiments, R2is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted oxazolyl. In some embodiments, R2is an optionally substituted isooxazolyl. In some embodiments, R2is an oxazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments, R2is isoxazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments,17BUSINESS.33510111.1

[0090] In some embodiments, R2is optionally substituted pyrazolyl. In some embodiments, R2is optionally substituted imidazolyl. In some embodiments, R2is pyrazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments, R2is imidazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments, R2is

[0091] In some embodiments, R2is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3,-NHz, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2OH, -CH2CF3, cyclopropyl, cyclobutyl, cyclohexyl,

[0092] In some embodiments, R2is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3,-NH2, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2OH, -CH2CF3, cyclopropyl, cyclobutyl,

[0093] In some embodiments, R2is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3,

[0094] In some embodiments, R3is selected from hydrogen, fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5 - to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0095] In some embodiments, R3is selected from fluoro, chloro, -CN, -OR5. -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, a 3- to 8-membered saturated or18BUSINESS.33510111.1partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is selected from hydrogen, fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is selected from fluoro, chloro, -CN, -OR’, - NR2, -C(O)R, -C(O)NR3, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0096] In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is -CN.

[0097] In some embodiments, R3is -OR5. In some embodiments, R3is -OH. In some embodiments, R3is -OCH3. In some embodiments, R3is -OCH2CH3. In some embodiments, R3is -OCH(CH3)2. In some embodiments, R3is -OCF3.

[0098] In some embodiments, R3is -NR2. In some embodiments, R3is -NH2. In some embodiments, R3is -NR2, wherein each R is independently C1.6 aliphatic.

[0099] In some embodiments, R3is -C(O)NR3. In some embodiments, R3is -C(O)NH2. In some embodiments, R3is -C(O)NR2, wherein each R is independently C1-6 aliphatic.

[0100] In some embodiments, R3is -C(O)OR. In some embodiments, R3is -C(O)OH. In some embodiments, R3is -C(O)OR, wherein R is Ci-6 aliphatic.

[0101] In some embodiments, R3is -NRC(O)R. In some embodiments, R3is -NHC(O)R. In some embodiments, R3is -NHC(O)R, wherein R is Ci-e aliphatic.

[0102] In some embodiments, R3is -OC(O)R. In some embodiments. R3is -OC(O)R, wherein R is Ci-6 aliphatic.

[0103] In some embodiments, R3is optionally substituted C1.6 aliphatic. In some embodiments, R3is Ci-6 aliphatic. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is n-propyl. In some embodiments, R3is isopropyl. In some embodiments, R3is n-butyl. In some embodiments, R3is s-butyl. In some embodiments. R3is t-butyl.

[0104] In some embodiments, R3isIn some embodiments, R3isIn some embodiments,19BUSINESS.33510111.1

[0105] In some embodiments, R3is Ci.6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Cue aliphatic. In some embodiments, R3is Cue aliphatic, optionally substituted with halogen. In some embodiments, R3is -CHF2. In some embodiments, R3is -CF3. In some embodiments, R3is -CH2CF3. In some embodiments, R3is Cue aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R3is -CH2OH.

[0106] In some embodiments, R3is -CF2CH3. In some embodiments, R3is -CH(CH3)CF3. In some embodiments, R3is. ,

[0107] In some embodiments, R3is -CH(CH )OH. In some embodiments, R3is. In some embodiments. R3is V ' ^OH . In some embodiments, R3is - CHs OH. In some embodiments, R3is -C(CH3)2OCH3.

[0108] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted cyclopropyl. In some embodiments, R3is an optionally substituted cyclobutyl . In some embodiments, R3is an optionally substituted cyclopentyl. In some embodiments, R3is an optionally substituted cyclohexyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0109] In some embodiments,

[0110] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. R3is an optionally substituted oxetanyl. In some embodiments, R3is an optionally substituted tetrahydrofuranyl . In some embodiments, R3is an optionally substituted tetrahydropyranyl. In some embodiments.

[0111] In some embodiments, R3is an optionally substituted phenyl. In some embodiments, R3is an20BUSINESS.33510111.1optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted oxazolyl. In some embodiments, R3is an optionally substituted isooxazolyl. In some embodiments, R3is an oxazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments. R3is isoxazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments,

[0112] In some embodiments, R3is optionally substituted pyrazolyl. In some embodiments, R3is optionally substituted imidazolyl. In some embodiments. R3is pyrazolyl optionally substituted with -R°, wherein -R° is C1-6 aliphatic. In some embodiments, R3is imidazolyl optionally substituted with -R°, wherein -R° is Ci-e aliphatic. In some embodiments, R3is

[0113] In some embodiments, R3is hydrogen, fluoro, chloro, bromo, -CN. -OH, -OCH3. -OCH2CH3, -NH2, -C(O)NH2, methyl, ethyl, n-propyl. isopropyl, n-butyl, -CH2OH, -CH2CF3, cyclopropyl, cyclobutyl,21BUSINESS.33510111.1

[0116] In some embodiments, R4is selected from hydrogen, fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5 - to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0117] In some embodiments, R4is selected from fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is selected from hydrogen, fluoro, chloro, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfiir. In some embodiments, R4is selected from fluoro, chloro, -CN, -OR5, - NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0118] In some embodiments, R4is hydrogen. In some embodiments, R4is halogen. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is bromo. In some embodiments, R4is -CN.

[0119] In some embodiments, R4is -OR5. In some embodiments, R4is -OH. In some embodiments, R4is -OCHs. In some embodiments, R4is -OCH2CH3. In some embodiments, R4is -OCH(CH3)2. In some embodiments, R4is -OCF3.

[0120] In some embodiments, R4is -NR2. In some embodiments, R4is -NH2. In some embodiments, R4is -NR2, wherein each R is independently C1-6 aliphatic.

[0121] In some embodiments, R4is -C(O)NR2. In some embodiments, R4is -C(O)NH2. In some embodiments, R4is -C(O)NR2, wherein each R is independently Ci-e aliphatic.

[0122] In some embodiments, R4is -C(O)OR. In some embodiments, R4is -C(O)OH. In some embodiments, R4is -C(O)OR, wherein R is C1-6 aliphatic.

[0123] In some embodiments, R4is -NRC(O)R. In some embodiments. R4is -NHC(O)R. In some embodiments, R4is -NHC(O)R, wherein R is C1.6 aliphatic.

[0124] In some embodiments, R4is -OC(O)R. In some embodiments, R4is -OC(O)R, wherein R is 22BUSINESS.33510111.1Ci-6 aliphatic.

[0125] In some embodiments, R4is optionally substituted Ci-e aliphatic. In some embodiments, R4is Ci-6 aliphatic. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is n-propyl. In some embodiments, R4is isopropyl. In some embodiments, R4is n-butyl. In some embodiments, R4is s-butyl. In some embodiments. R4is t-butyl.

[0126] In some embodiments, R4is. In some embodiments. R4is. In some embodiments. R4is '

[0127] In some embodiments, R4is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R4is Ci-e aliphatic, optionally substituted with halogen. In some embodiments, R4is -CHF2. In some embodiments, R4is -CF3. In some embodiments, R4is -CH2CF3. In some embodiments, R4is C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R4is -CH2OH.

[0128] In some embodiments, R4is -CF2CH3. In some embodiments, R4is -CH(CH3)CF3. In someA- / ~Fembodiments, R4is. In some embodiments, R4is

[0129] In some embodiments, R4is -CH(CH )OH. In some embodiments, R4is. In some embodiments. R4is. In some embodiments, R4is - ChU OH. In some embodiments. R4is -C(CH3)2OCH3.

[0130] In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R4is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R4is an optionally substituted cyclopropyl. In some embodiments, R4is an optionally substituted cyclobutyl . In some embodiments, R4is an optionally substituted cyclopentyl. In some embodiments, R4is an optionally substituted cyclohexyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is cyclobutyl. In some embodiments, R4is cyclopentyl. In some embodiments, R4is cyclohexyl.23BUSINESS.33510111.1

[0131] In some embodiments,

[0132] In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted oxetanyl. In some embodiments, R4is an optionally substituted tetrahydrofuranyl. In some embodiments, R4is an optionally substituted tetrahydropyranyl . In some embodiments,

[0133] In some embodiments, R4is an optionally substituted phenyl. In some embodiments, R4is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted oxazolyl. In some embodiments, R4is an optionally substituted isooxazolyl. In some embodiments, R4is an oxazolyl optionally substituted with -R°, wherein -R° is Ci-e aliphatic. In some embodiments, R4is isoxazolyl optionally substituted with -R°, wherein -R° is Cue aliphatic. In some embodiments,

[0134] In some embodiments, R4is optionally substituted pyrazolyl. In some embodiments, R4is optionally substituted imidazolyl. In some embodiments, R4is pyrazolyl optionally substituted with -R°, wherein -R° is Ci-6 aliphatic. In some embodiments, R4is imidazolyl optionally substituted with -R°,7y NH wherein -R° is Ci-6 aliphatic. In some embodiments, R4is '•

[0135] In some embodiments, R4is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -NH2, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2OH, -CH2CF3, cyclopropyl, cyclobutyl, cyclohexyl,

[0136] In some embodiments, R4is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -NH2, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2OH, -CH2CF3, cyclopropyl, cyclobutyl,24BUSINESS.33510111.1

[0137] In some embodiments, R4is hy drogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3,

[0138] In some embodiments, R1and R2, R2and R3, or R3and R4may be taken together to form an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0139] In some embodiments, R1and R2may be taken together to form an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0140] In some embodiments, R1and R2may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 5- to 6-membered saturated or partially unsaturated carbocyclyl .

[0141] In some embodiments, R1and R2may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1and R2may be taken together to form an optionally25BUSINESS.33510111.1substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R1and R2may be taken together to form an optionally substituted fused. In 17 / ° some embodiments. R1and R2may be taken together to form an optionally substituted fused > . In some embodiments, R1and R2may be taken together to fonn an optionally substituted fused. i zT / O some embodiments, R1and R2may be taken together to form an optionally substituted fused •

[0142] In some embodiments, R1and R2may be taken together to form an optionally substituted fused 5 -membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom.

[0143] In some embodiments, R1and R2may be taken together to fonn an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1-2 oxygen heteroatoms. In some embodiments, R1and R2may be taken together to fonn an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 2 oxygen heteroatoms. In some embodiments. R1and R2may be taken together to form an optionally substituted fused 5 -membered partially unsaturated heterocyclyl having 2 oxygen heteroatoms. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 6-mcmbcrcd partially unsaturated heterocyclyl having 2 oxygen hctcroatoms. In some embodiments, R1and R2may be taken together to form an optionally substituted fusedIn some embodiments, R1and R2may be taken together to fomr an optionally substituted fused. In some embodiments, R1and R2may be taken together to form an optionally substituted fused26BUSINESS.33510111.1

[0144] In some embodiments, R1and R2may be taken together to form an optionally substituted fused benzo. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 5- to 6-mcmbcrcd hctcroaryl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. R1and R2may be taken together to fonn an optionally substituted fused 5 -membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1and R2may be taken together to form an optionally substituted fused 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0145] In some embodiments, R2and R3may be taken together to fonn an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0146] In some embodiments, R2and R3may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated carbocyclyl.

[0147] In some embodiments, R2and R3may be taken together to fonn an optionally substituted fused 3- to 8-membered partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R2and R3may be taken together to form an optionally substituted fused. In / ° some embodiments, R2and R3may be taken together to form an optionally substituted fused < . In some embodiments, R2and R3may be taken together to fomr an optionally substituted fused. hr27BUSINESS.33510111.1some embodiments, R2and R3may be taken together to form an optionally substituted fused

[0148] In some embodiments, R2and R3may be taken together to form an optionally substituted fused 5 -membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom.

[0149] In some embodiments, R2and R3may be taken together to fonn an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1-2 oxygen heteroatoms. In some embodiments. R2and R3may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 2 oxygen heteroatoms. In some embodiments, R2and R3may be taken together to fonn an optionally substituted fused 5 -membered partially unsaturated heterocyclyl having 2 oxygen heteroatoms. In some embodiments, R2and R3may be taken together to fonn an optionally substituted fused 6-membered partially unsaturated heterocyclyl having 2 oxygen heteroatoms. In some embodiments. R and R may be taken together to form an optionally substituted fused r> . In some v° embodiments, R2and R3may be taken together to fonn an optionally substituted fused . In some embodiments, R2and R3may be taken together to form an optionally substituted fused

[0150] In some embodiments, R2and R3may be taken together to form an optionally substituted fused benzo. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 5 -membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2and R3may be taken together to form an optionally substituted fused 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0151] In some embodiments, R3and R may be taken together to form an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3and R4may be taken together to fonn an optionally substituted fused 3- to 8-membered28BUSINESS.33510111.1partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0152] In some embodiments, R3and R4may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl. In some embodiments, R3and R4may be taken together to fonn an optionally substituted fused 5- to 6-membered partially unsaturated carbocyclyl.

[0153] In some embodiments, R3and R may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3and R4may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3and R may be taken together to fonn an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R3and R4may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R3and R4may be taken together to form an optionally substituted fused. In t / ° some embodiments, R3and R4may be taken together to fomi an optionally substituted fused • . In some embodiments, R3and R4may be taken together to form an optionally substituted fused. In some embodiments, R3and R may be taken together to form an optionally substituted fused

[0154] In some embodiments, R3and R4may be taken together to fonn an optionally substituted fused 5 -membered partially unsaturated heterocyclyl having 1 oxygen heteroatom. In some embodiments, R3and R4may be taken together to fonn an optionally substituted fused 6-membered partially unsaturated heterocyclyl having 1 oxygen heteroatom.

[0155] In some embodiments, R3and R may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 1-2 oxygen heteroatoms. In some embodiments, R3and R4may be taken together to form an optionally substituted fused 5- to 6-membered partially unsaturated heterocyclyl having 2 oxygen heteroatoms. In some embodiments, R3and R4may be taken together to form an optionally substituted fused 5 -membered partially unsaturated heterocyclyl having 2 oxygen heteroatoms. In some embodiments, R3and R4may be taken together to form an optionally29BUSINESS.33510111.1substituted fused 6-membered partially unsaturated heterocvclyl having 2 oxygen heteroatoms. In some embodiments, R3and R4may be taken together to form an optionally substituted fused « O . In some embodiments, R3and R4may be taken together to form an optionally substituted fused. |nsome embodiments, R3and R4may be taken together to form an optionally substituted fused

[0156] In some embodiments, R3and R4may be taken together to form an optionally substituted fused benzo. In some embodiments, R3and R4may be taken together to form an optionally substituted fused 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. R3and R4may be taken together to form an optionally substituted fused 5 -membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3and R4may be taken together to form an optionally substituted fused 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0157] As defined above and described herein, R5is hydrogen or an optionally substituted group selected from Ci-6 aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0158] In some embodiments. R5is hydrogen or an optionally substituted Ci-e aliphatic. In some embodiments. R5is hydrogen. In some embodiments, R5is optionally substituted Ci-6 aliphatic. In some embodiments, R5is Ci-e aliphatic. In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is n-propyl. In some embodiments, R5is isopropyl. In some embodiments, R is n-butyl. In some embodiments, R5is s-butyl. In some embodiments, R5is t-butyl.

[0159] In some embodiments, R5is Ci-6 aliphatic, optionally substituted with one or more halogen (e.g., fluoro). In some embodiments, R5is -CF3.

[0160] In some embodiments. R5is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. R5is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments. R5is an optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R5is an optionally substituted cyclopropyl. In some embodiments, R5is an optionally substituted cyclobutyl . In some embodiments, R5is an optionally substituted cyclopcntyl. In some embodiments, R5is an optionally substituted cyclohcxyl. In some embodiments, R5is cyclopropyl. In some embodiments, R5is cyclobutyl. In some embodiments,30BUSINESS.33510111.1R5is cyclopentyl. In some embodiments, R5is cyclohexyl.

[0161] In some embodiments. R’ is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl or hctcrocyclyl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0162] As defined above and described herein, Rbis hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, R6is hydrogen. In some embodiments, R6is optionally substituted Ci-e aliphatic. In some embodiments, R6is Ci-6 aliphatic. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is n-propyl. In some embodiments, R6is isopropyl. In some embodiments. R6is n-butyl. In some embodiments. R6is s-butyl. In some embodiments. R6is t-butyl. In some embodiments, R6is hydrogen or methyl.

[0163] As defined above and described herein, each R7is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1-6 aliphatic; or two R7groups on the same atom may be taken together to fonn an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R7groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged carbocyclyl or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each R7is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1-6 aliphatic. In some embodiments, R7is halogen. In some embodiments, R7is fluoro. In some embodiments, R7is chloro. In some embodiments, R7is bromo. In some embodiments. R7is -CN. In some embodiments, R7is -OR. In some embodiments, R7is -OH. In some embodiments, R7is -OR wherein R is Cue aliphatic. In some embodiments, R7is -NR2. In some embodiments, R7is -NH2. In some embodiments, R7is -NR2, wherein each R is independently Ci-e aliphatic. In some embodiments, R7is an optionally substituted Ci-e aliphatic. In some embodiments, R7is C1-6 aliphatic. In some embodiments, R7is methyl. In some embodiments, R7is ethyl. In some embodiments. R7is n-propyl. In some embodiments. R7is isopropyl. In some embodiments, R7is n-butyl. In some embodiments, R7is s-butyl. In some embodiments, R7is t- butyl. In some embodiments, R7is cyclopropyl. In some embodiments, R7is cyclobutyl. In some embodiments, R7is cyclopentyl. In some embodiments, R7is cyclohexyl. In some embodiments, R7is Ci- e aliphatic, optionally substituted with halogen. In some embodiments, R7is Ci-e aliphatic, optionally substituted with fluoro. In some embodiments, R7is -CF3.

[0164] In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or31BUSINESS.33510111.1spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl. In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted 3- to 6-membered saturated or partially unsaturated spirocarbocyclyl. In some embodiments, two R7groups on tire same atom may be taken together to form an optionally substituted cyclopropyl. In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted cyclobutyl. In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted cyclopentyl . In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted cyclohexyl.

[0165] In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R7groups on the same atom may be taken together to form an optionally substituted 3- to 6-membered saturated or partially unsaturated spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0166] In some embodiments, two R7groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged carbocyclyl or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R7groups on different atoms may be taken together to fomi an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged carbocyclyl. In some embodiments, two R7groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0167] As defined above and described herein, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.

[0168] As defined above and described herein, each R is independently hydrogen or optionally substituted Ci-e aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted Ci-6 aliphatic. In some embodiments, R is Ci-6 aliphatic. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is n-propyl. In some embodiments, R is isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is s-butyl. In some embodiments.32BUSINESS.33510111.1R is t-butyl.

[0169] In some embodiments, the compound is other than

[0170] In some embodiments, the present disclosure provides a compound of formulae Il-a, Il-b, II-or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R6, R7, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0171] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Il-a, Il-b, II-c, Il-d, or Il-e, embodiments of variables R1, R2, R3, R4, R6, R7, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae Il-a, Il-b, II-33BUSINESS.33510111.1c, Il-d, or Il-e, both singly and in combination.

[0172] In some embodiments, the present disclosure provides a compound of formulae Ill-a, Ill-b,III-c, Ill-d, or Ill-e:Ill-d Ill-e or a pharmaceutically acceptable salt thereof, wherein each of R1, R2. R3. R4. R7. and n is defined and described in classes and subclasses herein, both singly and in combination.

[0173] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Ill-a, Ill-b, III-c, Ill-d, or Ill-e, embodiments of variables R1, R2, R3, R4, R7, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae Ill-a, Ill-b,III-c, Ill-d, or Ill-e, both singly and in combination.

[0174] In some embodiments, the present disclosure provides a compound of formulae IV-a, IV-b,IV-c, IV-d, or IV-e:34BUSINESS.33510111.1IV-d IV-e or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R7, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0175] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV-a, IV-b, IV-c, IV-d, or IV-e, embodiments of variables R1, R2. R3, R4, R7, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-a, IV-b, IV- c, IV-d, or IV-e. both singly and in combination.

[0176] In some embodiments, the present disclosure provides a compound of formulae V-a, V-b, V-c, V-d, or V-e:35BUSINESS.33510111.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0177] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae V-a, V-b, V-c, V-d, or V-e, embodiments of variables R1, R2, R3, R4, and R7as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae V-a, V-b. V-c, V-d. orV-e, both singly and in combination.

[0178] In some embodiments, the present disclosure provides a compound of fonnulae Vl-a, Vl-b,VI-c, VLd, or Vi e:36BUSINESS.33510111.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0179] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Vl-a, Vl-b. VI-c. Vl-d, or Vl-e, embodiments of variables R1, R2. R3, R4, and R7as defined above and described in classes and subclasses herein, also apply to compounds of formulae Vl-a. Vl-b, VI- c, Vl-d, or Vl-e, both singly and in combination.

[0180] In some embodiments, the present disclosure provides a compound of formulae VH-a, Vll-b, VII-c, Vll-d, or VH-e:37BUSINESS.33510111.1Vll-d Vll-e or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R4is defined and described in classes and subclasses herein, both singly and in combination.[001811 It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Vll-a, Vll-b, VII-c, Vll-d, or Vll-e, embodiments of variables R1, R2, R3, and R4as defined above and described in classes and subclasses herein, also apply to compounds of formulae VII-a, VII-b, VII-c, Vll-d, or Vll-e, both singly and in combination.

[0182] In some embodiments, the present disclosure provides a compound of fonnulae Vlll-a, VIII- b, VIII-c, Vlll-d, or VUI-e:38BUSINESS.33510111.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R4is defined and described in classes and subclasses herein, both singly and in combination.

[0183] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VUI-a. VUI-b, VIII-c, VUI-d, or Vlll-e, embodiments of variables R1, R2, R3, and R4as defined above and described in classes and subclasses herein, also apply to compounds of formulae VIII- a, Vlll-b, VIII-c, Vlll-d, or Vlll-e, both singly and in combination.

[0184] In some embodiments, the present disclosure provides a compound selected from those depicted in Table 1, or a pharmacally acceptable salt thereof.Table 1.39BUSINESS.33510111.140BUSINESS.33510111.141BUSINESS.33510111.142BUSINESS.33510111.143BUSINESS.33510111.144BUSINESS.33510111.145BUSINESS.33510111.146BUSINESS.33510111.1

[0185] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above.4. Uses, Formulation and AdministrationPharmaceutically acceptable compositions

[0186] According to another embodiment, the invention provides a composition comprising a47BUSINESS.33510111.1provided compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate 5-HT2AR, or a mutant thereof, in a biological sample or in a patient. In some embodiments, a composition of this invention is formulated for administration to a patient in need of such composition.

[0187] In some embodiments, the present invention provides a pharmaceutical composition comprising a provided compound (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a provided compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0188] The term “patient" as used herein, means an animal, preferably a mammal, and most preferably a human.

[0189] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy tire pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0190] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension48BUSINESS.33510111.1in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0191] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, for the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage fomis may also be used for the purposes of formulation.

[0192] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers may be included. Lubricating agents are also typically added. For oral administration in a capsule form, diluents may be included. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Such fonnulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmacally acceptable compositions of this invention are administered with food.

[0193] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the fomi of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.

[0194] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical fonnulations are readily- prepared for each of these areas or organs.

[0195] Topical application for the lower intestinal tract can be effected in a rectal suppository' formulation (see above) or in a suitable enema fonnulation. Topically-transdermal patches may also be used.

[0196] For topical applications, provided pharmacally acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Alternatively, provided pharmaceutically acceptable compositions can be fonnulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers49BUSINESS.33510111.1410095-001WG (221124)

[0197] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, cither with or without a preservative . Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment .

[0198] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0199] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.

[0200] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0201] In some embodiments, provided compounds and compositions are for use in medicine.

[0202] Compounds and compositions described herein are generally usefid as agonists of 5-HT2AR.

[0203] According to one embodiment, the invention relates to a method of activating 5-HT2AR, or a mutant thereof, in a biological sample comprising contacting said biological sample with a provided compound, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.

[0204] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, 5-HT2AR is from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0205] Activation of 5-HT2AR, or a mutant thereof, in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0206] In some embodiments, the invention also provides a compound described herein, or a50BUSINESS.33510111.1pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for activating 5-HT2AR, or a mutant thereof, as described herein.

[0207] In some embodiments, the invention also provides a compound described herein, or a pharmacally acceptable salt thereof, or pharmacal compositions described herein, for use in a method for selectively activating 5-HT2AR, or a mutant thereof, (e.g., over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) as described herein. In some embodiments, such methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound selectively binds to 5-HT2AR over 5-HT2BR and / or 5-HT2CR. The method of selectively agonizing 5-HT2AR, or a mutant thereof, can be used to treat, ameliorate, and / or prevent disorders that are affected by, associated with, or would benefit from selective activation of 5-HT2AR. In selectively binding to and activating 5-HT2AR, or a mutant thereof, over the 5-HT2BR and / or 5-HT2CR. or one or more mutants thereof, the method provides, for example, reduced side effects such as, but not limited to, drug- induced valvular heart disease associated with binding and activating 5-HT2BR. In some embodiments, a provided compound is a 5-HT2BR, or a mutant thereof, antagonist. In some embodiments, a provided compound is a 5-HT2CR, or a mutant thereof, antagonist.

[0208] In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for treating a 5-HT2AR-mediated disorder as described herein. Such disorders are described in detail herein.

[0209] G protein-coupled receptors (GPCRs) signal through numerous pathways, including disease- associated but also non-disease-associated pathways, and as a result modulation of GPCRs can cause undesired side effects. Modulators of GPCRs can bind and preferentially activate specific pathways over others, often referred to as ligand-mediated bias or pathway bias. 5-HT2AR may interact with multiple signaling pathways upon ligand binding, e.g., pathways that engage with G proteins or [3-arrestins. See Kossatz, E., et al. Nature Communications 2024, 15:4307. In some embodiments, the invention also provides a compound described herein, or a pharmacally acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for binding 5-HT2AR. or a mutant thereof, resulting in increased ('‘biased7’) activation of a particular signaling pathway (e.g.. a G protein signaling pathway) over others (e.g., a -arrestin signaling pathway). In some embodiments, provided methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound binds to 5-HT2AR and results in increased (“biased”) activation of a G protein signaling pathway over a [3-arrestin signaling pathway. In some embodiments, provided methods include administering to a patient a provided compound, or a pharmacally acceptable salt thereof, wherein the compound is characterized in that, upon binding 5-HT2AR, or a mutant thereof, the compound effects51BUSINESS.33510111.1increased (“biased”) activation of a G protein signaling pathway over a P-arrestin signaling pathway.

[0210] In some embodiments, provided methods include increasing activation of a G protein signaling pathway associated with 5-HT2AR over a p-arrestin signaling pathway associated with 5-HT2AR in a patient in need thereof, comprising administering to tire patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0211] In some embodiments, G protein signaling pathways are evaluated through detection of calcium, e.g., as described in Example 23. In some embodiments, P-arrestin signaling pathways are evaluated as described in Example 24.

[0212] In some embodiments, a G protein signaling pathway is increased by at least 50%, at least 100%. at least 500%, at least 1,000%. at least 5,000%, or at least 10,000% (e.g., as measured in Example 23) as compared to P-arrestin signaling pathways (e.g., as measured in Example 24).

[0213] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, may exhibit anxiolytic, anti-depressive, and antidrug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions. For example, a provided compound, or a pharmaceutically acceptable salt thereof, may confer antidepressant like activities without incurring psychedelic drug-like actions. For example, in some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, may be safe and effective for use in a method described herein, yet lack the hallucinogenic effects of known psychedelics such as, for example, DMT and psilocybin. In some embodiments, a patient does not experience a hallucinogenic effect as a result of the activating or treating.

[0214] The activity of a compound, or a pharmaceutically acceptable salt thereof, utilized in this invention as an activator of 5-HT2AR, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine activation and / or the subsequent functional consequences of activated 5-HT2AR, or a mutant thereof. Alternate in vitro assays quantitate the ability of the agonist to bind to 5-HT2AR. or a mutant thereof. Agonist binding may be measured by radiolabeling the compound prior to binding, isolating the compound / 5-HT2AR complex and determining the amount of radiolabel bound. Alternatively, agonist binding may be determined by running a competition experiment where additional agonists are incubated with 5-HT2AR, or a mutant thereof, bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention as an agonist of 5-HT2AR, or a mutant thereof, arc set forth in the Examples below.

[0215] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For52BUSINESS.33510111.1example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0216] Provided compounds are agonists of 5-HT2AR, or a mutant thereof, and are therefore useful for treating one or more disorders associated with activity of 5-HT2AR. In some embodiments, the present invention provides a method for treating a 5-HT2AR-mediated disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0217] As used herein, the term “5-HT2AR-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which 5-HT2AR, or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which 5-HT2AR, or a mutant thereof, are known to play a role.

[0218] In some embodiments, the present invention provides a method for treating a neurological disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0219] Non-limiting examples of a neurological disease or disorder include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods herein include, but are not limited to, migraine headaches and cluster headaches.

[0220] In some embodiments, the present invention provides a method for treating a depressive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the depressive disorder is a major depressive disorder. In other embodiments, the depressive disorder includes treatment resistant depressions.

[0221] In some embodiments, the present invention provides a method for treating an anxiety disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the anxiety disorder is generalized anxiety disorder. In other embodiments, the anxiety disorder is social anxiety disorder.

[0222] In some embodiments, the present invention provides a method for treating trauma and / or stress disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, such a disorder is post-traumatic stress disorder. In other embodiments, such a disorder is an adjustment disorder.

[0223] In some embodiments, tire present invention provides a method for treating an obsessive-53BUSINESS.33510111.1compulsive disorder, e.g., body dysmorphic disorder, comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0224] In some embodiments, tire present invention provides a method for treating an eating disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the eating disorder is anorexia. In other embodiments, the eating disorder is bulimia.

[0225] In some embodiments, the present invention provides a method for treating a sleep-wake disorder, e.g., insomnia, comprising administering to a patient in need thereof provided compound, or a pharmacally acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0226] In some embodiments, the present invention provides a method for treating a psychotic disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the psychotic disorder is schizophrenia. In other embodiments, the psychotic disorder is schizoaffective disorder. In still other embodiments, the psychotic disorder is schizotypal personality disorder.

[0227] In some embodiments, the present invention provides a method for treating a substance-related and / or addictive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, such a disorder is an alcohol use disorder. In other embodiments, such a disorder is an opioid use disorder. In still other embodiments, such a disorder is a tobacco use disorder. For example, in some embodiments provided compound, or a pharmacally acceptable salt thereof, may be useful in facilitating smoking cessation.

[0228] In some embodiments, the present invention provides a method for treating a neurocognitive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmacally acceptable salt thereof, or pharmacally acceptable composition thereof. In some embodiments, the neurocognitive disorder includes those due to a primary neurodegenerative disease, for example, Alzheimer's disease or Parkinson’s disease.

[0229] In some embodiments, the present invention provides a method for treating a personality disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmacally acceptable composition thereof.

[0230] In some embodiments, the present invention provides a method for treating an autism spectrum disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0231] In some embodiments, the present invention provides a method for treating a bipolar disorder 54BUSINESS.33510111.1410095-001WG (221124) comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the bipolar disorder is bipolar I disorder. In some embodiments, the bipolar disorder is bipolar II disorder.

[0232] In some embodiments, the present invention provides a method for treating a pain disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the pain disorder is neuropathic pain. In some embodiments, the pain disorder is migraine. In some embodiments, the pain disorder is a cluster headache. In some embodiments, the pain disorder is a trigeminal neuralgia. In some embodiments, the pain disorder is cancer pain. In some embodiments, the pain disorder is a regional pain disorder. In some embodiments, the pain disorder is phantom limb pain. In some embodiments, a contemplated pain disorder is a chronic pain.EXAMPLES

[0233] As depicted in tire Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0234] Example 1 (1-44)

[0235] To a solution of 9-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (100 mg, 0.376 mmol) in DME (1 mL) was added trimethylboroxine (142 mg, 50% in THF, 1.13 mmol), Pd(dppf C12 (28 mg. 0.037 mmol) and K2CO3 (156 mg. 1.13 mmol). The reaction mixture was sealed and stirred for 20 h at 90 °C under nitrogen atmosphere. The reaction mixture was combined with another 50 mg batch and directly evaporated under reduced pressure. The residue was dispersed in DCM / MeOH(10: 1) and un-dissolvcd solids were filtered out. Tire filtrate was then purified by prcp-TLC (DCM / McOH=10: 1, NH4OH buffer) to afford 9-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (62 mg, 54%) as a light-brown solid (1-44). LCMS (m / z): 202.2 [M+H]+:1H NMR (400 MHz, DMSO-d6) 5 7.3755BUSINESS.33510111.1410095-001WG (221124)(d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.22 - 4.13 (m, 2H), 3.08 - 3.02 (m, 2H), 2.94 - 2.89 (m, 2H), 2.89 - 2.82 (m, 2H), 2.41 (s, 3H).

[0236] Additional Exemplary Compounds Prepared via Example 1 Methods

[0237] Example 2 (1-3)DIEAMel DMF 0 °C-RT, 1h

[0238] To a solution of 9-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (50 mg, 0.188 mmol) in DMF (1 mL) was added DIEA (49 mg, 0.376 mmol), followed by addition of Mel (27 mg, 0.188 mmol) at 0 °C under Ns. The reaction mixture was stirred for 1 h at RT under nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over NaiSCL, fdtered and concentrated. The crude was purified by prep-TLC (DCM / MeOH=10: 1, one drop of NH4OH) to give 9-bromo-3-methyl-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][1.4]diazepine (1-3) (15 mg, 30%) as a grey solid. LCMS (m / z): 280.1 [M+H]+; ’HNMR (400 MHz. Methanol-^) 8 7.74 (d. J = 1.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.5, 1.5 Hz, 1H), 4.48 - 4.39 (m, 2H), 3.30 - 3.28 (m, 2H), 3.09 - 2.93 (m, 4H), 2.64 (s, 3H).56BUSINESS.33510111.1410095-001WG (221124)

[0239] Example 3 (T-l 2)

[0240] Step 1. To a solution of 9-bromo-2.3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (100 mg, 0.37mmol, 1.00 equiv.) in 1,4-dioxane / H?O (2mL / 0.4 mL) was added potassium trifluoro(vinyl)borate (75.5 mg, 0.56 mmol, 1.50 equiv.), Pd(dppf)C12 (27.49 mg, 0.03 mmol, 0.1 equiv.) and K2CO3 (103.86 mg, 0.75 mmol, 2 equiv.). The reaction mixture stirred at 100 °C overnight under N2. Tire mixture was filtered and concentrated. The residue was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 9-vinyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (60 mg, 74%) as a brown solid. LCMS (m / z): 214.4 [M+H]+.

[0241] Step 2. To a solution of 9-vinyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (50 mg, 0.23 mmol, 1.00 equiv.) in MeOH (2 mL) was added Pd / C (15 mg, 10%) and the mixture stirred at 50 °C for 5 h, or until the reaction is complete, under H2balloon. Tire mixture was filtered and concentrated to obtain a crude residue. Tire residue was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 9-ethyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[1.2-d][l,4]diazepine (I- 12) (33.8 mg, 66%) as a yellow solid. LCMS (m / z): 216.0 [M+H]+; 'H NMR (400 MHz, DMSO-t / e) 8 7.42 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 4.42 - 4.32 (m, 2H), 3.23 - 3.17 (m, 2H), 3.15 -3.09 (m, 2H), 3.09 - 3.01 (m, 2H), 2.70 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H).

[0242] Additional Exemplary Compounds Prepared via Example 3 Methods57BUSINESS.33510111.158BUSINESS.33510111.1410095-001WG (221124)

[0243] Example 4 (1-27)

[0244] Step 1. To a solution of tert-butyl 8-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][ l,4]diazepine-3-carboxylate (350 mg, 0.95 mmol) in l,4-dioxane / H2O (6 rnL / 3 mL) was added t- BuXphos (40 mg, 0.09 mmol), KOH (107 mg, 1.91 mmol) and Pd2(dba)3(43 mg, 0.04 mmol). Hie mixture was stirred at 90 °C for 2 h or until complete under N2 atmosphere. Hie mixture was diluted with water (150 mL), extracted with EtOAc (50 mL x 3). Hie combined layers were washed with brine, dried over Na2SO4, concentrated under vacuum and the residue was purified by prep-TLC (DCM : MeOH = 15: 1) to afford tert-butyl 8-hydroxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (100 mg, 34%) as a yellow solid. LCMS (m / z): 304.1 [M+H]+.

[0245] Step 2. To a solution of tert-butyl 8-hydroxy-1.2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (100 mg, 0.32 mmol) in DMF (4 mL) was added iodoethane (77 mg, 0.49 mmol) and K2CO3 (136 mg, 0.98 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was diluted with water (60 mL), extracted with EtOAc (20 mL x 3). The combined layers were washed with brine, dried over Na2SO4, concentrated under vacuum and the residue was purified by prcp-TLC to afford tert-butyl 8- ethoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (30 mg, 27%) as a yellow solid. LCMS (m / z): 332.1 [M+H]+.

[0246] Step 3. To a solution of tert-butyl 8-ethoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (30 mg, 0.09 mmol) in DCM (2 mL) was added a solution of HC1 in 1,4- dioxanc (4 M, 2 mL). Hie reaction mixture was stirred at room temperature for 1 h. Hie solvent was removed under vacuum, and the crude residue was purified by trituration (DCM / Hexane=l / 5) to afford 8- ethoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-27) (HC1 salt, 21.6 mg, 103%) as59BUSINESS.33510111.1410095-001WG (221124) a yellow solid. LCMS (m / z): 232.1 [M+H]+; H NMR (400 MHz, DMSO-d6) 8 9.86 (s, 2H), 7.78 (d, J = 9.0 Hz, 1H), 7.24 (s, 1H), 7.16 (dd, J = 9.0, 1.0 Hz, 1H), 4.84-4.78 (m, 2H), 4.11 (q, J = 7.0 Hz, 2H), 3.68- 3.62 (m, 2H), 3.60-3.42 (m, 4H), 1.37 (t, J = 7.0 Hz, 3H).

[0247] Additional Exemplary Compounds Prepared via Example 4 Methods

[0248] Example 5 (1-2)MeOH

[0249] Step 1. To a solution of 9-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (100 mg, 0.37 mmol, 1.00 equiv.) in MeOH (6 mL) was added Pd(dppf)C12 (27.49 mg, 0.03 mmol, 0.1 equiv.) and TEA (114.07 mg, 1.13 mmol, 3 equiv.). The reaction mixture stirred at 80 °C overnight under a CO balloon. The mixture was filtered and concentrated. The mixture was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford methyl 2.3.4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][l,4]diazepine-9-carboxylate (60 mg, 65%) as a brown solid. LCMS (m / z): 246.0 [M+H]+.

[0250] Step 2. At 0 °C, to a solution of methyl 2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][l,4]diazcpinc-9-carboxylatc (60 mg, 0.24 mmol, 1.00 equiv.) in THF (3 mL) was added LiAlH4(27.85 mg, 2.5 M, 3.00 equiv.) and the mixture was stirred at RT overnight. The mixture was filtered and concentrated to obtain a crude residue. The residue was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford (2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepin-9- yl)methanol (1-2) (18 mg, 27%) as a white solid. LCMS (m / z): 218.1 [M+H]+; ’H NMR (400 MHz, DMSO-60BUSINESS.33510111.1d6) 5 7.49 - 7.37 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H), 5.15 (s, 1H), 4.58 (d, J = 4.0 Hz, 2H), 4.32 - 4.18 (m, 2H), 3.15 - 3.06 (m, 2H), 3.01 - 2.87 (m, 4H).

[0251] Example 6 (1-16)1 ,10-phenanthrolineCui

[0252] A solution of 9-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (50 mg, 0.18 mmol), 1 , 10-Phenanthroline (6.4 mg, 0.03 mmol), Cui (46 mg, 0.24 mmol) and CS2CO3 (67 mg, 0.20 mmol) in MeOH (3 mL) was stirred at 120 °C for 1.5 h and 140 °C for 1 h under microwave. The mixture was diluted with MeOH (10 mL), filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=5 / l) to afford 9-methoxy-2,3,4,5-tetrahydro- lH-benzo[4,5]imidazo[ 1 ,2-d] [ l,4]diazepine (1-16) (16.2 mg. 39%) as a yellow solid. LCMS (m / z): 218.1 [M+H]+; ' H NMR (400 MHz, DMSO-d6) 8 7.43 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.5, 2.5 Hz, 1H), 4.50 (br s, 2H), 3.79 (s, 3H), 3.35-3.30 (m, 4H), 3.26-3.24 (m, 2H).

[0253] Additional Exemplary Compounds Prepared via Example 6 Methods61BUSINESS.33510111.1

[0254] Example 7 (T-46)

[0255] Step 1. To a solution of tert-butyl 9-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (200 mg, 0.546 mmol) and cyclopropylboronic acid (234.6 mg, 2.73 mmol) in 1,4-dioxane / H2O (3.0 mL / 0.6 mL) was added tricyclohexylphosphane (15.4 mg, 0.055 mmol), Pd(OAc)2 (12.3 mg, 0.055 mmol) and K3PO4 (347.7 mg, 1.64 mmol). The reaction mixture was stirred at 100 °C overnight under N2. The mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (20 mL) and dried over Na2SC>4, filtered and concentrated. The mixture was purified by prep-TLC (Pet.Ether : EtOAc=l: l) and prep-HPLC to afford tert-butyl 9-cyclopropyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (102 mg, 57%) as an off-white solid. LCMS (m / z): 328.2 [M+H]+.

[0256] Step 2. To a solution of tert-butyl 9-cyclopropyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (102mg, 0.311 mmol) in DCM (1 mL) was added 4 M HC1 in 1,4-dioxane (5 mL). The reaction mixture was stirred at RT for Ih. The mixture was concentrated and freeze-dried to afford 9-cyclopropyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (I- 46) (HC1 salt, 81.2 mg, 98%) as an off-white solid. LCMS (rn / z): 228.1 [M+H]+;]H NMR (400 MHz, DMSO-d6) 8 10.16 (s, 2H), 7.66 (d, J = 8.5 Hz, IH). 7.63 (s, IH), 7.33 (dd, J = 8.5, 1.5 Hz, IH), 4.88 (d, J = 8.0 Hz, 2H), 3.75 - 3.69 (m, 2H). 3.58-3.52 (m, 2H). 3.52-3.46 (m, 2H). 2.12 (tt, J = 8.5, 5.0 Hz, IH), 1.05 (qd, J = 6.5, 4.5 Hz, 2H), 0.80 (qd, J = 6.5, 4.5 Hz, 2H).62BUSINESS.33510111.1410095-001WG (221124)

[0257] Additional Exemplary Compounds Prepared via Example 7 Methods63BUSINESS.33510111.1

[0258] Example 8 (1-17)64BUSINESS.33510111.1

[0259] A mixture of 9-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l ,4]diazepine (50 mg, 0.18 mmol, 1.0 eq.) in THF (4 mL) and Pd / C (50 mg, 10%wt) was stirred at room temperature for 6 hours under H2. The reaction mixture was directly concentrated and triturated with hexane to give 2, 3,4,5- tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-17) (16 mg, 45%) as a yellow solid. LCMS (m / z): 188.0 [M+H] ; 'H NMR (400 MHz, DMSO-de) 5 7.51 (dd, J = 13.5, 8.0 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 4.37 - 4.30 (m, 2H), 3.20 - 3.14 (m, 2H), 3.11 - 3.07 (m, 2H), 3.05 - 3.00(m, 2H).

[0260] Example 9 (1-11)

[0261] A solution of 9-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (50 mg, 187.87 pmol), 5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (157 mg, 751.48 pmol), NaHCOs (79 mg, 939.35 pmol) and Pd(dppf)Cl2(13 mg, 18.79 pmol) in DMF / H2O (0.8 mL / 0.2 mL) was stirred at 90 °C for 1 h under microwave. The mixture was diluted with water (15 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=20 / l) to afford 5-methyl-4-(2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepin-9-yl)isoxazole (1-11) (10 mg, 20%) as a grey solid. LCMS (m / z): 269.0 [M+H]+, ’H NMR (400 MHz, DMSO-de) 5 9.28 (br s, 1H), 8.85 (s, 1H), 7.72 (s, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.33 (dd, J = 8.5, 1.0 Hz, 1H), 4.66 - 4.60 (m, 2H), 3.48 - 3.38 (m, 4H), 3.36-3.32 (m, 2H), 2.62 (s, 3H).65BUSINESS.33510111.1

[0262] Example 10 (1-47)

[0263] Step 1. To a solution of l-bromo-3-fluoro-2 -nitrobenzene (4.5 g, 20.4 mmol) in DMF (50 mL) was added 2-aminoethan-l-ol (1.5 g, 24.5 mmol) and K2CO3 (7 g, 51.8 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (1200 mL). extracted with EtOAc (400 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-((3-bromo-2-nitrophenyl)amino)ethan-l-ol (4 g, 75.4%) as a yellow solid. LCMS (m / z): 261.0 [M+H]+.

[0264] Step 2. To a solution of 2-((3-bromo-2-nitrophenyl)amino)ethan-l-ol (11.7 g, 44.8 mmol) in EtOH / H2O (2 / 1.150 mL) was added Fe (12.5 g, 224 mmol) and NH4CI (12 g, 224 mmol). The mixture was stirred at 80 °C for 3 hours. The mixture was filtered, and the filtrate was diluted with water (600 mL), extracted with EtOAc (200 mL * 3). The combined organic phases were washed with brine, dried over66BUSINESS.33510111.1Na2SC>4, filtered and concentrated to obtain 2-((2-amino-3-bromophenyl)amino)ethan-l-ol (8.8 g, 85 %) as a black solid. LCMS (m / z): 231.1 [M+H]+.

[0265] Step 3. To a solution of 2-((2-amino-3-bromophcnyl)amino)cthan-l-ol (7.8 g, 33.7 mmol) in DCM (100 mL) was added 3-((tert-butoxycarbonyl)amino)propanoic acid (7 g, 37.1 mmol) and EEDQ (16.7 g, 67.5 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (100 mL) and washed with H?O (50 mL x 2). The organic phases were dried over Na2SC>4 and concentrated, the crude was used to the next step directly. LCMS (m / z): 402. 1 [M+H]+.

[0266] Step 4. A solution of tert-butyl (3-((2-bromo-6-((2-hydroxyethyl)amino)phenyl)amino)-3- oxopropyl)carbamate (13.5 g, 33.7 mmol) in AcOH (100 mL), was stirred at 60 °C for 1 hours. Hie mixture was diluted with water (500 mL), extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine and NaHCO, solution, dried over NazSCL. filtered and concentrated, the crude was used to the next step directly. LCMS (m / z): 406.1 [M+Na]+.

[0267] Step 5. To a solution of tert-butyl (2-(4-bromo-l-(2-hydroxyethyl)-lH-benzo[d]imidazol-2- yl)ethyl)carbamate (12.9 g, 33.7 mmol) in DCM (100 mL) was added TsCl (9.6 g, 50.5 mmol) and TEA (8.5 g. 84 mmol). The mixture was stirred at room temperature for overnight. The mixture was diluted with water (100 mL). extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over NazSOj. filtered and concentrated. The residue was purified by column chromatography (eluent: DCM:MeOH=100: l) to afford 2-(4-bromo-2-(2-((tert-butoxycarbonyl)amino)ethyl)-lH- benzo[d]imidazol-l-yl)ethyl 4-methylbenzenesulfonate (15 g, 82.8 %) as awhite solid. LCMS (m / z): 538.0 [M+H]+.

[0268] Step 6. To a solution of 2-(4-bromo-2-(2-((tert-butoxycarbonyl)amino)etliyl)-lH- benzo[d]imidazol-l-yl)ethyl 4-methylbenzenesulfonate (1 g, 1.8 mmol) in DCM (8 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the crude was uses to the next step directly. LCMS (m / z): 437.9 [M+H]+.

[0269] Step 7. To a solution of 2-(2-(2-aminoethyl)-4-bromo-lH-benzo[d]imidazol-l-yl)ethyl 4- methylbenzenesulfonate (1.3 g, 1.8 mmol) in i-PrOH / ELO (1 / 4, 20 mL) was added K2CO3 (2.65 g, 14.4 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was diluted with water (60 mL), extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 7-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (400 mg, 83.6%) as a red solid. LCMS (m / z): 266.0 | M+H| .

[0270] Step 8. To a solution of 7-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4 J diazepine (500 mg. 1.88 mmol) in DCM (5 mL) was added (Boc O (820 mg, 3.76 mmol) and TEA (570 mg, 5.6 mmol). The mixture was stirred at RT for 2 hours. The mixture was diluted with water (60 mL), extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over67BUSINESS.33510111.1410095-001WG (221124)Na2SC>4, filtered and concentrated to give tert-butyl 7 -bromo- 1, 2,4,5 -tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (480 mg, 69.7%) as a brown solid. LCMS (m / z): 366.0 [M+H]+.

[0271] Step 9. To a solution of tert-butyl 7-bromo-l, 2,4, 5-tetrahydro-3H-benzo[4,5]imidazo[l, 2- d][l,4]diazepine-3-carboxylate (100 mg, 0.273 mmol) and 1,10-phenanthroline (10 mg, 0.054 mmol) in MeOH (3 mb) was added CS2CO3 (267 mg, 0.82 mmol) and Cui (26 mg, 0.14 mmol). The mixture was stirred at 130 °C overnight then stirred at 150 °C for 2 hours under N2 in sealed tube. The mixture was diluted with water(60 mL), extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SC>4, filtered and concentrated. Tire residue was purified by prep-TLC (DCM:MeOH=20: 1) to obtain tert-butyl 7-methoxy-l,2,4,5-tetraliydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (28 mg, 32.5%) as a white solid. LCMS (m / z): 318.1 [M+H]1.

[0272] Step 10. To a solution of tert-butyl 7-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[L2- d][l,4]diazepine-3-carboxylate (28 mg, 0.09 mmol) in DCM (0.5 mL) was added 4M HCl / l,4-dioxane (0.5 mL). The mixture was stirred at RT for 1 h. Tire mixture was concentrated and triturated by Et2O to give 7- methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-47) (HC1 salt. 13.3 mg, 70%) as a white solid. LCMS (m / z): 218.2 [M+H]+; ' H NMR (400 MHz, DMSO-de) 5 10.15 (s, 2H), 7.52 - 7.44 (m, 2H). 7.11 (d, J = 7.0 Hz. 1H), 4.86 (d, J = 7.0 Hz, 2H). 4.02 (s. 3H), 3.70 - 3.67 (m, 2H). 3.53-3.50 (m, 2H), 3.50-3.45 (m, 2H).

[0273] Additional Exemplary Compounds Prepared via Example 10 Methods68BUSINESS.33510111.1410095-001WG (221124)

[0274] Example 11 (1-18)

[0275] Step 1. To a solution of tert-butyl 8-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazcpinc-3-carboxylatc (50 mg, 0. 14 mmol) and NMP (1.5 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol) and Zn(CN); (32 mg, 0.273 mmol). Hie reaction mixture was stirred at 110 °C for 2 h under N2 atmosphere under microwave. The mixture was diluted with water (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (50 mL) and dried over Na2SC>4, filtered and concentrated. The mixture was purified by prep-TLC (DCM :MeOH =15: 1) to afford tert-butyl 8- cyano-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (10 mg, 23.4%) as an off-white solid. LCMS (m / z): 313.1 [M+H]+.

[0276] Step 2. To a solution of tert-butyl 8-cyano-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (20 mg, 0.066 mmol) in DCM (0.5 mL) was added 4 M HCl / dioxane (0.5 mL). The reaction mixture was stirred at RT for 1 h. The mixture was concentrated. The residue was triturated with Et2O to afford 2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d] [l,4]diazepine-8-carbonitrile (1-18) (HC1 salt, 11.1 mg, 83%) as an off-white solid. LCMS (m / z): 213.1 [M+H]+; ’H NMR (400 MHz,69BUSINESS.33510111.1410095-001WG (221124)DMSO-de) 5 9.90 (s, 2H), 8.20 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 8.5, 1.5 Hz, 1H), 4.79 - 4.71 (m, 2H), 3.58 - 3.52 (m, 2H), 3.52-3.48 (m, 2H), 3.46-3.35 (m, 2H).

[0277] Additional Exemplary Compounds Prepared via Example 11 Methods

[0278] Example 12 (1-9)

[0279] To a solution of 2,3,4, 5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine-8-carbonitrile (34 mg, 0.16 mmol) in dry THF (1.5 mL) at 0 °C was added NaH ( 19.2 mg, 0.48 mmol). After stirring 10 min, CHsI (45 mg, 0.32 mmol) was added. The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (70 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL) and dried over NaiSCL, filtered and concentrated. Hie mixture was purified by prep-TLC (DCM: MeOH=10: l) to afford 3-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][l,4]diazepine-8-carbonitrile (1-9) (12.1 mg, 33.4%) as a white solid. LCMS (m / z): 227.1 [M+H]+; 'H NMR (400 MHz, DMSO-de) 5 8.06 (d, J = 1.0 Hz, 1H), 7.75 (d. J = 8.5 Hz. 1H), 7.60 (dd, J = 8.5, 1.0 Hz, 1H), 4.42 - 4.36 (m, 2H), 3.21 - 3.15 (m, 2H), 2.72 - 2.67 (m, 2H), 2.67 - 2.61 (m, 2H), 2.38 (s, 3H)70BUSINESS.33510111.1

[0280] Additional Exemplary Compounds Prepared via Example 12 Methods

[0281] Example 13 (1-49)4 M HCI / 1 ,4-dioxane DCM RT, 2hStep 4

[0282] Step 1. To a solution of 3-(tert-butoxycarbonyl)-9-bromo-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine (250 mg, 0.68 mmol, 1.00 equiv.) in MeOH (10 mL) was added Pd(dppf)Cl2(50 mg, 0.07 mmol, 0.1 equiv.), TEA (207 mg, 2.0 mmol, 3 equiv.). The reaction mixture was stirred at 80 °C overnight under a CO balloon. Tire mixture was filtrated and concentrated. Tire mixture was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 3 -(tert-butyl) 9-methyl 1, 2,4,5 -tetrahydro- 3H-benzo[4.5]imidazo[l,2-d][1.4]diazepine-3,9-dicarboxylate (150 mg, 63.8%) as a brown solid. LCMS (m / z): 346.1 [M+H]+.

[0283] Step 2. To a solution of 3 -(tert-butyl) 9-methyl l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3,9-dicarboxylate (200 mg, 0.58 mmol, 1.0 equiv.) in THF / H2O (2 mL / 2 mL) was added71BUSINESS.33510111.1Li OH (41.6 mg, 1.7 mmol, 3.0 equiv.) and the reaction mixture stirred at room temperature for 5 h. The mixture was adjusted to pH 5-6 by 1 M HO. The resulting mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, concentrated and purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine-9- carboxylic acid (60 mg, 31.2 %) as a brown solid. LCMS (m / z): 332.1 [M+H]+.

[0284] Step 3. To a solution of 3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine-9-carboxylic acid (60 mg, 0.18 mmol, 1.0 equiv.) in DMF (2 mL) was added HATU (137.7 mg, 0.36 mmol, 2.0 equiv.), N,N-diisopropylethylamine (70 mg, 0.54 mmol, 3.0 equiv.) and NH4CI (14.5 mg, 0.27 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (2 x 10 mL). Hie organic layers were combined, washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford tert-butyl 9-carbamoyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (40 mg, 66.7%) as an off-yellow solid. LCMS (m / z): 331.1 [M+H]+.

[0285] Step 4. To a solution of tert-butyl 9-carbamoyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (40 mg. 0.12 mmol, 1.0 eq.) in DCM (1 mL) was added 4 M HCl / 1,4- dioxane (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated, triturated with DCM and hexane and freeze-dried to give 2,3,4, 5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine-9- carboxamide (1-49) (8.1 mg, 30 %, HCI salt) as a yellow solid. LCMS (m / z): 231.2 [M+H]+; 'HNMR (400 MHz, DMSO-de) 5 9.75 (s, 2H), 8.27 (s, 1H), 8.00 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.37 (s. 1H), 4.72 (d, J = 6.5 Hz, 2H), 3.56-3.47 (m, 4H), 3.42 (br s, 2H).

[0286] Example 14 (1-34)BOCNH2Pd(OAc)2

[0287] Step 1. A mixture of tert-butyl 8-bromo-l,2,4,5-tetraliydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (50 mg. 0.13 mmol, 1.0 eq.), B0CNH2 (48 mg, 0.409 mmol, 3.0 eq.), Pd(OAc)2 (3.1 mg, 0.013 mmol, 0.1 eq.), Xantphos (7.9 mg, 0.013 mmol, 0.1 eq.) and CS2CO3 (133 mg, 0.409 mmol, 3.0 eq.) in 1,4-dioxane (2 mL) was stirred at 100 °C overnight under N2 in a sealed tube. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (3 x 20 mL). The combined organic72BUSINESS.33510111.1layers were washed with brine (2 x lOOmL), dried overNa2SO4, filtered and concentrated to crude product. The residue was purified by prep-TLC (DCM:MeOH=20: l) to give tert-butyl 8-((tert- butoxycarbonyl)amino)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (36 mg, 66%) as a white solid. LCMS (m / z): 403.2 [M+H]+.

[0288] Step 2. To a solution of tert-butyl 8-((tert-butoxycarbonyl)amino)- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (35 mg, 0.08 mmol, 1.0 eq.) in DCM (1 mL) was added 4 M HCl / l,4-di oxane (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated and purified by prep-HPLC to give 2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepin-8-amine (1-34) (6 mg, 35%) as a white solid. LCMS (m / z): 203.1 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 7.09 (d. J = 8.5 Hz. 1H), 6.67 (d. J = 2.0 Hz, 1H), 6.51 (dd, J = 8.5, 2.0 Hz, 1H), 4.62 (s, 2H), 4.11 - 4.05 (m, 2H). 3.00 - 2.96 (m. 2H), 2.90 - 2.86 (m, 2H), 2.85 - 2.81 (m, 2H).

[0289] Example 15 (1-21)

[0290] Step 1. To a solution of 8-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (250 mg, 0.93 mmol) in dry THF (5 mL) was added NaH (112.7 mg. 2.8 mmol). The reaction mixture was stirred at 0 °C for 0.5 h, then CH3I (133.2 mg, 0.93mmol) was added. The reaction mixture stirred at RT for 2 h. The mixture was diluted with water (50 mL) and stirred at 0°C for 1 h, then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (30 mL) and dried over NajSCL. filtered and concentrated. The mixture was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 8-bromo-3-methyl-2.3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (120 mg, 46.3%) as a white solid. LCMS (m / z): 280.0 [M+H]+.

[0291] Step 2. To a solution of 8-bromo-3-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (100 mg, 0.36 mmol), t-BuXphos (15 mg, 0.04 mmol), KOH (60 mg, 1.1 mmol) in 1,4- dioxane / H2O (3 mL / 3 mL) was added Pd:(dbaL (32.8 mg, 0.03 mmol). The mixture was stirred at 90 °C overnight under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4. concentrated, and purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 3-methyl-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepin-8-ol (50 mg, 64%) as yellow solid. LCMS (m / z): 218.1 [M+H]+.73BUSINESS.33510111.1

[0292] Step 3. To a solution of 3-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l ,2- d][l,4]diazepin-8-ol (50 mg, 0.23mmol) in dry DMF (2 mL) was added K2CO3 (95 mg, 2.8 mmol) and CH3I (98 mg, 0.69 mmol). The reaction mixture stirred at RT for 3 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (30 mL) and dried over Na2SO4, fdtered and concentrated. The mixture was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 8-methoxy-3-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (1-21) (10.1 mg, 18.8%) as a yellow' solid. LCMS (m / z): 232.2 [M+H]+; H NMR (400 MHz, DMSO-d6) 5 7.41 (d, J = 9.0 Hz, 1H), 7.16 (s, 1H), 6.83 (dd, J = 9.0, 1.5 Hz, 1H), 4.38 - 4.26 (m, 2H), 3.75 (s, 3H), 3.25-3.12 (m, 2H), 2.75-2.61 (m, 4H), 2.40 (s, 3H).

[0293] Example 16 (1-8)1 ,10-phenanthroline Cui

[0294] Step 1. To a solution of 9-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (200 mg, 0.75 mmol) in dry THF (8 mL) at 0 °C was added NaH (60%) (90 mg, 2.25 mmol). After stirring at 0 °C for 0.5 h, CH3I (106 mg, 2.25 mmol) was added and the reaction mixture stirred at RT for 2h. The mixture was diluted with water (100 mL) and stirred at 0 °C for 1 h, then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (30 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 9-bromo-3-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l ,4]diazepine (130 mg, 61 %) as a yellow solid. LCMS (m / z): 280.0 [M+H]+.

[0295] Step 2. A solution of 9-bromo-3-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (130 mg, 0.46 mmol), 1,10-phenanthroline (16 mg, 0.09 mmol), Cui (177 mg, 0.93 mmol) and CS2CO3 (167 mg. 0.51 mmol) in MeOH (4 mL) was stirred at 140 °C for 2 h under microwave. The mixture was diluted with MeOH (10 mL), filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=10 / l) and prep-HPLC to afford 9-methoxy-3-methyl-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-8) (HCOOH salt, 2.6 mg, 2.4%) as a white solid. LCMS (m / z): 232.1 [M+H]+; ’HNMR (400 MHz, DMSO-dg) 5 8.14 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H). 6.74 (dd, J = 8.5, 2.0 Hz, 1H), 4.27 (d, J = 8.5 Hz, 2H). 3.78 (s, 3H), 3.09 - 3.06 (m, 2H), 2.66 - 2.65 (m, 2H). 2.61 - 2.59 (m. 2H), 2.37 (s, 3H).74BUSINESS.33510111.1

[0296] Example 17 (1-1)1 ,10-phenanthroline

[0297] Step 1. To a solution of 10-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (200 mg, 0.75 mmol) and formaldehyde (45 mg, 1.50 mmol) in DCE (10 mL) was added AcOH (45.1 mg, 0.75 mmol). Tire mixture was stirred at RT for 3 h, then NaBH(OAc)s (477.8 mg, 2.25 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was diluted with ice cold NaHCOs (aq.) (200 mL) and extracted with DCM (70 ml x 3). The combined organic layers were washed with brine, dried over Na2SO :. filtered and concentrated to afford 10-bromo-3-m ethyl-2, 3, 4, 5 -tetrahydro- 1H- benzo[4,5]imidazo[l,2-d][l,4]diazepine (140 mg, 66.7%) as a yellow solid. LCMS (m / z): 280.0 [M+H]+.

[0298] Step 2. To a solution of 10-bromo-3-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (110 mg. 0.39 mmol), 1,10-phenanthroline (14.2 mg, 0.08 mmol) in MeOH (3 mL) was added CS2CO3 (383.8 mg, 1.18 mmol), Cui (37.4 mg, 0.20 mmol). Tire mixture was stirred at 120 °C overnight under N2 in a sealed tube. Tire mixture was diluted with water (200 mL), extracted with (DCM / MeOH=10 / l) (70 mL * 5). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prcp-TLC (DCM / McOH = 10: 1) to afford 10-methoxy-3-methyl-2,3,4.5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-1) (35 mg, 38.8%) as a white solid. LCMS (m / z): 232.2 [M+H]1; ’H NMR (400 MHz, DMSO-de) 5 7.12 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.72 - 4.62 (m, 2H), 3.89 (s, 3H), 3.11 (dd, J = 6.5, 4.0 Hz, 2H), 2.79 - 2.69 (m, 2H), 2.69 - 2.60 (m, 2H), 2.37 (s, 3H).

[0299] Example 18 (1-45)(CH3)4NCI

[0300] Step 1 . A mixture of tert-butyl 8-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (100 mg, 0.27 mmol, 1.0 eq.), tetramethylammonium chloride (300 mg, 2.7 mmol, 10.0 eq.), CU2O (39 mg, 0.27 mmol, 1.0 eq.) and L-Proline (62 mg, 0.54 mmol, 2.0 eq.) in EtOH75BUSINESS.33510111.1(3 mL) was stirred at 110 °C overnight under N2 in a sealed tube. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SC>4, fdtered and concentrated to crude product. The residue was purified by prep-HPLC to give tert-butyl 8-chloro-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3- carboxylate (68 mg, 52%) as a yellow solid. LCMS (m / z): 322.1 [M+H]+.

[0301] Step 2. To a solution of tert-butyl 8-chloro-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (68 mg, 0.15 mmol, 1.0 eq.) in DCM (1 mL) was added 4M HCl / 1,4- dioxane (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated, triturated with DCM and hexane and freeze-dried to give 8-chloro-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (1-45) (50 mg, 99%, HC1 salt) as a yellow solid. LCMS (m / z): 222.1 [M+H]+; ’H NMR (400 MHz, DMSO-de) 5 10.13 (s, 2H), 7.87 - 7.79 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H). 4.82 (s, 2H), 3.67 - 3.62 (m, 2H), 3.51 (s, 2H), 3.45 (s, 2H).

[0302] Example 19 (1-5)

[0303] Step 1. To a solution of tert-butyl (R)-3-methyl-l,4-diazepane-l-carboxylate (200 mg, 0.933 mmol) and 2-fluoro-4-methyl-l -nitrobenzene (173.7 g, 1.12 mmol) in DMF (4 mL) was added K2CO3 (387 mg, 2.8 mmol). The reaction mixture was stirred at 100 °C overnight. Hie reaction mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL). dried over Na2SO4. filtered and concentrated. The mixture was purified by prep-TLC (Pet.Ether: EtOAc=5: l) to afford tert-butyl (R)-3-methyl-4-(5-methyl-2-nitrophenyl)-l,4- diazepane-1 -carboxylate (141 mg, 43%) as a yellow solid. LCMS (m / z): 350.2 [M+H]+.

[0304] Step 2. To a solution of tert-butyl (R)-3-methyl-4-(5-methyl-2 -nitrophenyl)-!, 4-diazepane-l- carboxylate (187 mg, 0.535 mmol) in MeOH (4 mL) was added Pd / C (40 mg). The reaction mixture was76BUSINESS.33510111.1410095-001WG (221124) stirred at RT overnight under H2. The mixture was fdtered and concentrated. The mixture was purified by prep-TLC (Pet. Ether: EtOAc=l: l) to afford tert-butyl (R)-4-(2-amino-5-methylphenyl)-3-methyl-l,4- diazepane-1 -carboxylate (65 mg, 38%) as an off-white solid. LCMS (m / z): 320.2 [M+H]+.

[0305] Step 3. To a solution of tert-butyl (R)-4-(2-amino-5-methylphenyl)-3-methyl-l,4-diazepane- 1-carboxylate (65 mg. 0.203 mmol) in DCM (2 mL) was added H2O2 (115 mg, 1.02 mmol) and TFA (229 mg, 2.34 mmol). The reaction mixture was stirred at 40 °C for Ih. The reaction mixture was adjusted pH to 8-9 by NaHCOg aq. solution. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with water (15 mL) and dried over IS^SCL, filtered and concentrated. Tire mixture was purified by prep-TLC (Pet.Ether: EtOAc=5: l) to afford tert-butyl (R)-l,9- dimethyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (14 mg, 21%) as an off-white solid. LCMS (m / z): 316.2 [M+H]1.

[0306] Step 4. To a solution of tert-butyl (R)- 1,9-dimethyl- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (14 mg, 0.044 mmol) in DCM (1 mL) was added 4 M HC1 in 1,4-dioxane (2 mL). The reaction mixture was stirred at RT for 1 h. The mixture was concentrated and triturated with DCM (5 mL) to afford (R)-L9-dimethyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine hydrochloride salt (1-5) (3.7 mg, 33%) as a yellow solid. LCMS (m / z): 216.2 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 10.40 (s. IH), 9.49 (s, IH). 7.69 (s. IH). 7.65 (d. J = 8.0 Hz, IH), 7.31 (d, J = 8.5 Hz, IH), 5.40-3.28 (m, IH), 3.79 (dd, J = 14.5, 4.5 Hz, IH), 3.69 - 3.53 (m, 5H), 3.50-3.25 (m, 3H), 1.61 (d, J = 7.5 Hz, 3H).

[0307] Example 20 (1-37)

[0308] To a solution of (E)-9-(prop-l-en-l-yl)-2.3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (40 mg, 0.17 mmol; prepared using methods of Example 3) in MeOH (6 mL) was added Pd / C (40%) (16 mg). The mixture was stirred at 50 °C overnight under H2. The mixture was filtered and concentrated under vacuum. The residue was purified by prep-TLC and prep-HPLC to afford 3-methyl-9- propyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-37) (5.1 mg, 12%) as a white solid. LCMS (m / z): 244.1 [M+H]+; 'H NMR (400 MHz. DMSO-de) 8 7.40 (d, J = 8.0 Hz, IH). 7.31 (s, IH). 6.97 (d, J = 8.0 Hz. IH), 4.35-4.25 (m, 2H). 3.15-3.05 (m, 2H), 2.67 - 2.63 (m, 4H), 2.55 (s, 3H), 2.39 - 2.33 (m, 3H), 1.63 (q, J = 7.5 Hz, IH), 0.90 (t, J = 7.5 Hz, 3H).77BUSINESS.33510111.1

[0309] Example 21 (1-41)

[0310] Step 1. To a solution of tert-butyl 5 -oxo- 1.4-diazepane-l -carboxylate (1.1 g, 5.13 mmol, 1.2 eq.) in anhydrous DMF (10 mL) at 0 °C was added NaH (256 mg, 6.41 mmol, 1.5 eq.). The mixture was stirred at 0 °C for 30 mins. 1 -bromo-5-fluoro-2 -methyl -4-nitrobenzene (1 g, 4.27 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature overnight under a N2 atmosphere. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 4-(5-bromo-4- methyl-2-nitrophenyl)-5-oxo-l,4-diazepane-l -carboxylate (1.83 g, 100%) as a yellow solid, which was used directly into the next step. LCMS (m / z): 372.0 [M-56+H]+.

[0311] Step 2. To a solution of tert-butyl 4-(5-bromo-4-methyl-2-nitrophenyl)-5-oxo- l,4-diazepane- 1-carboxylate (1.92 g, 4.48 mmol, 1.0 eq.) in AcOH / toluene (10 mL / 6 mL) at room temperature was added Fc (2.5 g, 44.83 mmol, 10.0 eq.). The mixture was stirred at 120 °C for 30min. Tire mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. Tire residue obtained was purified by column chromatography on silica gel (eluent: Pet.Ether: EtOAc=5: 1 to 1: 1) to afford tert-butyl 9-bromo- 8-methyl-l,2,4,5-tetrahydro-3FI-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (1.1 g, 62.5%) as a yellow solid. LCMS (m / z): 380.0 [M+H]+.

[0312] Step 3. To a solution of tert-butyl 9-bromo-8-methyl-l,2,4,5-tetraliydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (200 mg, 0.53 mmol, 1.0 eq.) in NMP (3 mL) at room temperature was added Zn(CN)2 (123 mg, 1.05 mmol . 2.0 eq.) and Pd(PPhs)4 (61 mg. 0.05 mmol, 0.1 eq ). The reaction was stirred at 110 °C for 2 h under microwave. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with78BUSINESS.33510111.1brine, dried over Na2SC>4, fdtered and concentrated in vacuum. The residue obtained was purified by prep- TLC (Pet. Ether: EtOAc=l:2) to afford tert-butyl 9-cyano-8-methyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (160 mg, 93.5%) as a yellow solid. LCMS (m / z): 327.2 [M+H]+.

[0313] Step 4. To a solution of tert-butyl 9-cyano-8-methyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (160 mg, 0.49 mmol, 1.0 eq.) in DCM (6 m ) at room temperature was added 4M HCl / l,4-dioxane (3 mb). The mixture was stirred at room temperature for 2 h. Hie reaction mixture was concentrated in vacuum and the residue was purified by trituration (DCM) to afford 8-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine-9-carbonitrile hydrochloride (1-41) (124.7 mg, 96.7%) as a yellow solid. LCMS (m / z): 227.2 [M+H]+; 'H NMR (400 MHz, DMSO-de) 5 9.93 (s, 2H). 8.31 (s, 1H), 7.75 (s, 1H), 4.79 - 4.76 (m, 2H). 3.63 - 3.57 (m, 2H), 3.50 (br s, 2H), 3.43 (br s, 2H), 2.59 (s, 3H).

[0314] Additional Exemplary Compounds Prepared via Example 21 Methods79BUSINESS.33510111.1410095-001WG (221124)80BUSINESS.33510111.1

[0315] Example 22 (1-42)81BUSINESS.33510111.1410095-001WG (221124)

[0316] Step 1. Tn a sealed tube, to a solution of l-iodo-2-nitro-4-(trifluoromethyl)benzene (100 mg, 0.315 mmol) and tert-butyl 5 -oxo- 1 ,4-diazepane- 1 -carboxylate (81.2 mg, 0.378 mmol) in toluene (3 mL) was added (R)-BINAP (15.7 mg, 0.025 mmol), Pd(TFA)2 (8.4 mg, 0.025 mmol) and CS2CO3 (143.9 mg, 0.441 mmol). The reaction mixture was stirred at 80 °C overnight under N2. Tire reaction mixture was directly used. LCMS (m / z): 348.1 [M-55+H]1.

[0317] Step 2. To a solution of tert-butyl 4-(2-nitro-4-(trifluoromethyl)phenyl)-5-oxo-l,4-diazepane- 1-carboxylate (127 mg, 0.315 mmol) in AcOH (2 mL) was added Fe (176.2 mg, 3.15 mmol). Tire reaction mixture was stirred at 120 °C for 0.5 h. The mixture was filtered and adjusted pH to 8-9 by NaHCCL aq. solution. Tire mixture was diluted with water (10 mL) and extracted with EtOAc (20 mLx 2). Tire combined organic layers were washed with water (20 mL), dried over Na2SO4, filtered and concentrated. Hie mixture was purified by prep-TLC (Pet.Ether: EtOAc=l: l) to afford tert-butyl 8-(trifluoromethyl)-l,2,4,5- tetrahydro-3H-benzo[4,5]imidazo[l ,2-d][l,4]diazepine-3-carboxylate (78 mg, 69%) as an off-white solid. LCMS (m / z): 356.15 [M+H]+.

[0318] Step 3. To a solution of tert-butyl 8-(trifluoromethyl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (78 mg, 0.219 mmol) in DCM (2 mL) was added 4 M HC1 in 1,4-dioxane (5 mL). The reaction mixture was stirred at RT for 1 h. The mixture was concentrated and the residue was triturated with DCM (20 mL) to afford 8-(trifluoromethyl)-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-42) (56 mg, 87%) as an off-yellow solid. LCMS (m / z): 256.1 | M+H| : 'HNMR (400 MHz, DMSO-d6) 59.90 (s, 2H), 8.03 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 4.85 - 4.77 (m, 2H), 3.63 - 3.57 (m, 2H), 3.51 (s, 2H), 3.43 (s, 2H).

[0319] Additional Exemplary Compounds Prepared via Example 22 Methods82BUSINESS.33510111.1

[0320] Example 23 (1-65)Step 7

[0321] Step 1. A solution of 3-bromo-lH-pyrazole (5.0 g,34.02 mmol), potassium trifluoro(vinyl)borate (6.84 g, 51.03 mmol), I<2CO, (9.4 g, 68.04 mmol) and Pd(dppf)Cl2(2.49 g, 3.40 mmol) in l,4-dioxane / H2O (120 mL / 30 mL) was stirred at 100 °C for 16 h under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (3x40 mL). The combined organic layers were dried over Na2SO4, fdtered and concentrated. The residue was purified by column (Pet.ether / EtOAc=5 / l-l / l) to afford 3-vinyl-lH-pyrazole (2.14 g, 66%) as a yellow oil. LCMS (m / z): 95.2 [M+H]+.

[0322] Step 2. A solution of 3-vinyl-lH-pyrazole (2.14 g, 22.74 mmol) and PtO2(516 mg, 2.28 mmol) in EtOAc (40 mL) was stirred at RT for 16 h under H2balloon. The mixture was directly filtered, and the filtrate was concentrated in vacuo to afford 3-ethyl-lH-pyrazole (2.0 g, 93%) as a colorless oil. LCMS (m / z): 97.2 [M+H]+.83BUSINESS.33510111.1

[0323] Step 3. To a stirring solution of AcONa (3.07 g, 37.45 mmol) in AcOH / H2O (30 mL / 6 mL) was added 3-ethyl-lH-pyrazole (1.50 g, 15.60 mmol), then Br2(2.74 g, 17.16 mmol) was added, and the mixture was stirred at RT for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). Hie combined organic phases were washed ith water (20 mL) and brine (20 mL), dried over NaiSOi. filtered and concentrated to afford 4-bromo-3-ethyl-lH-pyrazole (2.52 g, 92%) as a light-yellow' oil. LCMS (m / z): 176.9 [M+H]+.

[0324] Step 4. A solution of 4-bromo-3-ethyl-lH-pyrazole (500 mg, 2.86 mmol), TsOH (49 mg, 0.28 mmol) and 3,4-dihydro-2H-pyran (480 mg, 5.71 mmol) in DCE (5 mL) was stirred at RT for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na;SO_ filtered and concentrated. The residue was purified by prep-TLC (Pet.ether / EtOAc=10 / l) to afford 4-bromo-3-ethyl-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole (254 mg, 34%) as a yellow' oil. LCMS (m / z): 259.0 [M+H]+.

[0325] Step 5. A solution of tert-butyl 9-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (500 mg, 1.37 mmol), B2(pin)2 (416 mg, 1.64 mmol), KOAc (402 mg, 4.10 mmol) and Pd(dppf)C12 (50 mg, 0.07 mmol) in DMF (5 mL) was stirred at 100 °C for 1 h in a sealed tube. The mixture was diluted with water (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layers w'ere washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=20 / l) to afford tert-butyl 9-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (435 mg, 77%) as an off-white solid. LCMS (m / z): 414.3 [M+H]+.

[0326] Step 6. A solution of tert-butyl 9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,4,5- tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (220 mg, 0.53 mmol), 4-bromo-3- ethyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (207 mg, 0.80 mmol), K2CO2(147 mg, 1.06 mmol) and Pd(dppf)Cl2(39 mg, 0.05 mmol) in l,4-dioxane / H2O (4mL / 0.8 mL) was stirred at 85 °C for 16 h under N2in a sealed tube. The mixture was diluted with water (15 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=20 / l) to afford tert-butyl 9-(3-ethyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (107 mg, 43%) as an off- white solid. LCMS (m / z): 466.3 | M+H| .

[0327] Step 7. A solution of tcrt-butyl 9-(3-cthyl-l-(tctrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)- l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (50 mg, 107.39 umol) in 4M HCl / dioxane (4 mL) and DCM / MeOH (2 mL / 1 mL) was stirred at RT for 2 h. The reaction was directly concentrated in vacuo, and the residue was purified by trituration (hexane) to afford 9-(3-ethyl- IH-pyrazol- 4-yl)-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-65) (32 mg, 80%) as a grey solid.84BUSINESS.33510111.1LCMS (m / z): 282.1 [M+H]+; 'H NMR (400 MHz, DMSO-dfi) 5 10.16 (s, 2H), 7.97 (s, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 4.97 - 4.92 (m, 2H), 3.80 - 3.73 (m, 2H), 3.62 - 3.49 (m,4H), 2.90 - 2.83 (m, 2H), 1.22 - 1.17 (m, 3H).

[0328] Example 24 (1-54)

[0329] Step 1. To a stirred solution of tert-butyl 5-oxo-l,4-diazepane-l -carboxylate (1.9 g, 11.23 mmol, 1.5 eq.) in DMF (20 mL) at 0 °C was added NaH (450 mg, 8.98 mmol, 1.2 eq.). After stirring at 0 °C for 0.5 hour, a solution of l-fluoro-4-iodo-2-nitrobenzene (2 g, 7.49 mmol, 1.0 eq.) in DMF (20 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over Na2SO4, filtered and concentrated to afford tert-butyl 4-(4- iodo-2-nitrophenyl)-5 -oxo- 1,4-diazepane-l -carboxylate (3 g, 99%) as yellow oil. LCMS (m / z): 405.9 [M- 55]+.

[0330] Step 2. A mixture of tert-butyl 4-(4-iodo-2-nitrophenyl)-5-oxo-L4-diazepane-l-carboxylate (3 g, 6.5 mmol, 1.0 eq.) and Fe (3.6 g, 65 mmol, 10.0 eq.) in AcOH / toluene (20 mL / 12mL) was stirred at 120 °C for 0.5 hour. The mixture was concentrated, diluted with water (200 mL) and extracted with EtOAc (3 x 50 mL). Tire combined organic layers were washed with NaHCOs.aq (3 x 100 mL) and dried over 85BUSINESS.33510111.1410095-001WG (221124)Na2SC>4, filtered and concentrated. The mixture was purified by column (DCM / MeOH=100: l~50: 1, v / v) to afford tert-butyl 8-iodo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (940 mg, 36%) as a yellow solid. LCMS (m / z): 414.0 [M+H]+.

[0331] Step 3. To a stirred solution of cyclobutanecarboxylic acid (1 g, 9.98 mmol.l.Oeq.) and 2- hydroxyisoindoline-1.3-dione (2.44 g. 14.98 mmol,1.5eq.) in DCM (30 mL) at 0 °C was added DIC (1.89 g, 14.98 mmol,1.5eq.) and DMAP (120 mg, 0.9 mmol,0.1eq.). The reaction mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water (200 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (3 x 60 mL) and dried over Na2SCL, filtered and concentrated. The mixture was purified by column (Pet.Ether: EtOAc=50: 1-20: 1, v / v) to afford l,3-dioxoisoindolin-2-yl cyclobutanecarboxylate (1.3 g, 53%) as a yellow solid.

[0332] Step 4. To a stirred solution of NiBr2(dme) (74 mg. 0.24 mmol.0.2eq.) and t-BuBpyCanCN (81 mg, 0.24 mmol,0.2eq.) in DMAc / THF (0.3 mL / 3 mL) was added Zn (dust) ( 158 mg, 2.4 mmol,2.0eq.), tert-butyl 8-iodo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (500 mg, 1.2 mmol,1.0eq.) and l,3-dioxoisoindolin-2-yl cyclobutanecarboxylate (296 mg, 1.2 mmol,1.0eq.) under N2. The reaction mixture was stirred at room temperature under N2 overnight. The mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 40 mL) and dried over Na2SC>4, filtered and concentrated. The mixture was purified by prep-TLC (Pet.Ether: EtOAc=l: l, v / v) and prep-HPLC to afford tert-butyl 8-cyclobutyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (25 mg, 6%) as a yellow oil. LCMS (m / z): 342.2 [M+H]+.

[0333] Step 5. To a solution of tert-butyl 8-cyclobutyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (25 mg. 0.07 mmol, 1.0 eq.) in DCM (3 mL) was added 4 M HCl / 1,4- di oxane (0.3 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and triturated with DCM / hexane (10 mL) to afford 8-cyclobutyl-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-54) (12.6 mg, 64%) as an off-white solid. LCMS (m / z): 242.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 10.05 (s, 2H), 7.77 (d, J = 8.6 Hz, 1H). 7.55 (s, 1H). 7.40 (d, J = 8.6 Hz, 1H), 4.87 - 4.78 (m. 2H), 3.70 (d, J = 8.8 Hz, 1H), 3.68 - 3.65 (m, 2H), 3.52 (s, 2H). 3.47 (s. 2H), 2.36 (qt. J = 7.8. 2.4 Hz. 2H), 2.19 - 2.09 (m, 2H). 2.05 - 1.95 (m, 1H), 1.84 (dt. J = 10.8, 8.4 Hz, 1H).86BUSINESS.33510111.1

[0334] Example 25 (1-50)p Step 5

[0335] Step 1. To a solution of tert-butyl 5 -oxo- 1,4-diazepane-l -carboxylate (2 g, 9.33 mmol) in DCM (20 mL) was added trimethyloxonium tetrafluoroborate (1.38 g, 9.33 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated. The residue was diluted with saturated NaHCOs aqueous solution (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated NaHCCL aqueous solution (50 mL) and water (30 mL), dried over Na2SO4, fdtered and concentrated to afford tert-butyl 5-methoxy-2,3,6,7-tetrahydro- 1 H- 1 ,4-diazepine- 1 -carboxylate (1.77 g, 83%) as yellow oil. LCMS (m / z): 229.2 [M+H]+.

[0336] Step 2. To a solution of tert-butyl 5-methoxy-2,3,6,7-tetrahydro-lH-l,4-diazepine-l- carboxylate (1.27 g, 5.56 mmol) in EtOH (12mL) was added NH4CI (297.6 mg. 5.56 mmol). The reaction mixture was stirred at 90 °C for 4 h. The mixture was concentrated to afford crude tert-butyl 5-imino- 1,4- diazepane-l -carboxylate as an off-white solid, which was used directly. LCMS (m / z): 214.2 [M+H]+.

[0337] Step 3. A solution of tert-butyl 5-imino- 1,4-diazepane-l -carboxylate (1.19 g, 5.58 mmol), 5- bromo-2-fluoro-3-iodopyridine (1.3 g, 4.29 mmol), Cui (81.8 mg, 0.429 mmol) and CS2CO3 (4.2 g, 12.88 mmol) in dry DMSO (20 mL) was stirred at 90 °C overnight under N2. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (80 mL x 3), dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.Ether :EtOAc=10:l - 1: 1) to afford tert-butyl 3-bromo-6,7,9,10- tetrahydro-8H-pyrido[2',3':4,5]imidazo[l,2-d][l,4]diazepine-8-carboxylate (259 mg, 16%) as an off- yellow solid. LCMS (m / z): 367.1 [M+H]+.87BUSINESS.33510111.1

[0338] Step 4. To a solution of tert-butyl 3-bromo-6,7,9,10-tetrahydro-8H- pyrido[2',3':4,5]imidazo[l,2-d][l,4]diazepine-8-carboxylate (58 mg, 0.158 mmol), Pd(dppf)C12 (11.6 mg, 0.015 mmol) and K2CO3 (65.5 mg, 0.474 mmol) in 1,4-dioxanc (1 mL) and H2O (0.2 mL) was added 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane (50 wt%, 119 mg, 0.473 mmol). The reaction mixture was stirred at 100 °C overnight under N?. The mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (20 mL), dried over Na2SC>4, filtered and concentrated. The mixture was purified by prep-TLC (DCM:MeOH=20: 1) and prep-HPLC to afford tertbutyl 3-methyl-6,7,9,10-tetrahydro-8H-pyrido[2',3':4,5]imidazo[l,2-d][l,4]diazepine-8-carboxylate (28 mg, 58%) as an off-white solid. LCMS (m / z): 303.2 [M+H]+.

[0339] Step 5. To a solution of tert-butyl 3-methyl-6, 7,9.10-tetrahydro-8H- pyrido[2',3':4.5Jimidazo[L2-d][l,4]diazepine-8-carboxylate (28 mg, 0.092 mmol) in DCM (1 mL) was added 4M HC1 in 1,4-dioxane (5 mL). The reaction mixture was stirred at RT for 2h. The mixture was concentrated and freeze-dried to afford 3-methyl-7,8,9,10-tetrahydro-6H-pyrido[2',3':4,5]imidazo[l,2- d][ 1,4] diazepine (1-50) (HC1 salt, 17.3 mg, 77%) as an off-white solid. LCMS (m / z): 203.1 [M+H]+; *H NMR (400 MHz, DMSO-d6) 5 10.13 (s, 2H), 8.47 (d. J = 1.6 Hz, 1H), 8.35 (s, 1H), 4.87 - 4.77 (m, 2H), 3.65 (dd, J = 7.0, 3.6 Hz, 2H), 3.52 (s. 2H), 3.43 (d, J = 7.2 Hz, 2H). 2.51 (s, 3H).

[0340] Example 26 (1-52)

[0341] Step 1. To a solution of tert-butyl 9-chloro-8-ethyl- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (70 mg, 0.2 mmol) in DMAc (1 mL) was added Zn(CN)2 (47 mg, 0.2 mmol). [PdCftallyl)]: (8 mg. 0,02 mmol) and X-Phos (19 mg, 0.04 mmol). After stirring at 120 °C overnight in a sealed tube under N2, the mixture was poured into water (10 mL) and extracted with EtOAc (20 mL x 3). The combined oiganic phases were washed with brine, dried over Na2SO_i and concentrated. The residue was purified by p-TLC (DCM / MeOH = 15 / 1) to give tert-butyl 9- cyano-8-ethyl-1.2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (40 mg, 58.7%) as an off-white solid. LCMS (m / z): 341.2 [M+H]+.

[0342] Step 2. To a solution of tert-butyl 9-cyano-8-ethyl-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (40 mg, 0.117 mmol) in DCM (3 mL) was added HCl / dioxane (4M, 1.5 mL). After stirring at RT for 2 h, the mixture was concentrated, and the residue was freeze-dried to give 8-ethyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d] [l,4]diazepine-9-carbonitrile88BUSINESS.33510111.1410095-001WG (221124)(1-52) (28 mg, 95%) as a white solid. LCMS (m / z): 241 .2 [M+H]+; 'H NMR (400 MHz, DMSO-de) 8 9.96 (s, 2H), 8.33 (s, 1H), 7.74 (s, 1H), 4.83 - 4.73 (m, 2H), 3.64 - 3.54 (m, 2H), 3.50 (s, 2H), 3.42 (s, 2H), 2.92 (q, J = 7.4 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H).

[0343] Example 27 (1-56)

[0344] Step 1. To a stirred solution of tert-butyl 5 -oxo- 1,4-diazepane-l -carboxylate (2.4 g, 11 .2 mmol, 1.5 eq.) in DMF (20 mL) at 0 °C was added NaH (60%, 562 mg, 14.0 mmol, 1.2 eq.). The reaction mixture was stirred at 0 °C for 0.5 hour, and a solution of l-fluoro-4-iodo-2-nitrobenzene (2.5 g, 9.36 mmol, 1.0 eq.) in DMF (20 mL) was added. Tire reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over Na2SO4. filtered and concentrated to afford tert-butyl 4-(4-iodo-2-nitrophenyl)-5 -oxo- 1,4-diazepane-l -carboxy late (3.4 g,99%) as yellow oil. LCMS (m / z): 406.0 [M-55]+.

[0345] Step 2. A mixture of tert-butyl 4-(4-iodo-2-nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (3.4 g. 7.3 mmol, 1.0 eq.) and Fe (4.1 g, 73 mmol, 10.0 eq.) in AcOH / toluene (20 mL / 12mL) was stirred at 120 °C for 0.5 hour. The mixture was concentrated. The residue was diluted with water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaHCO .aq (3 x 100 mL) and dried over Na2SO4, filtered and concentrated to crude. The mixture was purified by column (DCM / MeOH=100: l~50: 1) to afford tert-butyl 8-iodo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (1.2 g, 40%) as a yellow solid. LCMS (m / z): 414.1 [M+H]+.

[0346] Step 3. To a stirred solution of Zn (360 mg, 5.5 mmol,3.0eq.) in 1,2-dibromoethane (0.2 mL) was added a solution of TMSC1 (10.2 mL) in DMF (2 mL). The reaction mixture was stirred at room temperature for 15 min under N2. 3-iodooxetane (1 g, 5.5 mmol,3.0eq.) was added and the mixture was89BUSINESS.33510111.1stirred at room temperature for 15 min under N2. Tert-butyl 8-iodo-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (786 mg. 1.8 mmol, 1.Oeq.), Pd2(dba)3 (84 mg, 0.09 mmol,0.05eq.) and P(OMePh)3(118 mg, 0.36 mmol,0.2eq.) were added. The reaction mixture was stirred at room temperature 3 hours under N2. Tire mixture was diluted with water (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by column (Pet.Ether: EtOAc=10: 1). prep-TLC (DCM / MeOH=20: 1) and prep-HPLC to afford tert-butyl 8-(oxetan-3-yl)-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3- carboxylate (6 mg) as a yellow solid. LCMS (m / z): 344.2 [M+H]+.

[0347] Step 4. To a solution of tert-butyl 8-(oxctan-3-yl)-l,2,4,5-tctrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (18 mg, 0.03 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (0.6 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated and adjusted pH to ~7-8 with Na-T'CE aq. solution, dried over N’a-SCL and re-dissolved with EtOAc. The organic phases was concentrated, and the residue was purified by prep-HPLC to afford 8- (oxetan-3-yl)-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-56) (13.3 mg) as a white solid. LCMS (m / z): 244.1 [M+H]+; 'H NMR (400 MHz, DMSO-de) 5 7.58 - 7.49 (m, 1H), 7.43 (dd, J = 8.4, 4.2 Hz, 1H), 7.34 - 7.26 (m, 1H), 5.32 (d, J = 55.4 Hz, 1H). 4.36 (s. 1H), 4.22 (s, 1H), 4.16 - 4.10 (m, 2H). 3.64 - 3.58 (m. 2H), 3.57 - 3.50 (m, 2H), 3.10-3.00 (m, 1H). 3.10-2.95 (m, 2H), 2.95-2.85 (m. 2H).

[0348] Example 28 (1-57)I) HCI, H2O NaNO2i) K CO DMF90BUSINESS.33510111.1

[0349] Step l. To a solution of 2-amino-3-nitrophenol (3 g, 19.46 mmol) in DMF (30 mL) was added K2CO3 (3.23 g, 23.36mmol). The reaction mixture was stirred at RT for 1 h. Mel (3.32 g, 23.36mmol) was added, and the reaction mixture was stirred at RT overnight. Tire reaction mixture was diluted with water (50mL) and extracted with EtOAc (lOOmL x 2). The combined organic layers were washed with water (150 mLx 3) and brine (lOOmL), dried over Na?SO4. fdtered and concentrated to afford 2-methoxy-6-nitroaniline (3.09 g, 94%) as a red solid. LCMS (m / z): 169.0 [M+H]+.

[0350] Step 2. To a solution of 2-methoxy-6-nitroaniline (3.09 g, 18.38 mmol) and NaOAc (1.66 g, 20.21 mmol) in AcOH (42 mL) was added Br2(4.7 g, 29.4 mmol). Tire reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water (30 mL). The solid was collected by filtration to afford 4-bromo-2-methoxy-6-nitroaniline (4.27 g, 97%) as an orange solid. LCMS (m / z): 246.9 [M+H]+.

[0351] Step 3. To a solution of 4-bromo-2-methoxy-6-nitroaniline (3 g, 12.14 mmol) in cone. HC1 (30mL) and H2O (40mL) was added NaNO2(1.26 g, 18.22mmol). The reaction mixture was stirred at RT for 1 h. A solution of KI (6.05 g, 36.43 mmol) in H2O (40mL) was added, and the reaction mixture was stirred at RT overnight. Tire mixture was diluted with water (20 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.Ether to Pet.Ether: EtOAc=100: l) to afford 5-bromo-2-iodo-l-methoxy-3-nitrobenzene (2.77 g, 63%) as an off- yellow solid.

[0352] Step 4. A solution of 5 -bromo-2-iodo-l-methoxy-3 -nitrobenzene (1 g, 2.79 mmol), tert-butyl 5 -oxo- 1.4-diazepane-l -carboxylate (718 mg, 3.35 mmol), Pd2(dba)3 (242 mg, 0.419 mmol), Xantphos (384 mg, 0.419 mmol) and Cs2CO2(2.73 g. 2.79 mmol) in toluene (30 mL) was stirred at 80 °C overnight under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL, dried over Na2SO4, filtered and concentrated to afford crude tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo-l,4-diazepane-l- carboxylate (1.24 g) as black oil. LCMS (m / z): 388.0 [M-55]+.

[0353] Step 5. To a solution of tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo-l,4- diazepane-1 -carboxylate (1.24 g, 2.79 mmol) in toluene (30 mL) and AcOH (20 mL) was added Fe (1.56 g, 27.91 mmol). The reaction mixture was stirred at 120 °C for 0.5 h. The mixture was filtered, and the filtrate was diluted with water (30 mL) and extracted with EtOAc (50 mLx 2). The combined organic layers were adjusted pH = 9-10 by K2CO ; aq. solution, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. Hie mixture was purified by column chromatography on silica gel (Pet.Ether: EtOAc=3: l to EtOAc) to afford tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (256 mg, 23%) as a yellow solid. LCMS (m / z): 396.1 [M+H]+.91BUSINESS.33510111.1410095-001WG (221124)

[0354] Step 6. A solution of tert-butyl 8-bromo-10-methoxy- l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (100 mg, 0.252 mmol), potassium trifluoro(vinyl)boratc (68 mg, 0.504 mmol), Pd(dppf)C12 (18 mg, 0.025 mmol) and K2CO3 (105 mg, 0.757 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was stirred at 100 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (Pet.Ether: EtOAc=l: l) to afford tert-butyl 10-methoxy-8-vinyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (40 mg, 46%) as a yellow solid. LCMS (m / z): 344.2 [M+H]+.

[0355] Step 7. To a solution of tert-butyl 10-methoxy-8-vinyl- 1,2,4, 5-tetrahydro-3H- benzo[4.5]imidazo[l,2-d][L4Jdiazepine-3-carboxylate (40 mg, 0.116 mmol) in THF (1 mL) and MeOH (1 mL) was added Pd / C (15 mg). The reaction mixture was stirred at RT overnight under H2. The reaction mixture was filtered, and the filtrate was concentrated. The mixture was purified by prep-TLC (Pet.Ether: EtOAc=l: l) and prep-HPLC to afford tert-butyl 8-ethyl-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (63 mg, 78%) as a white solid. LCMS (m / z): 346.2 [M+H]+.

[0356] Step 8. To a solution of tert-butyl 8-ethyl-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (63 mg, 0.182mmol) in DCM (2 mL) was added 4 M HCl / l,4-dioxane (5 mL). The reaction mixture was stirred at RT for 1 h. Tire reaction mixture was concentrated. The mixture was triturated with DCM : hexane=l: l (lOmL) and freeze-dried to afford 8- ethyl-10-methoxy-2,3.4.5-tetrahydro-lH-benzo[4.5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-57) (47.1 mg, 91%) as a yellow solid. LCMS (m / z): 246.1 [M+H]T 1H NMR (400 MHz. DMSO-d6) 5 10.19 (s, 2H), 7.14 (d, J = 1.2 Hz, 1H), 6.97 (s, 1H), 5.10 (d, J = 7.8 Hz, 2H), 3.98 (s, 3H), 3.68 - 3.64 (m, 2H), 3.57 (s, 2H), 3.45 (s, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H).92BUSINESS.33510111.1

[0357] Example 29 (1-59)Step 4 Step 5

[0358] Step 1. A solution of l-bromo-2,4-difluoro-3-nitrobenzene (500 mg, 2.1 mmol) and CHsONa (120 mg, 2.2 mmol) in CH3OH (10 m ) was stirred at RT for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE:EtOAc= 10: 1) to give 1- bromo-4-fluoro-2-mcthoxy-3-nitrobcnzcnc (150 mg, 28.7%) as a yellow solid.

[0359] Step 2. To a solution of l-bromo-4-fluoro-2-methoxy-3 -nitrobenzene (3.2 g, 12.8 mmol) and NaH (60%, 768 mg. 19.2 mmol) in dry DMF ( 10 mL) at 0 °C was added tert-butyl 5-oxo-l,4-diazepane-l- carboxylate (3.28 g, 15.36 mmol). After stirring at RT for 16 h, the reaction mixture was diluted with water (120 mL) and extracted with EA (120 mL x 2). The combined organic phases were dried over Na2SO4, filtered and concentrated to give teit-butyl 4-(4-bromo-3-methoxy-2-nitrophenyl)-5-oxo-l,4-diazepane-l- carboxylate (5.67 g, crude), which was used into next step without further purification. LCMS (m / z): 388.0 [M+H-tBu]+.

[0360] Step 3. A solution of tert-butyl 4-(4-bromo-3-methoxy-2-nitrophenyl)-5-oxo-l,4-diazepane- 1-carboxylate (5.67 g, 12.8 mmol) and Fe (7.1 g, 128 mol)) in AcOH (15 mL) and toluene (9 mL) was stirred at 120 °C for 0.5 h. The reaction mixture was filtered and concentrated. The residue was purified by column (DCM: MeOH=100:0 to 20: 1) to give tert-butyl 8-bromo-7-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (1.5 g, 30%) as a brown solid. LCMS (m / z): 396.0 [M+H]+.

[0361] Step 4. A solution of tert-butyl 8-bromo-7-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (600 mg, 1.51 mmol), Et2Zn (IM, 15 mL, 15 mmol) and Pd(dppf)Cl2(112 mg. 0.15 mmol) in dry THF (5 mL) was stirred at 70 °C for 16 h under N2. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined93BUSINESS.33510111.1410095-001WG (221124) organic phases were dried over Na-NCL. filtered and concentrated. The residue was purified by prep-TLC (DCM:MeOH=20: 1) to give tert-butyl 8-ethyl-7-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (180 mg, 34.8%) as a white solid. LCMS (m / z): 346.2 [M+H]+.

[0362] Step 5. A solution of give tert-butyl 8-ethyl-7-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (180 mg, 0.52 mmol) in 4 M HCl / dioxane (2 mL) and DCM (3 mL) was stirred at RT for 2 h. Tire reaction mixture was concentrated. The residue was purified by prep-HPLC and prep-TLC (DCM:MeOH=10: 1) to give 8-ethyl-7-methoxy-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-59) (20 mg, 15.7 %) as colorless oil. LCMS (m / z): 246.2 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 8.22 (d, J = 3.0 Hz, 1H), 7.12 - 7.04 (m, 1H), 7.02 - 6.97 (m, 1H). 4.34 - 4.24 (m, 2H), 4.22 - 4.19 (m. 3H), 3.68 (dq, J = 30.6, 5.6, 5.0 Hz, 2H), 3.23 - 3.17 (m, 2H), 3.17 - 3.14 (m, 2H). 2.63 (qd, J = 7.4. 2.0 Hz. 2H), 1.12 (td. J = 7.4. 1.2 Hz. 3H).

[0363] Additional Exemplary Compounds Prepared via Example 29 Methods94BUSINESS.33510111.1

[0364] Example 30 (1-35)

[0365] Step 1. To a solution of 2-fluoro-3 -methoxyaniline (2.0 g, 14.17 mmol) in DMF (10 mL) at 0 °C was added NBS (2.52 g, 14.17 mmol). The mixture was stirred at room temperature for 2 h. Tire mixture was diluted with water (200 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SCL. and concentrated under vacuum to afford crude 4-bromo-2- fluoro-3-methoxyaniline (3.2 g, 102%) as a brown solid. LCMS (m / z): 221.9 [M+H]+.

[0366] Step 2. To a solution of 4-bromo-2-fluoro-3-metlioxyaniline (2.7 g, 12.27 mmol) in TFA (14 mL) was added H2O2 (6.9 g, 61.35 mmol, 30% wt) at room temperature. The mixture was stirred at 75 °C for 0.5 h. The mixture was diluted with water (150 mL), fdtered and concentrated under vacuum to afford crude l-bromo-3-fluoro-2-methoxy-4-nitrobenzene (1.3 g, 42%) as a yellow solid.

[0367] Step 3. To a solution of tert-butyl 5 -oxo- 1,4-diazepane-l -carboxylate (1.33 g, 6.23 mmol) in anhydrous DMF (13 mL) at 0 °C under a N2atmosphere was added NaH (312 mg, 7.79 mmol 60%) dropwise. The reaction mixture was stirred at 0 °C for 0.5 h. and l-bromo-3-fluoro-2-methoxy-4-nitrobenzene ( 1.3 g. 5.19 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water (150 mL), extracted with EtOAc (50 mL x 3), the layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford crude tert-butyl 4-(3-bromo-2- methoxy-6-nitrophenyl)-5 -oxo- 1,4-diazepane-l -carboxylate (1.58 g, 68%) as a brown solid. LCMS (m / z): 388.0 [M-55]+.95BUSINESS.33510111.1410095-001WG (221124)

[0368] Step 4. To a solution of tert-butyl 4-(3-bromo-2-methoxy-6-nitrophenyl)-5-oxo-l ,4- diazepane-1 -carboxylate (628 mg, 1.41 mmol) in AcOH / Toluene (5 mL / 3 mL) was added Fe (789 mg, 14.13 mmol) at room temperature, and the mixture was stirred at 120 °C for 0.5 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). Tire combined organic layers were washed with brine, dried over TsfeSCL and concentrated under vacuum. The mixture was purified by prep-TLC (eluent: Pet. Ether : EtOAc = 1: 1) to afford tert-butyl 9-bromo-10-methoxy-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (290 mg, 51%) as a yellow solid. LCMS (m / z): 396.0 [M+H]+.

[0369] Step 5. To a solution of tert-butyl 9-bromo-10-methoxy-l,2,4,5-tetraliydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (210 mg, 0.53 mmol), Zn(CN)2 (124 mg, 1.05 mmol) and X-phos (50 mg. 0.10 mmol) in DMAc (4 mL) was added [PdCl(allyl)]2 ( 19 mg, 0.05 mmol). The reaction mixture was stirred at 120 °C overnight under N2 atmosphere in a sealed tube. The mixture was diluted with water (100 mL) and extracted w ith EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated. Tire crude product was purified by prep- TLC (Pet. Ether: EtOAc = 1 : 1) to afford tert-butyl 9-cyano-10-methoxy-l,2,4,5-tetraliydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (130 mg. 71%) as colorless oil. LCMS (m / z): 365.1 [M+Na]+.

[0370] Step 6. To a solution of tert-butyl 9-cyano- 10-methoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (50 mg, 0.14 mmol) in DCM (1 mL) was added HCl / l,4-dioxane (4 M, 1 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum, and the residue was triturated by DCM / Hexane (lmL / 5mL) to afford tertbutyl 4-(3-bromo-2-methoxy-6-nitrophenyl)-5-oxo-1.4-diazepane-l-carboxylate (1-35) (41 mg. 97%. HC1 salt) as a white solid. LCMS (m / z): 243.0 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 39.68 (brs, 2H), 7.52- 7.50 (m, 2H), 4.89 (brs, 2H), 4.09 (s, 3H), 3.58 (brs, 2H), 3.47 (brs, 2H), 3.37 (brs, 2H).96BUSINESS.33510111.1

[0371] Example 31 (1-76)

[0372] Step 1. To a solution of tert-butyl 5 -oxo- 1,4-diazepane-l -carboxylate (411 mg, 1.92 mmol) in dry DMF (8 mL) at 0 °C was added NaH (96 mg 2.40 mmol). After stirring at 0 °C for 0.5 h under N2, a solution of l-bromo-2-fluoro-4-methoxy-3 -nitrobenzene (400 mg, 1.60 mmol) in dry DMF (8 mL) was added, and the mixture was stirred at RT for 16 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated to give tert-butyl 4-(6-bromo-3-methoxy-2- nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (650 mg, 91%) as a yellow solid. LCMS (m / z): 389.0 [M- 55]+.

[0373] Step 2. A solution of tert-butyl 4-(6-bromo-3-methoxy-2-nitrophenyl)-5-oxo-l,4-diazepane- 1-carboxylate (650 mg, 1.46 mmol) and Fe (817 mg, 14.63 mmol) in AcOH (5 mL) and toluene (3 mL) was stirred at 120 °C for 0.5 h. Tire reaction was directly concentrated in vacuum, and the residue was dissolved in EtOAcTLO (50 mL) and filtered. The filtrate was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with NaHCOs (aq.) (20 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by prep-TLC (Pet.ether / EtOAc=l / l) to afford tert-butyl 10-bromo-7-methoxy- l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (366 mg, 63%) as a light yellow solid. LCMS (m / z): 398.1 [M+H]+.

[0374] Step 3. A solution of tert-butyl 10-bromo-7-methoxy-l,2,4,5-tetraliydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (100 mg, 252.34 umol). CS2CO3 (246 mg, 757.03 umol). Cui (24 mg, 126. 17 umol) and 1, 10-phenanthroline (9 mg, 50.47 umol) in MeOH (2 mL) was stirred at 120 °C for 16 h in sealed tube. The reaction was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by prep-TLC (Pet.ether / EtOAc=l / l) and 97BUSINESS.33510111.1410095-001WG (221124) prep-HPLC (column: C18 column; Gradient: 31%MeCN in water (0.1%formic acid)) to afford tert-butyl 7, 1 O-dimethoxy-1 ,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[ 1,2-d] [ l,4]diazepine-3-carboxylate (25 mg, 28%) as an off-white solid. LCMS (m / z): 348.2 [M+H]+.

[0375] Step 4. A solution of tert-butyl 7, 1 O-dimethoxy-1, 2, 4, 5-tetrahydro-3H-benzo[4,5]imidazo[ 1,2- d][l,4]diazepine-3-carboxylate (25 mg, 71.96 umol) in 4M HCl / dioxane (2 mL) and DCM (1 mL) was stirred at RT for 2 h. The reaction was directly concentrated in vacuum, and the residue was purified by trituration (ether) to afford 7,10-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-76) (17 mg HC1 salt, 88%) as a grey solid. LCMS (m / z): 248.1 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 8 9.96 (s, 2H), 6.99 - 6.91 (m, 2H), 5.12 - 5.05 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.62 - 3.56 (m, 4H), 3.45 (s, 2H).

[0376] Additional Exemplary Compounds Prepared via Example 31 Methods98BUSINESS.33510111.1

[0377] Example 32 (1-26)

[0378] Step 1. To a solution of 4-bromo-5-methoxy-2-nitroaniline (1.0 g, 4.048mmol, l.Oeq.) in MeCN (20 mL) at -10 °C was added concentrated sulfuric acid (931.02 mg, 9.31mmol, 2.3eq.) slowly, following NaNCL (558.54 mg, 8.096 mmol, 2.0eq.). After stirring at -10 °C for 30 minutes. KI (2.67 g, 16.19mmol, 4.0eq.) was added, and the mixture solution was stirred at room temperature for 30 minutes. The reaction solution was quenched with sodium metabisulfite solution and stirred for one hour. Water was added, and the mixture was stirred for another 30 minutes. The solid was collected by filtration and dryness to afford l-bromo-4-iodo-2-m ethoxy-5 -nitrobenzene (1 g, 65%) as a yellow solid.

[0379] Step 2. A mixture of l-bromo-4-iodo-2-methoxy-5-nitrobenzene (300 mg, 0.717 mmol, l.Oeq.), tert-butyl 5-oxo-l,4-diazepane-l -carboxylate (233.47 mg. 1.09 mmol. 1.3eq.), Pd2dbas (38.37 mg, 0.042 mmol, 0.05 eq.), XantPhos (72.73 mg, 0.126 mmol. 0.15 eq.) and CS2CO3 (819.11 mg, 2.514 mmol, 3.0 eq.) in toluene (12 mL) was stirred at 80 °C for 2 h under N2. The mixture was diluted with water (100 mL) and extracted with EtOAc (2 * 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na^SCL. filtered and concentrated under reduced pressure to afford tert-butyl 4-(4-bromo- 5 -methoxy-2-nitrophenyl)-5 -oxo- 1,4-diazepane-l -carboxylate (320 mg) as a yellow solid, which was used in the next step directly. LCMS (m / z): 388.0 [M-55]+.99BUSINESS.33510111.1410095-001WD (221124)

[0380] Step 3. To a solution of tert-butyl 4-(4-bromo-5-methoxy-2-nitrophenyl)-5-oxo-l ,4- diazepane-1 -carboxylate (320 mg, 1.0 eq., 0.72 mmol) in AcOH (15 mL) was added Fe (403.35 mg, 10.0 eq., 7.2 mmol). The mixture was stirred at 120 °C for 0.5 h under N2. The reaction solution was diluted with water (200 mL) and fdtered through diatomaceous earth to remove metal impurities, and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (eluting with: DCM: methanol = 80: 1—50: 1, v / v) to afford tert-butyl 8-bromo-9-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (150 mg) as a light yellow solid. LCMS (m / z): 396.1 [M+H]+.

[0381] Step 4. A mixture of tert-butyl 8-bromo-9-methoxy-l,2,4,5-tetrahydro-3H- benzo[4.5]imidazo[l,2-d][L4Jdiazepine-3-carboxylate ( 150 mg. 0.379 mmol, 1.0 eq.). 4,4.5.5-tetramethyl- 2-vinyl- l,3,2-dioxaborolane (116.6 mg, 0.757 mmol, 2.0 eq.), Pd(dppf)C12.DCM (31 mg, 0.0379 mmol, 0.1 eq.) and KzCOs (157. 14 mg, 1.137mmol, 3.0eq.) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at 100 °C for 2 h under N2. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na:SO_. fdtered and concentrated under reduced pressure to obtain the crude product. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: methanol = 80: 1—60: 1, v / v) to afford tert-butyl 9-m ethoxy-8 -vinyl- 1 ,2,4,5 -tetrahydro-3H-benzo[4,5]imidazo [ 1 ,2-d] [1,4] diazepine-3 -carboxylate (100 mg, 75%) as a light yellow solid. LCMS (m / z): 344.2 [M+H]+.

[0382] Step 5. A solution of tert-butyl 9-metiioxy-8-vinyl- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (100 mg, 0.292 mmol, 1.0 eq.) in methanol (8 mL) was added 10% Pd / C (20 mg). The mixture solution was stirred at room temperature under H2 for 16 h. After filtration, the filtrate was concentrated under reduced pressure. The residue obtained was purified by Prep-TLC (DCM / MeOH = 20: 1, v / v) to afford tert-butyl 8-ethyl-9-methoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (40 mg, 40%) as a white solid. LCMS (m / z): 346.2 [M+H]+.

[0383] Step 6. To a solution of tert-butyl 8-ethyl-9-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (40 mg, 1.0 eq., 0.116 mmol) in DCM (2 mL) was added 4 M HCl / l,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and triturated with DCM (5 mL). The solid was collected by filtration to afford 8-ethyl-9-methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-26) (33.4 mg) as a white solid. LCMS (m / z): 246.2 [M+H]+;1H NMR (400 MHz, DMSO-de) 5 10.02 (brs, 2H), 7.55 (s, 2H). 4.88 (d, J = 8.2 Hz, 2H), 3.91 (s, 3H), 3.70 - 3.66 (m, 2H). 3.56 (t. J = 4.2 Hz, 2H), 3.48 (d, J = 6.4 Hz, 2H), 2.71 (q, J = 7.4 Hz, 2H), 1.16 (t, J = 7.4 Hz, 3H).100BUSINESS.33510111.1410095-001WG (221124)

[0384] Example 33 (1-68)

[0385] Step 1. To a solution of 4-bromo-3-fluoro-2-nitroaniline (1 g, 4.26 mmol) in cone HCI (8.5 mL) at 0 °C was added NaNC (323 mg. 4.68 mmol). After stirring at 0 °C for 1 h. a solution of CuCI (631 mg, 6.38 mmol) in cone HCI (0.5 mL) was added, and the mixture was stirred at 0 °C for 1 h. Tire mixture was adjusted pH=7 with NaHCCL (aq.) solution and filtered. The filtrate was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column (pet.ether) to give l-bromo-4-chloro-2-fluoro- 3 -nitrobenzene (600 mg, 50%) as an off-white solid. The methodology from example 31, steps 1-4 was used to prepare 7-chloro-10-methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[1.2-d][l,4]diazepine (I- 68) (57 mg HCI salt) as an off-white solid from l-bromo-4-chloro-2-fluoro-3-nitrobenzene. LCMS (m / z): 252.1 [M+H]+; 'H NMR (400 MHz, DMSO-de) 6 9.85 (s, 2H), 7.29 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.03 - 5.00 (m, 2H), 3.94 (s, 3H), 3.56 - 3.49 (m, 4H), 3.39 (s, 2H).101BUSINESS.33510111.1410095-001WG (221124)

[0386] Example 34 (1-1 )( xamp e s ep )

[0387] Step 1. To a solution of 4-chloro-2-methoxy-6-nitroaniline (1 g, 4.94 mmol) in MeCN (8.5 mL) was added HBr (2.78 mL, 24.53 mmol) and a solution of NaNCL (0.37 g, 5.38 mmol) in H2O (4.28 mL). The mixture was stirred at RT for 1 h. CuBr (0.84 g. 5.87 mmol) was added. The mixture was stirred at RT for 1 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated. The residue was purified by silica column chromatography (Pet. Ether / EtOAc=30 / l) to give 2-bromo-5 -chloro- 1-m ethoxy-3 - nitrobenzene (1.16 g, 87.9%) as a yellow solid. Tire methodology from example 32 (steps 2, 3 and 6) was then used to prepare 8-chloro-10-methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-14) (44.6 mg HC1 salt) as a pink solid from 2-bromo-5-chloro-l-methoxy-3-nitrobenzene. LCMS (m / z): 252.2 [M+H]+; 'H NMR (400 MHz, DMSO-A) 5 9.26 (s, 1H), 7.27 (s, 1H), 6.91 (s, 1H), 4.93 - 4.86 (m, 2H), 3.95 (s. 3H), 3.52 (s, 2H), 3.37 (t, J= 3.6 Hz. 4H).102BUSINESS.33510111.1

[0388] Example 35 (1-82)tep 4

[0389] Step 1. To a solution of tert-butyl 5-oxo-l,4-diazepane-l -carboxylate (2.02 g, 9.43mmol) and K2CO3 (3.26 g, 23.58mmol) in DMF (40 mL) was added 5-bromo-l-chloro-2-fluoro-3-nitrobenzene (2 g, 7.86mmol). Hie reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water (150 mL x 3) and brine (100 mL), dried overNa2SC>4, filtered and concentrated to afford tert-butyl 4- (4-bromo-2-chloro-6-nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (1.3 g. 36%) as brown oil. LCMS (m / z): 392.0 [M-55]+.

[0390] Step 2. To a solution of tert-butyl 4-(4-bromo-2-chloro-6-nitrophenyl)-5-oxo-l,4-diazepane- 1-carboxylate (1.3 g, 2.9 mmol) in toluene (30 mL) and AcOH (20 mL) was added Fe (1.62 g, 28.97 mmol). The reaction mixture was stirred at 120 °C for 0.5 h. The mixture was filtered, and the filtrate was diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were adjusted to pH 9-10 with K2CO3 aq. solution, washed with water (50 mL) and brine (20 mL). dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet. Ether: EtOAc=5: l to 1: 1) to afford tert-butyl 8-bromo-10-chloro-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazcpinc-3-carboxylatc (523 mg, 45%) as an off-yellow solid. LCMS (m / z): 400.0 [M-55]+.

[0391] Step 3. To a solution of tert-butyl 8-bromo-10-chloro- 1,2,4, 5-tetrahydro-3H- benzo[4.5]imidazo[l,2-d][L4]diazepine-3-carboxylate (713 mg, 1.78 mmol) and Pd(dppf)C12 ( 130 mg, 0.178 mmol) was added EtiZn (IM in hexane, 18 mL, 17.79 mmol) under N2. The reaction mixture was stirred at 70 °C for 2 h under N2. Tire mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (50 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.Ether:103BUSINESS.33510111.1410095-001WD (221124)EtOAc=10: l to EtOAc) to afford tert-butyl 8,10-diethyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (131 mg, 21%) as an off-white solid. LCMS (m / z): 344.1 [M+H]+.

[0392] Step 4. To a solution of tcrt-butyl 8,10-dicthyl-l,2,4,5-tctrahydro-3H-bcnzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (65 mg, 0.189 mmol) in DCM (2 mL) was added 4 M HCl / l,4-dioxane (5 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated. The mixture was triturated with DCM (lOmL) and freeze-dried to afford 8,10-diethyl-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-82) (33 mg, 71%) as an off-white solid. LCMS (m / z): 244.1 [M+H]+. H NMR (400 MHz, DMSO- ,.) 5 10.03 (s, 2H), 7.45 (d, J= 1.4 Hz, 1H), 7.21 (d, J = 1.4 Hz, 1H), 4.96 (d, J= 8.0 Hz, 2H), 3.71 - 3.66 (m, 2H), 3.61 (d, J= 6.2 Hz, 2H), 3.49 (s, 2H), 3.09 (q, J= 7.6 Hz, 2H), 2.74 (q. J= 7.6 Hz, 2H), 1.24 (dt, J= 15.0, 7.4 Hz, 6H).

[0393] Example 36 (1-13)

[0394] Step 1. To a solution of l-bromo-2-chloro-4-iodo-5-nitrobenzene (500 mg, 1.38 mmol) in toluene (15 mL) was added tert-butyl 5-oxo-l,4-diazepane-l -carboxylate (326 mg, 1.52 mmol), R-BINAP (69 mg, 0.11 mmol) and Pd(TFA)2(37 mg, 0.11 mmol). The reaction mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. The mixture was evaporated to remove most solvent before being diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried overNa2SO4, filtered and concentrated. The crude was purified by gel silica column (pet.ether / EtOAc=5: l) to give tert-butyl 4-(4-bromo-5-chloro-2-nitrophenyl)-5-oxo-l,4- diazepane-1 -carboxylate (280 mg, 45%) as a grey solid. LCMS (m / z): 391.9 [M-55]+.

[0395] Step 2. To a mixture of tert-butyl 4-(4-bromo-5-chloro-2-nitrophenyl)-5-oxo-l,4-diazepane- 1-carboxylate (280 mg, 0.62 mmol) in HOAc (5 mL) and toluene (3 mL) was added Fe powder (348 mg, 6.24 mmol). The mixture was stirred at 120 °C for 0.5 h. Tire mixture was evaporated to remove most104BUSINESS.33510111.1410095-001WG (221124) solvent before being diluted with sat. NaHCCh (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness to give tert-butyl 8-bromo-9-chloro-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (230 mg, 92%) as a grey solid. LCMS (m / z): 400.0 [M+H]+.

[0396] Step 3. To a solution of tert-butyl 8-bromo-9-chloro-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (500 mg, 1.25 mmol) in fresh THF (10 mL) was added Pd(dppf)CL (91 mg, 0. 125 mmol) and Zn(Et)2 (IM in hexane, 12.5 mL) under nitrogen atmosphere. Tire reaction mixture was stirred at 70 °C for 3 h under nitrogen atmosphere. The mixture was quenched with water (5 mL) and evaporated to remove most solvent before being diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by gel silica column (pet.ether / EtOAc=3: l) to give tert-butyl 9-chloro-8-ethyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (280 mg, 64%) as a grey solid.

[0397] Step 4. To a solution of tert-butyl 9-chloro-8-ethyl- 1,2,4, 5-tetraliydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (50 mg, 0.143 mmol) in DCM (3 mL) was added 4M HCl / dioxane (0.5 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated to dryness and freeze-dried to give 9-chloro-8-ethyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-13) (28 mg, 80%) as an off-white solid. LCMS (m / z): 250.1 [M+H]+. 'HNMR (400 MHz, DMSO-r / s) 8 9.97 (s, 2H), 8.06 (d, J = 1.8 Hz, 1H), 7.72 (s, 1H), 4.84 - 4.77 (m, 2H), 3.68 - 3.62 (m, 2H), 3.54 - 3.49 (m, 2H), 3.48 - 3.40 (m. 2H), 2.85 (q, J = 7.4 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H).105BUSINESS.33510111.1

[0398] Example 37 (1-72)Mel HCI H O

[0399] Step 1. To a solution of 2-amino-3 -nitrophenol (3 g, 19.46 mmol) in DMF (30 mL) was added K2CO3 (3.23 g, 23.36 mmol). After stirring at RT for 1 h. Mel (3.32 g, 23.36mmol) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (150 mL x 3) and brine (lOOmL), dried overT^SCL, filtered and concentrated to afford 2-methoxy-6-nitroaniline (3.09 g, 94%) as a red solid. LCMS (m / z): 169.0 [M+H]+.

[0400] Step 2. To a solution of 2-methoxy-6-nitroaniline (3.09 g, 18.38 mmol) and NaOAc (1.66 g, 20.21 mmol) in AcOH (42 mL) was added Br2 (4.7 g. 29.4 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into water, and the solid was collected by filtration and triturated with water (30 mL x 2) to afford 4-bromo-2-methoxy-6-nitroaniline (4.27 g, 97%) as an orange solid. LCMS (m / z): 246.9 [M+H]+.

[0401] Step 3. To a solution of 4-bromo-2-methoxy-6-nitroaniline (3 g, 12.14 mmol) in cone. HCI (30mL) and H2O (40mL) was added NaNO2 (1.26 g, 18.22mmol). The reaction mixture was stirred at RT for 1 h. A solution of KI (6.05 g, 36.43 mmol) in H2O (40mL) was added, and the reaction mixture was stirred at RT overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.Ether: EtOAc=100: l) to afford 5-bromo-2-iodo-l-methoxy-3-nitrobenzene (2.77 g, 63%) as an off-yellow solid.106BUSINESS.33510111.1410095-001WG (221124)

[0402] Step 4. A solution of 5-bromo-2-iodo-l-methoxy-3-nitrobenzene (850 mg, 2.37 mmol), tertbutyl 5 -oxo- 1,4-diazepane-l -carboxylate (611 mg, 2.85 mmol), Pdj(dba):; (326 mg, 0.356 mmol), Xantphos (206 mg, 0.356 mmol) and CS2CO3 (2.32 g, 7.12 mmol) in toluene (24 mL) was stirred at 80 °C overnight under N2. Hie mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). Hie combined organic layers were washed with water (30 mL), dried over NaiSOi. filtered and concentrated to afford crude tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo- 1,4-diazepane-l -carboxylate (1.06 g) as black oil, which was used directly. LCMS (m / z): 388.0 [M-55]+.

[0403] Step 5. To a solution of tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo-l,4- diazepane-1 -carboxylate (1.06 g, 2.39 mmol) in toluene (24 mL) and AcOH (16 111L) was added Fe (1.33 g, 23.86 mmol) . The reaction mixture was stirred at 120 °C for 0.5 h. Hie mixture was filtered, and the filtrate was diluted with water (30 mL) and extracted with EtOAc (50 mLx 2). The combined organic layers were adjusted to pH = 9-10 with K^CCLaq. solution, washed with water (50 mL) and brine (50 mL), dried over Na^SCf. filtered and concentrated. Hie mixture was purified by column chromatography on silica gel (Pet. Ether: EtOAc=3: l to EtOAc) to afford tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (359 mg, 37%) as an off- yellow solid. LCMS (m / z): 340.0 [M-55]+.

[0404] Step 6. In a steal tube, a solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (100 mg, 0.252 mmol), 4,4,5,5-tetramethyl-2- (prop-l-en-2-yl)-l,3,2-dioxaborolane (51 mg, 0.302 mmol), tricyclohexylphosphane (7 mg, 0.025mmol), Pd(OAc) 2 (6 mg, 0.025 mmol) and K3PO4 (161 mg, 0.757 mmol) in 1.4-dioxane (1 mL) and H2O (0.2 mL) was stirred at 100 °C overnight under N2. Hie mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (20 mL). dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (Pet. Ether: EtOAc=l: l) to afford tertbutyl 10-methoxy-8-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3- carboxylate (51 mg , 56%) as an off-white solid. LCMS (m / z): 358.2 [M+H]+.

[0405] Step 7. To a solution of tert-butyl 10-methoxy-8-vinyl- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (51 mg, 0.142 mmol) in THF (1 mL) and MeOH (1 mL) was added Pd / C (10%, 15 mg). The reaction mixture was stirred at RT overnight under H2. The reaction mixture was filtered, and the filtrate was concentrated. The mixture was purified by prep-TLC (Pet.Ether: EtOAc=l: l) and triturated (EtOAc:hexane=l:20) to afford tert-butyl 8-isopropyl-10-methoxy-l, 2,4,5- tetrahydro-3H-benzo[4,5]imidazo[1.2-d][l,4]diazepine-3-carboxylate (36 mg, 62%) as a white solid. LCMS (m / z): 360.3 [M+H]+.

[0406] Step 8. To a solution of tert-butyl 8-isopropyl-10-methoxy-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (36 mg, 0.1 mmol) in DCM (2 mL) was added 4 M107BUSINESS.33510111.1410095-001WG (221124)HCl / l,4-dioxane (5 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated. Tire mixture was triturated (DCM : hexane=l: l, 10 mL) and freeze-dried to afford 8- isopropyl-10-methoxy-2,3,4,5 -tetrahydro- lH-benzo[4,5]imidazo[ 1 ,2-d] [ 1 ,4]diazepine hydrochloride (I- 72) (24.4 mg, 82%) as an off-white solid. LCMS (m / z): 260.2 [M+H]+. 'l l NMR (400 MHz, DMSO-r / 6) 5 9.95 (brs, 2H), 7.15 (s, 1H), 6.99 (s, 1H), 5.13 - 5.05 (m, 2H), 3.99 (s, 3H), 3.63 (brs, 2H), 3.57 (brs, 2H), 3.05 (p, J= 6.8 Hz, 1H). 1.26 (d, J= 6.8 Hz, 6H).

[0407] Example 38 (1-77)[00408J Step 1. To a solution of 2-methoxy-5-nitrophenol (5 g, 29.56 mmol, 1 equiv) in DCM (100 mL) was added NBS (5.26 g, 29.56 mmol, 1 equiv). After stirring at RT for 2 h, the reaction mixture was quenched with Na2S2O3solution (100 mL) and extracted with DCM (2 x 100 mL). Tire combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered, and evaporated under reduced pressure. The crude was purified by column (PE / EtOAc = 3 / 1) to give 2-bromo-6-methoxy-3-nitrophenol (5.99 g, 81%) as a yellow solid. LCMS (m / z): 247.9 [M+H]+.

[0409] Step 2. At -78 °C, to a solution of 2-bromo-6-methoxy-3-nitrophenol (5.99 g, 24.15 mmol, 1 equiv) in DCM (100 mL) was added BBr3(1 M in DCM, 36.2 mL, 36.23 mmol, 1.5 equiv). The mixture was stirred at -78 °C to RT overnight. The reaction mixture was quenched with H2O (100 mL) and extracted with DCM (4 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4. filtered, and evaporated under reduced pressure. The crude was purified by RP column (7% MeCN in water) to give 3-bromo-4-nitrobenzene-l,2-diol (4.12 g,72%) as a green solid. LCMS (m / z): 231.9 [M- H]-.

[0410] Step 3. To a solution of 3-bromo-4-nitrobenzene-l,2-diol (3.55 g, 15.17 mmol, 1 equiv) in DMF (6 mL) at 0 °C was added diiodomethane (12.19 g, 45.51 mmol, 3 equiv) and K2CO3(6.29 g, 45.51mmol, 3 equiv). After stirring at 80 °C overnight, the reaction mixture was quenched with H2O (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (60 mL),108BUSINESS.33510111.1410095-001WG (221124) dried over Na2SC>4, filtered, and evaporated under reduced pressure. The crude was purified by column (PE / EtOAc = 3 / 1) to give 4-bromo-5-nitrobenzo[d][l,3]dioxole (780 mg, 70%) as a yellow solid.

[0411] Step 4. To a solution of 4-bromo-5-nitrobcnzo[d][l,3]dioxolc (780 mg, 3.17 mmol, 1 cquiv) in toluene(10 mL) was added tert-butyl 5-oxo-l,4-diazepane-l-carboxylate (815 mg. 3.80 mmol, 1.20 equiv), Pd2<dbab (145.17 mg. 0.15 mmol. 0.05 equiv), Xantphos(275.18 mg, 0.47 mmol. 0.15 equiv) and CS2CO3 (3.10 g, 9.51 mmol, 3 equiv). The reaction mixture stirred at 80 °C for 2 h under N2. The reaction mixture was quenched with H2O (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give crude tert-butyl 4-(5-nitrobenzo[d][l,3]dioxol-4-yl)-5-oxo-l,4-diazepane-l-carboxylate (1.2 g, 99%) as a brown solid, which was used in next step directly. LCMS (m / z): 324.3 [M-55]+.

[0412] Step 5. To a solution oftert-butyl 4-(5-nitrobenzo[d][1.3]dioxol-4-yl)-5-oxo-l,4-diazepane-l- carboxylate (1.2 g, 3.16 mmol, 1.00 equiv) in AcOH (5 mL) and toluene (3 mL) was added Fe (1.77 g, 31.63 mmol, 10 equiv). Tire reaction mixture stirred at 120 °C for 0.5 h. The reaction mixture was filtered and washed with H2O (60 mL). Tire filtrate was extracted with EtOAc (2 x 60 mL). Tire combined organic layers were washed with NaHCO: solution (100 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. Hie residue was purified by column (PE / EtAOc =1 / 1) and pre-HPLC (30% MeCN in H2O (0.1% HCOOH)) to afford tert-butyl 7,8,10.11-tetrahydro-9H- [L3]dioxolo[4",5":3',4,]benzo[r,2':4,5]imidazo[l,2-d][l,4]diazepine-9-carboxylate (55 mg, 5%) as an off- white solid. LCMS (m / z): 332.1 [M-55]+.

[0413] Step 6. A solution of tert-butyl 7,8,10.1 l-tetrahydro-9H-[1.3]dioxolo[4",5":3',4']benzo[l',2':4,5]imidazo[l,2-d][l,4]diazepine-9-carboxylate (55 mg, 0.16 mmol, 1.00 equiv) in HCl / dioxane(4M, 2mL) and DCM (2 mL) was stirred at RT for 2 h. The mixture was concentrated and the residue was triturated with DCM / hexane to give 8,9,10,l l-tetrahydro-7H-[1.3]dioxolo[4",5":3',4,]benzo[r,2':4,5]imidazo[l,2-d][l,4]diazepine (40.3 mg HC1 salt, 99%) as a white solid.LCMS (m / z): 232.1 [M+H]+.]H NMR (400 MHz, DMSO-ri6) 8 10.07 (s, 2H), 7.25 (d, J = 8.6 Hz, 1H), 7.16 (dd, J= 8.6, 1.2 Hz, 1H), 6.24 (s, 2H), 4.76 (d, J= 6.8 Hz, 2H), 3.62 (t, J= 3.6 Hz, 4H), 3.47 (s, 2H).109BUSINESS.33510111.1

[0414] Example 39 (1-74)

[0415] Step 1. To a solution of 2-amino-3-nitrophenol (30 g, 194.65 mmol) in DMF (300 mL) was added K2CO3 (32.28 g, 233.58 mmol). The reaction mixture was stirred at RT for 1 h. Mel (33.15 g, 233.58 mmol) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (200mL x 3). Tire combined organic layers were washed with water (200 mL x 3) and brine (200mL), dried over Na2SC>4, filtered and concentrated to afford 2-methoxy- 6-nitroaniline (31.5 g, 96%) as a brown solid. LCMS (m / z): 169. 1 [M+H] .

[0416] Step 2. To a solution of 2-methoxy-6-nitroaniline (10 g, 59.47 mmol) and NaOAc (5.37 g, 20.21 mmol) in AcOH (140 mL) was added Br2(15.21 g, 95.15 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (200 mL) and filtered. The filter cake was washed with water (300 mL x 3) to afford 4-bromo-2-methoxy-6-nitroaniline (14 g, 95%) as an orange-red solid. LCMS (m / z): 247.0 [M+H]+.

[0417] Step 3. To a solution of 4-bromo-2-methoxy-6-nitroaniline (21 g, 85 mmol) in cone. HCI (210 mL) and H2O (280 mL) at 0 °C was added a solution of NaNO2(8.8 g, 127.51 mmol) in H2O (140 mL). The reaction mixture was stirred at RT for 1 h. A solution of KI (42.23 g, 255.01 mmol) in H2O (280 mL) was added, and the reaction mixture was stirred at RT overnight. The mixture was extracted with DCM (200 mL x 3). The combined organic layers were washed with water (200 mL x 2) and brine (200 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on110BUSINESS.33510111.1silica gel (Pet.Ethe to Pet.Ether: EtOAc=100: 1) to afford 5 -bromo-2-iodo-l-methoxy-3 -nitrobenzene (22 g, 72%) as an orange-red solid.

[0418] Step 4. A solution of 5-bromo-2-iodo-l-mcthoxy-3-nitrobcnzcnc (10 g, 27.94 mmol), tcrt- butyl 5-oxo-l,4-diazepane-l-carboxylate (7.18 g, 33.53 mmol), Pd(TFA)2 (1.39 g, 2.24 mmol), R-BINAP (1.39 g, 2.24 mmol) and CS2CO3 (12.74 g, 39.11 mmol) in toluene (300 mL) was stirred at 80 °C overnight under N2. The mixture was diluted with water (200 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, fdtered and concentrated to afford crude tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo-l,4-diazepane-l- carboxylate, which was used directly. LCMS (m / z): 388.0 [M+H]+.

[0419] Step 5. To a solution of tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo-l,4- diazepane-1 -carboxylate (24.88 g, 55.89 mmol) in toluene (300 mL) and AcOH (200 mL) was added Fe (31 .21 g, 588.88 mmol) . The reaction mixture was stirred at 120 °C for 0.5 h. The mixture was fdtered and the fdtrate was diluted with water (200 mL) and extracted with EtOAc (300 mL x 2). The combined organic layers were adjusted pH to 9-10 by K2CO3 aq. solution, washed with water (200 mL x 2) and brine (200 mL), dried over Na2SO4, fdtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.Ether: EtOAc=5: l to Pet.Ether: EtOAc=l: l) to afford tert-butyl 8-bromo-10-methoxy- 1,2,4, 5-tetrahydro-3H-benzo[4,5]imidazo[L2-d][l,4]diazepine-3-carboxylate (11.55 g. 52%) as an off- yellow solid. LCMS (m / z): 396.1 [M+H]+.

[0420] Step 6. A solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (1 g, 2.52 mmol), KOH (424 mg, 7.57 mmol), Pd2(dba)3 (231 mg, 0.252 mmol) and tert-butyl Xphos (429 mg, 1.01 mmol) in 1,4-dioxane (10 mL) and H2O ( 10 mL). was stirred at 100 °C for 2 h under N2. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (DCM: MeOH=100: 1 to DCM: MeOH=15 : 1) to afford tert-butyl 8-hydroxy-10-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (430 mg, 53%) as an off-white solid. LCMS (m / z): 334.2 [M+H]+.

[0421] Step 7. A solution of tert-butyl 8-hydroxy-10-methoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (420 mg, 1.26 mmol) and K2CO3 (522 mg, 3.78 mmol in 1,4-dioxane (4 mL) was stirred at RT for 1 h. Mel (178 mg, 1.26 mmol) was added. Tire reaction mixture was stirred at RT overnight. Hie mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (Pet.Ether: EtOAc=l: l) C to afford tert-butyl 8, 10-dimethoxy- 1 ,2,4.5-tetrahydro-3H-benzo[4.5]imidazo[ 1 ,2-d] [ 1.4]diazepine-3- carboxylate (81 mg, 18%) as an off-white solid. LCMS (m / z): 348.2 [M+H]+.111BUSINESS.33510111.1

[0422] Step 8. To a solution of tert-butyl 8,10-dimethoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (81 mg, 0.233 mmol) in DCM (2 mL) was added 4 M HCl / l,4-dioxanc (5 mL). The reaction mixture was stirred at RT for 1 h. Tire reaction mixture was concentrated. The mixture was triturated with DCM : hexane=l:l (10 mL) and freeze-dried to afford 8,10- dimethoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-74) (64 mg, 96%) as an off-yellow solid. LCMS (m / z): 248.2 [M+H]+. 'H NMR (400 MHz, DMSO-6) 5 9.97 (s, 2H), 6.81 (d, J= 2.0 Hz, 1H), 6.72 (d, J= 2.0 Hz, 1H), 5.11 - 5.01 (m, 2H), 3.96 (s, 3H), 3.84 (s, 3H), 3.64 (d, J= 5.2 Hz, 2H), 3.58 (s, 2H), 3.47 (s, 2H).

[0423] Example 40 (1-88)

[0424] Step 1. To a solution of 4-bromo-3-fluoro-2-nitroaniline (4 g, 0.02 mol) in CH3OH (80 mL) was added CH3ONa (30.64 g, 0.1702 mol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water (50 mL), dried overNa2SO4. filtered and concentrated. The residue was purified by column chromatography (PE: EtOAc = 20: 1 - 5: 1) to afford 4-bromo-3-methoxy-2- nitroaniline (2.4 g, 92 % yield) as a yellow solid. LCMS (m / z): 246.9 [M+H]+.112BUSINESS.33510111.1

[0425] Step 2. To a solution of 4-bromo-3-methoxy-2 -nitroaniline (2.64 g, 0.0107 mol) and L (27.12 g, 0.1068 mol) in CH3CN (30 mL) was added isoamyl nitrite (6.25 g, 0.0534 mol). The mixture was stirred at 60 °C overnight. Tire mixture was quenched with saturated Na3S20i aq. solution (30 mL), diluted with water (300 mL) and extracted with EtOAc (200 mL x 2). The combined organic phases were washed with water (200 mL), dried over Na2SO4, filtered and concentrated. Tire residue was purified by column (PE: EtOAc = 20: 1) to afford l-bromo-4-iodo-2-m ethoxy-3 -nitrobenzene (3.7g, 96 % yield) as a yellow solid. 'HNMR (400 MHz, DMSO-ds) 5 7.76 - 7.62 (m, 2H), 3.87 (s, 3H).

[0426] Step 3. A solution of 1 -bromo-4-iodo-2-methoxy-3-nitrobenzene (3.5 g, 9.8 mmol), tert-butyl 5 -oxo- 1,4-diazepane-l -carboxy late (2.5 g, 12 mmol), Pd(TFA)2 (260 mg, 0.78 mmol), R-BINAP (487 mg, 0.782 mmol) and CS2CO3 (4.78 g, 14.7 mmol) in toluene (40 mL) was stirred at 80 °C overnight under an N2 atmosphere. The mixture was diluted with water (100 mL). extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water (150 mL x 2) and brine (150 mL), dried over Na SO4, filtered and concentrated to give the crude tert-butyl 4-(4-bromo-3-methoxy-2-nitrophenyl)-5-oxo-l,4- diazepane-l-carboxylate, which was used into the next step directly. LCMS (m / z): 889.0 |2M+H| .

[0427] Step 4. To a solution of tert-butyl 4-(4-bromo-3-methoxy-2-nitrophenyl)-5-oxo-l,4- diazepane-1 -carboxylate (834.8 mg, 1.879 mmol) in AcOH (2 mL) and toluene (1.2 mL) was added Fe (1.04 g, 18.8 mmol). The mixture was stirred at 120 °C for 0.5 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water (150 mL x 2) and brine (150 mL), dried over Na SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EtOAc=20: 1 to 3: 1) to afford tertbutyl 8-bromo-7-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (276.7 mg, 37 % yield) as a brown solid. LCMS (m / z): 396.1 [M+H]+.

[0428] Step 5. A solution of tert-butyl 8-bromo-7-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (400 mg, 1.01 mmol), (E)-prop-l-en-l-ylboronic acid (173.4 mg, 2.019 mmol), Pd / C (28.30 mg, 0.1009 mmol), Pd(OAc)2 (24.67 mg, 0.1009 mmol) and K3PO4 (642.8 mg, 3.028 mmol) in 1,4-dioxane / water (12 mL / 3 mL) was stirred at 100 °C overnight under an N2 atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x2). The combined organic phases were washed with brine (150 mL), dried over Na SO4. filtered and concentrated. The residue was purified by p-TLC (PE:EtOAc=l: 1) to afford tert-butyl (E)-7-methoxy-8- (prop-l-en-l-yl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (350 mg, 97 % yield) as a yellow solid. LCMS (m / z): 358.1 [M+H]+.

[0429] Step 6. To a solution of tert-butyl (£)-7-methoxy-8-(prop-l-en-l-yl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (450 mg, 1.26 mmol) in CH3OH (4 mL) was added Pd / C (45 mg, 0.42 mmol). The mixture was stirred at 30 °C overnight under H2atmosphere. The mixture113BUSINESS.33510111.1410095-001WG (221124) was filtered and the filtrate was concentrated under vacuum. The residue was purified by p-TLC (PE:EtOAc= 3: 1) to afford tert-butyl 7-methoxy-8-propyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (289 mg, 63.8 % yield) as a yellow solid. LCMS (m / z): 360.2 [M+H]+.

[0430] Step 7. A solution of tert-butyl 7-methoxy-8-propyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (111.1 mg, 0.309 mmol) in DCM / 4 M HC1 in dioxane (2 mL / 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to afford 7-methoxy-8-propyl-2,3,4,5-tetrahydro-lI4-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-88) (93.6 mg, 97 % yield) as a yellow solid. LCMS (m / z): 260.2 [M+H]+. 'H NMR (400 MHz, DMSO- e) 5 10.10 (s, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 4.89 - 4.74 (m, 2H), 4.05 (s, 3H). 3.75 - 3.68 (m, 2H), 3.55 - 3.44 (m, 4H), 2.74 - 2.64 (m, 2H), 1.64 - 1.51 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H).

[0432] Step 1. A solution of tert-butyl 8-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (1 g, 2.7 mmol), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2- dioxaborolane (551 mg, 3.28 mmol), tricyclohexylphosphine (77 mg, 0.27 mmol), Pd(OAc)2 (61 mg, 0.27 mmol) and K3PO4 (1.74 g, 8.19 mmol) in 1,4-dioxane (10 mL) and H2O (5 mL) was stirred at 100 °C overnight under N2. The reaction mixture was filtered. The filtrate was diluted with water (25 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pct.cthcrEtOAc = 2: 1 to 1 : 1) to afford tcrt-butyl 8-(prop-l-cn-2 -yl)-l, 2,4,5- tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (695 mg, 77%) as an off-red solid. LCMS (m / z): 328.3 [M+H]+.

[0433] Step 2. To a solution of tert-butyl 8-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (695 mg, 2.12 mmol) in THF (15 mL) and H2O (5114BUSINESS.33510111.1410095-001WD (221124) mL) was added OsCU (54 mg, 0.21 mmol) and NMO (50 wt%, 995 mg, 4.25 mmol). The reaction mixture was stirred at room temperature for 2h. NaKL (1.82 g, 8.49 mmol) was added. The reaction mixture was stirred at room temperature for Ih. Tire mixture was quenched with saturated aqueous Na2S20s (50 mL). Tire mixture was diluted with water (20 mL) and extracted with EtOAc (70 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4. filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.ether:EtOAc=2: 1 ~ 0: 1) to afford tert-butyl 8-acetyl- 1 ,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[ 1 ,2-d] [ 1 ,4]diazepine-3 -carboxylate (548 mg, 78%) as an off-white solid. LCMS (m / z): 330.2 [M+H]+.

[0434] Step 3. To a solution of tcrt-butyl 8-acctyl-l,2,4,5-tctrahydro-3H-bcnzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (548 mg, 1.66 mmol) in DCM (10 mL) was added triethylamine trihydrofluoride (805 mg, 4.99 mmol) and DAST (2.15 g, 13.3 mmol). The reaction mixture was stirred at 50 °C overnight in a sealed tube. The mixture was adjusted pH = 9-10 with K2CO3 aq. solution. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (DCM:MeOH=30: 1) and prep-HPLC (48% MeCN in water with 0.1 % TFA) to afford tert-butyl 8-( 1, 1 -difluoroethyl)- 1,2, 4.5-tetrahydro-3H-benzo[4.5]imidazo[l ,2-d] [ l,4]diazepine-3- carboxylate (35 mg. 5.9 %) as a white solid. LCMS (m / z): 352.2 [M+H]+.

[0435] Step 4. To a solution of tert-butyl 8-(l,l-difluoroethyl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (35 mg, 0.096 mmol) in DCM (2 mL) was added 4 M HC1 in 1,4-dioxanc (5 mL).Thc reaction mixture was stirred at room temperature for 1 h. Tire reaction mixture was concentrated. Tire residue was triturated with DCM : hexane=l: 1 (10 mL) and freeze-dried to afford 8-( 1 , 1 -difluoroethyl)-2.3.4.5 -tetrahydro- lH-benzo[4.5]imidazo[ 1 ,2-d] [ 1 ,4]diazepine hydrochloride (1-89) (21 mg, 73 %) as an off-yellow solid. LCMS (m / z): 252.2 [M+H]+. 'H NMR (400 MHz, DMSO-r / 6) 5 10.13 (brs, 2H), 7.97 (d, J = 8.6 Hz, IH), 7.92 (s, IH), 7.71 (d, J = 8.6 Hz, IH), 4.92 - 4.85 (m, 2H), 3.74 - 3.68 (m, 2H), 3.53 (brs, 2H), 3.48 (brs, 2H), 2.05 (t, J = 18.8 Hz, 3H).

[0436] Additional Exemplary Compounds Prepared via Example 41 Methods115BUSINESS.33510111.1410095-001WG (221124)

[0437] Example 42 (1-91)CuBr, KF,NIS, MeCN, TMSCF3, DMF, 90 °C, 16h 120 °C, 16hStep 6 Step 74M HCI, 1 ,4-dioxane, DCM, RT, 2hStep 8

[0438] Step 1. To a solution of 2-amino-3 -nitrophenol (3 g, 19.46 mmol) in DMF (30 mL) was added K2CO3 (3.23 g, 23.4 mmol). After stirring at room temperature for 1 h. Mel (3.32 g, 23.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with116BUSINESS.33510111.1water (150 mL x 3), brine (100 mL) and dried over Na->SO4. filtered and concentrated to afford 2-methoxy- 6-nitroaniline (3.09 g, 94 %) as a red solid. LCMS (m / z): 169.0 [M+H]+.

[0439] Step 2. To a solution of 2-mcthoxy-6-nitroanilinc (3.09 g, 18.38 mmol) and NaOAc (1.66 g, 20.21 mmol) in AcOH (42 mL) was added Br2 (4.7 g, 29 mmol). The reaction mixture was stirred at room temperature for 1 h. Tire reaction mixture was poured into water and the solid was collected by filtration, then triturated with water (30 mL x 2) to afford 4-bromo-2-methoxy-6-nitroaniline (4.27 g, 97%) as an orange solid. LCMS (m / z): 246.9 [M+H]+.

[0440] Step 3. To a solution of 4-bromo-2-methoxy-6-nitroaniline (3 g, 12 mmol) in cone. HC1 (30 mL) and H2O (40 mL) was added NaNCL (1.26 g, 18.2 mmol). Tire reaction mixture was stirred at room temperature for 1 h. A solution of KI (6.05 g, 36.4 mmol) in H2O (40 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water (50 mL), brine (50 mL) and dried over Na2SC>4, filtered and concentrated. Hie mixture was purified by column chromatography on silica gel (Pet.Ether: EtOAc=100: l) to afford 5-bromo-2-iodo-l-methoxy-3- nitrobenzene (2.77 g, 63 %) as an off-yellow solid. 'H NMR (400 MHz, DMSO-de) 8 7.75 (d, J = 1.8 Hz, 1H). 7.45 (d, J = 1.8 Hz. 1H), 3.94 (s, 3H).

[0441] Step 4. A solution of 5-bromo-2-iodo-l-methoxy-3-nitrobenzene (850 mg, 2.37 mmol), tertbutyl 5 -oxo- 1,4-diazepane-l -carboxylate (611 mg, 2.85 mmol), Pdj(dba)i (326 mg, 0.356 mmol), Xantphos (206 mg, 0.356 mmol) and CS2CO3 (2.32 g, 7.12 mmol) in toluene (24 mL) was stirred at 80 °C overnight under N2. Hie mixture was diluted with water (30 111L) and extracted with EtOAc (50 mL x 2). Hie combined organic layers were washed with water (30 mL) and dried over NaiSOi. filtered and concentrated to afford crude tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo-1.4-diazepane-l -carboxylate (1.06 g) as black oil, which was used directly. LCMS (m / z): 388.0 [M-55]+.

[0442] Step 5. To a solution of tert-butyl 4-(4-bromo-2-methoxy-6-nitrophenyl)-5-oxo-l,4- diazepane-1 -carboxylate (1.06 g, 2.39 mmol) in toluene (24 mL) and AcOH (16 mL) was added Fe (1.33 g, 23.9 mmol). Hie reaction mixture was stirred at 120 °C for 0.5 h. The mixture was filtered, and the filtrate was diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were adjusted to pH = 9-10 with K2CO3 aq. solution, washed with water (50 mL), brine (50 mL) and dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.Ether: EtOAc=3: l to EtOAc) to afford tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4.5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (359 mg, 37 %) as an off- yellow solid. LCMS (m / z): 340.0 [M-55] .

[0443] Step 6. To a solution of tert-butyl 8-bromo-10-methoxy-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (2 g, 5 mmol) in MeCN (20 mL) was added NIS117BUSINESS.33510111.1410095-001WG (221124)(2.84 g, 12.6 mmol). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was quenched with saturated aqueous Na2S20s solution (30 mL), extracted with DCM (50 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50mL), dried over Na2SC>4, filtered and concentrated. The crude was purified by column chromatography on silica gel (DCM:MeOH=80: 1, v / v) to afford tert-butyl 8-bromo-7-iodo-10-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (1.78 g, 67 %) as a white solid. LCMS (m / z): 522.0 [M+H]+.

[0444] Step 7. To a solution of CuBr (275 mg, 1.92 mmol), KF (111.4 mg, 1.92 mmol) and TMSCFj (276 mg, 1.92 mmol) in DMF (3 mL) was stirred for 1 h at room temperature under N2 atmosphere. A solution of tert-butyl 8-bromo-7-iodo-10-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (200 mg. 0.38 mmol) in DMF (2 mL) was added and the mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with water (80 mL). extracted with EtOAc (50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1 : 1) to give tert-butyl 8-bromo-10-methoxy- 7-(trifluoromethyl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (70 mg, 39.7 yield) as a white solid. LCMS (m / z): 466.0 [M+H]+.

[0445] Step 8. A solution of 8-bromo-10-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydro-lH- benzo[4.5]imidazo[l,2-d][L4]diazepine (70 mg. 0.15 mmol) in DCM (1 mL) and 4M HCl / dioxane (1 mL) was stirred for 2 h at room temperature. The reaction mixture was concentrated, and the residue was triturated with MeCN (3 mL) to give 8-bromo-10-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydro-lH- bcnzo[4,5]imidazo[l,2-d][l,4]diazcpinc hydrochloride (1-91) (50 mg, 90 % yield) as a white solid. LCMS (m / z): 364.0 [M+H]+. 'H NMR (400 MHz, DMSO-r / 6) 5 9.47 (brs, 2H), 7.21 (s, 1H), 4.97 - 4.90 (m, 2H), 4.01 (d, J = 2.2 Hz, 3H). 3.51 (s. 2H), 3.45-3.34 (m, 2H), 3.40-3.33 (m, 2H).

[0446] Example 43 (1-28)

[0447] Step 1. To a solution of tert-butyl 8-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (1 g, 2.7 mmol) in dioxane / H2O (20 mL / 5 mL) was added potassium118BUSINESS.33510111.1trifluoro(vinyl)borate (549 mg, 4.10 mmol), Pd(dppf)C12 (200 mg, 0.27 mmol) and K2CO3 (1.13 mg, 8.19 mmol). The reaction mixture was stirred at 100 °C overnight under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SOs, filtered and concentrated. The crude residue was purified by column chromatography (Gradient: DCM / MeOH=20 / l) to afford tert-butyl 8-vinyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (810 mg, 94%) as a brown solid. LCMS (m / z): 314.1 [M+H]+.

[0448] Step 2. To a solution of tert-butyl 8-vinyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (810 mg, 2.58 mmol) in MeOH (10 mL) was added Pd / C (160 mg, 10%) and the mixture was stirred at room temperature overnight under H2 balloon. The mixture was filtrated and the filtrate was concentrated. The residue was purified by column (Gradient: DCM / MeOH=20 / l) to afford tert-butyl 8-ethyl- 1 ,2,4,5 -tetrahydro-3H-benzo [4,5] imidazo [ 1 ,2-d] [ 1 ,4] diazepine-3 -carboxylate (680 mg, 83%) as a yellow solid. LCMS (m / z): 316.3 [M+H]+.

[0449] Step 3. A solution of tert-butyl 8-ethyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (680 mg, 2.16 mmol) in DCM (6 mL) and 4M HCl / dioxane (6 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and adjusted pH = 9 ~ 10 with NaHCOs aq. solution, extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SC>3, filtered and concentrated. The crude was purified by prep-TLC (Gradient: DCM / MeOH=10 / l) to afford 8-ethyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-28) (320 mg, 71%) as an off-white solid. LCMS (m / z): 216.1 [M+H]+. 'H NMR (400 MHz, DMSO-r / 6) 5 7.37 - 7.30 (m, 2H), 7.02 (dd, J = 8.4, 1.6 Hz, 1H), 4.23 - 4.17 (m, 2H), 3.08 - 3.04 (m, 2H), 2.93 - 2.90 (m, 2H). 2.89 - 2.85 (m, 2H). 2.67 (q, J = 7.6 Hz. 2H), 1.20 (t, J = 7.6 Hz, 3H).

[0450] Example 44 (1-22)

[0451] Step 1. A solution of 8-bromo-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (300 mg, 1.13 mmol), (£)-prop-l-en-l-ylboronic acid (154 mg, 1.69 mmol), Pd(PPh3)4 (130 mg. 0.112 mmol) and K2CO3 (467 mg, 3.38 mmol) in L4-dioxane / H2O (12 mL / 2.4 mL) was stirred at 120 °C overnight under an N2atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). Tire combined organic layers were washed with water (20 mL) and dried over Na2SO4,119BUSINESS.33510111.1410095-001WG (221124) filtered and concentrated to afford (E)-8-(prop-l-en-l-yl)-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (118 mg, 46 %) as an off-white solid. LCMS (m / z): 228.2 [M+H]+.

[0452] Step 2. To a solution of (£)-8-(prop-l-cn-l-yl)-2,3,4,5-tctrahydro-lH-bcnzo[4,5]imidazo[l,2- d][ 1,4] diazepine (101 mg, 0.444 mmol) in THF (2 mL) and i-PrOH (2 mL) was added Pd / C (20 mg). Hie reaction mixture was stirred at 50 °C overnight under H2. The mixture was filtered, and the filtrate was concentrated. The mixture was purified by prep-HPLC and prep-TLC (DCM:MeOH=10: 1) to afford 8- propyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-22) (15 mg, 14%) as an off-white solid. LCMS (m / z): 230.2 [M+H]+. 'HNMR (400 MHz, DMSO-6) 5 7.37 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.02 (d, J = 8.5 Hz, 1H). 5.73 (s, 1H), 4.33 - 4.27 (m, 2H), 3.18 - 3.12 (m, 2H), 3.09 - 3.04 (m, 2H), 3.02 - 2.97 (m, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.65-1.55 (m. 2H), 0.88 (t, J = 7.5 Hz, 3H).

[0453] Example 45 (1-71)H2, Pd / C MeOH Dioxane,RT, 16h RT, 2hStep 6 Step 7

[0454] Step 1. To a solution of 4-bromo-3-fluoro-2-nitroaniline (6.8 g, 29 mmol) in cone. HCI (57.8 mL) at 0 °C was added NaNCL (2.2 g, 32 mmol). After stirring at 0 °C for 1 h, a solution of CuCl (4.3 g, 43 mmol) in cone. HCI (3.4 mL) was added and the mixture was stirred at 0 °C for 1 h. The mixture was adjusted to pH=7 with NaHCOs (aq.) at 0 °C and filtered. The filtrate was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. Tire residue was purified by column chromatography120BUSINESS.33510111.1(Pet.ether / EtOAc=20 / l) to give l-bromo-4-chloro-2-fluoro-3 -nitrobenzene (4.23 g, 57 % yield) as an off- white solid. 'H NMR (400 MHz, DMSO-r / s) 5 8.13 - 8.05 (m, 1H), 7.70 - 7.63 (m, 1H).

[0455] Step 2. To a solution of tert-butyl 5 -oxo- 1,4-diazcpanc-l -carboxylate (4.23 g, 20.0 mmol) in dry DMF (80 mL) at 0 °C was added NaH (60 %, 1 g, 25 mmol). After stirring at 0 °C for 0.5 h, a solution of l-bromo-4-chloro-2-fluoro-3-nitrobenzene (4.24 g, 16.7 mmol) in dry DMF (80 mL) was added and the mixture was stirred at room temperature for 16 h under N?. The mixture was quenched with ice water (100 mL), diluted with water (2 L), extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (2 L) and brine (2 L), dried over Na2SO4, filtered and concentrated to give tert-butyl 4- (6-bromo-3-chloro-2-nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (5.9 g, 78 %yield) as a yellow solid, which was used directly. LCMS (m / z): 393.9 [M-55]+.

[0456] Step 3. A solution of tert-butyl 4-(6-bromo-3-chloro-2-nitrophenyl)-5-oxo-l,4-diazepane-l- carboxylate (5.9 g, 13 mmol) and Fe (7.34 g, 131 mmol) in AcOH (32 mL) and toluene (20 mL) was stirred at 120 °C for 0.5 h. After cooling to room temperature, the reaction was concentrated under vacuum. The residue was re-dissolved with EtOAc (200 mL) and filtered. Tire filtrate was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with NaHCOs (aq.) (200 mL). dried over Na2SO4 and concentrated under vacuum. Tire residue was purified by column chromatography (Pet. ether / EtOAc=10 / l- 5 / 1-3 / 1) to give tert-butyl 10-bromo-7-chloro-L2.4.5-tetrahydro-3H-benzo[4.5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (2.8 g, 53 % yield) as an off-white solid. LCMS (m / z): 401.6 [M+H]+.

[0457] Step 4. A solution of tert-butyl 10-bromo-7-chloro-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (2.8 g, 6.5 mmol), CS2CO3 (6.34 g, 19.5 mmol), Cui (618 mg, 3.24 mmol) and 1.10-phenanthroline (234 mg. 1.30 mmol) in MeOH (60 mL) was stirred at 120 °C for 16 h under N2 in sealed tank. The reaction was filtered, and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated under vacuum and the residue was re-dissolved with EtOAc (200 mL) and water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column (Pet. ether / EtOAc= 10 / 1-5 / 1) to afford tert-butyl 7-chloro-10-methoxy- l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[1.2-d][l,4]diazepine-3-carboxylate (1.82 g, 80 % yield) as an off-white solid. LCMS (m / z): 296.0 [M-55]‘.

[0458] Step 5. A solution of tert-butyl 7-chloro-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (200 mg, 568 pmol), 4,4,5,5-tetramethyl-2-(prop-l- en-2-yl)-l,3,2-dioxaborolane (143 mg, 853 pmol), K3PO4 (361 mg, 1.71 mmol), PCys (16 mg, 57 pmol) and Pd(OAc)2 (13 mg. 57 pmol) in dioxanc / FLO (2 mL / 1 mL) was stirred at 100 °C for 16 h in sealed tube. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases 'ere washed with water (20 mL) and brine (20 mL),121BUSINESS.33510111.1410095-001WG (221124) dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-TLC (DCM / MeOH=30 / l) to afford tert-butyl 10-methoxy-7-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (93 mg, 45%yield) as acolourless oil. LCMS (m / z): 358.2 [M+H]+.

[0459] Step 6. A solution of tert-butyl 10-methoxy-7-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (93 mg, 260 pmol) and Pd / C (10 %, 18 mg) in MeOH (7 mL) was stirred at room temperature for 16 h under H2balloon. Tire reaction was filtered, and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (Column: Cl 8 column; Gradient: MeCN in water with 35 % modifier (0.1% formic acid)) to afford tert-butyl 7-isopropyl-10- methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (62 mg. 66 % yield) as a colourless oil. LCMS (m / z): 360.3 [M+H]1.

[0460] Step 7. A solution of tert-butyl 7-isopropyl-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (62 mg, 172 pmol) in 4M HCl / dioxane (2 mL) and DCM (1 mL) was stirred at room temperature for 2 h. The reaction was directly concentrated under vacuum and the residue was purified by trituration (ether) to afford 7-isopropyl-10-metlioxy-2,3,4,5-tetraliydro-lH- benzo[4,5]imidazo[l,2-d][L4]diazepine hydrochloride (1-71) (45.8 mg, 89 % yield) as an off-white solid. LCMS (m / z): 260.1 [M+H]+. ’H NMR (400 MHz. DMSO-ri.) 5 9.96 (br s, 2H). 7.33 - 7.26 (m. 1H). 7.09 - 7.03 (m, 1H), 5.16 - 5.09 (m, 2H), 3.96 (s, 3H), 3.76 - 3.70 (m, 2H), 3.65 - 3.55 (m, 2H), 3.52 - 3.45 (m, 3H), 1.29 (d, J = 6.8 Hz, 6H).122BUSINESS.33510111.1410095-001WG (221124)

[0461] Example 46 (1-92)ep Step 3Fe 1 ,10-phenanthroline AcOH Cui, Cs2CO3, Toluene MeOH 120 °C, 0.5h 120 °C, 16hStep 4Step 54M HCI, 1 ,4-dioxane, DCM, RT, 2hStep 6

[0462] Step 1. A solution of 4-(tert-butyl)-2-nitroaniline (5.0 g, 26 mmol) in AcOH (40 mL) was stirred at 50 °C for 10 min. The heating mantel was removed and Br2(4.53 g, 28.3 mmol) was added carefully via syringe. The reaction mixture was stirred at room temperature for 45 min. Tire reaction mixture was poured into ice-water (200 mL). The mixture was stirred for 30 min and the precipitated solid was collected by filtration to afford 2-bromo-4-(tert-butyl)-6-nitroaniline (6.9 g, 98%) as a yellow solid. LCMS (m / z): 273.0 [M+H]+.

[0463] Step 2. A solution of 2-bromo-4-(tert-butyl)-6-nitroaniline (3.5 g, 12 mmol) in HCI (12 M, 35 mL) at 0 °C was added NaNO2(1.59 g, 20.9 mmol). The reaction mixture was stirred at 0 °C for 30 min. Tire reaction mixture at 0 °C was added into a solution of KI (10.6 g, 58.1 mmol) in water (35mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc (50 mL x 4). The combined organic phases were washed with water (50 mL) and Na2S20s (aq., 50mL), dried over Na2SC>4, filtered and concentrated. The crude was purified by column chromatography on silica gel (eluent Pet. Ether :EtOAc=l 50: 1) to afford l-bromo-5-(tert-butyl)-2-iodo-3-nitrobenzene (3.36 g, 68.3%) as yellow oil. LCMS (m / z): 384.3 [M+H]+.

[0464] Step 3. A solution of l-bromo-5-(tert-butyl)-2-iodo-3-nitrobenzene (1.0 g, 2.6 mmol), tertbutyl 5-oxo-L4-diazepane-l-carboxylate (589 mg, 2.73 mmol) in toluene (10 mL) was added Pd(TFA)2(62.4 mg, 0.208 mmol). R-BINAP (130 mg, 0.208 mmol) and Cs2CO2(1.19 g. 3.65 mmol). The reaction mixture was stirred at 80 °C overnight under N2in sealed tube. The reaction mixture was diluted with H2O123BUSINESS.33510111.1410095-001WG (221124)(50 mL), extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (80 mL), dried over Na2SO-i, filtered and concentrated to afford tert-butyl 4-(2-bromo-4-(tert-butyl)-6- nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (1.56 g, 3.32 mmol) as a brown oil, which was used directly. LCMS (m / z): 416.0 [M-55]+.

[0465] Step 4. To a solution of tert-butyl 4-(2-bromo-4-(tert-butyl)-6-nitrophenyl)-5-oxo-l,4- diazepane-1 -carboxylate (1.56 g, 3.32 mmol) in toluene (4.5 mL) and AcOH (7.5 mL) was added Fe (1.85 g, 33.2 mmol). The reaction mixture was stirred at 120 °C for 0.5 h. The mixture was filtered, and the filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with NaHCCf aq. solution (50 mL) and brine (150 mL), dried over Na2SO4, filtered and concentrated. Hie mixture was purified by column chromatography on silica gel (eluent pet. ether:EtOAc=5: l) to afford tert-butyl 10-bromo-8-(tert-butyl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (755 mg, 53.9 %) as a purple oil. LCMS (m / z): 422.0 [M+H]+.

[0466] Step 5. To a solution of tert-butyl 10-bromo-8-(tert-butyl)- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (335 mg, 0.793 mmol) and 1.10-phenanthroline (28.6 mg, 0.159 mmol) in MeOH (4 mL) was added CS2CO3 (323.9 mg. 2.38 mmol) and Cui (75.5 mg, 0.396 mmol). The reaction mixture was stirred at 120 °C for 16 h under N2 in a sealed tube. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL x 4). The combined organic phases were washed with brine (50 mL) and dried overNa2SO4, filtered and concentrated. The crude residue was purified by prcp-HPLC to afford tcrt-butyl 8-(tcrt-butyl)-10-mcthoxy- 1,2,4, 5-tctrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (100 mg, 33.7 %) as an off-white solid. LCMS (m / z): 374.2 [M+H]1.

[0467] Step 6. To a solution of tert-butyl 8-(tert-buty l)-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (100 mg, 0.268 mmol) in DCM (3 mL) was added 4 M HC1 in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 2 h. Tire reaction mixture was concentrated, and the residue was triturated to afford 8-(tert-butyl)-10-methoxy-2, 3,4,5- tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride salt (1-92) (57.5 mg, 78.6 %) as yellow solid. LCMS (m / z): 274.2 [M+H]+. 'H NMR (400 MHz. DMSO-t / 5) 5 10.00 (brs, 2H). 7.21 (d, J = 1.4 Hz, 1H), 7.10 (s, 1H), 5.11 - 5.06 (m, 2H), 4.01 (s, 3H), 3.64 (brs, 2H), 3.57 (brs, 2H), 3.45 (brs, 2H), 1.36 (s, 9H).124BUSINESS.33510111.1410095-001WG (221124)

[0468] Additional Exemplary Compounds Prepared via Example 46 Methods[00469J Example 47 (1-94)

[0470] Step 1. A solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- bcnzo|4.5 |imidazo| l .2-d|| l .4|diazcpinc-3-carboxylate prepared as in example 42 (2 g, 5 mmol), KOH (849.5 mg, 15.14 mmol), Pd2(dba)s (462.2 mg, 0.5047 mmol) and tert-butyl Xphos (857.3 mg, 2.019 mmol) in 1.4-dioxane (20 mL) and H2O (20 mL) was stirred at 100 °C for 16 h under N2. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 100: 1 ~30 : 1, v / v) to afford tert-butyl 8-hydroxy-10-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (800 mg, 48 % yield) as a yellow solid. LCMS (m / z): 334.2 [M+H]+.

[0471] Step 2. To a solution of tert-butyl 8-hydroxy-10-methoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (150 mg, 0.44 mmol) in dry DMF (7 mL) at 0 °C was added NaH (60 %, 54 mg, 1.3 mmol). After stirring at 0 °C for 30 min, iodoethane (105 mg, 0.67 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture125BUSINESS.33510111.1410095-001WG (221124) was diluted with water (130 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, fdtered and concentrated under vacuum. The residue obtained was purified by Prep-TLC (DCM: MeOH=15 / l) to afford tert-butyl 8 -ethoxy- 10-methoxy-l, 2,4,5- tetrahydro-3H-benzo[4,5]imidazo[1.2-d][l,4]diazepine-3-carboxylate (100 mg, 61%) as a yellow solid. LCMS (m / z): 362.2 [M+H]+.

[0472] Step 3. To a solution of tert-butyl 8-ethoxy-10-methoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (100 mg, 0.3 mmol) in DCM (2 mL) was added 4 M HC1 in dioxane (2.5 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and purified by trituration (DCM / Hexane=l mL / 5 mL) to afford 8-ethoxy-10- methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-94) (76.7 mg, 95 %) as a yellow solid. LCMS (m / z): 262.1 [M+H]1. ’H NMR (400 MHz, DMSO-i / ,) 5 9.71 (brs. 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.69 (s, 1H), 5.02 (brs, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 3.56 (brs, 4H), 3.45 (brs, 2H), 1.36 (t, J = 7.0 Hz, 3H).

[0473] Example 48 (1-95)

[0474] Step 1. To a solution of tert-butyl 8-hydroxy- 10-methoxy-l, 2, 4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate prepared as in example 47 (150 mg, 0.45mmol) in DMF (6 mL) was added NaH (60 %, 54 mg, 1.4 mmol). After stirring at 0 °C for 1 h, 2-iodopropane (115 mg, 0.675 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Hie mixture was diluted with water (60 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH=20: 1, v / v) to afford tert-butyl 8-isopropoxy-10-methoxy-l,2,4,5-tetrahydro- 3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (100 mg, 59 % yield) as a grey solid. LCMS (m / z): 376.3 [M+H]+.

[0475] Step 2. To a solution of tert-butyl 8-isopropoxy-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (100 mg, 0.266 mmol) in DCM (3 mL) was added 4 M HCI / 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was triturated with DCM (5 mL). The solid was collected by filtration to afford 8-isopropoxy- 10-methoxy-2,3 ,4,5 -tetrahydro- IH-benzo [4,5] imidazo [ 1 ,2-d] [ 1 ,4]diazepine hydrochloride (1-95) (79 mg, 95% yield) as a grey solid. LCMS (m / z): 276.2 [M+H]+. 'H NMR (400 MHz,126BUSINESS.33510111.1410095-001WD (221124)DMSO-ay 5 9.74 (brs, 2H), 6.78 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 5.02 (d, J = 7.6 Hz, 2H), 4.68 (p, J = 6.2 Hz, 1H), 3.95 (s, 3H), 3.59 - 3.56 (m, 4H), 3.46 - 3.43 (m, 2H), 1.30 (d, J = 8 Hz, 6H).

[0476] Example 49 (1-39 & 1-40)From eluting fraction 1 & 2

[0477] Step 1. A solution of ethyl methacry late (1 g, 9 mmol) and benzyl (2-aminoethyl)carbamate (3.4 g, 18 mmol) in MeOH (10 mL) was stirred at 80 °C overnight in sealed tube. Tire mixture was diluted with water (200 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (70 mL), dried over Na2SC>4. and concentrated under vacuum. The mixture was purified by column chromatography on silica gel (eluent: Pet. Ether: EtOAc = 20: 1 to 10: 1) to afford ethyl 3-((2- (((benzyloxy)carbonyl)amino)ethyl)amino)-2-methylpropanoate (915 mg, 33 %) as yellow oil. LCMS (m / z): 309.1 [M+H]+.

[0478] Step 2. To a solution of ethyl 3-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)-2- methylpropanoate (915 mg, 2.96 mmol) in DCM (8 mL) was added TEA (900 mg, 8.90 mmol) and (Boc)2O (971 mg, 4.45 mmol) at room temperature. The mixture was stirred at room temperature for 3 h under N2. The mixture was diluted with DCM (100 mL) and washed with water (30 mL x 3). The organic lay er was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to afford crude ethyl 3- ((2-(((benzyloxy)carbonyl)amino)ethyl)(tert-butoxycarbonyl)amino)-2-methylpropanoate (1.2 g, 50%) as yellow oil, which was used directly in the next step without further purification. LCMS (m / z): 409.1 [M+H]+.127BUSINESS.33510111.1410095-001WD (221124)

[0479] Step 3. To a solution of ethyl 3-((2-(((benzyloxy)carbonyl)amino)ethyl)(tert- butoxycarbonyl)amino)-2-methylpropanoate (1.2 g, 2.9 mmol) in MeOH (12 mL) was added 20% Pd / C (240 mg) and K2CO3 (4.26 g, 30.8 mmol). The reaction mixture was stirred at room temperature overnight under a H2 atmosphere. The mixture was fdtered and concentrated under vacuum to afford crude tert-butyl 6-methyl-5 -oxo- 1.4-diazepane-l -carboxylate (700 mg, 88 %) as a white solid. LCMS (m / z): 173.2 [M-55]1.

[0480] Step 4. To a solution of 2-bromo-4-methyl-l -nitrobenzene (300 mg, 1.38 mmol), tert-butyl 6- methyl-5 -oxo- 1,4-diazepane-l -carboxylate (380 mg, 1.66 mmol), R-BINAP (69 mg, 0.11 mmol) and CS2CO3 (633 mg, 1.94 mmol) in toluene (12 mL) was added Pd(TFA)2(37 mg, 0.11 mmol). Tire reaction mixture was stirred at 80 °C overnight under N2 in sealed tube. Hie mixture was diluted with water (200 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over NaiSCL. and concentrated under vacuum to afford crude tert-butyl 6-methyl-4-(5-methyl-2- nitrophenyl)-5-oxo- 1,4-diazepane-l -carboxylate (672 mg, 93%) as yellow oil, which was used directly. LCMS (m / z): 308.0 [M-55]+.

[0481] Step 5. To a solution of tert-butyl 6-methyl-4-(5-methyl-2-nitrophenyl)-5-oxo-l,4-diazepane- 1 -carboxylate (672 mg, 1.84 mmol) in AcOH / toluene (4 mL / 2 mL) was added Fe (1.03 g. 18.49 mmol). The reaction mixture was stirred at 120 °C for 2 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO.t, and concentrated under vacuum. The mixture was purified by prep-TLC (eluent: Pet. Ether: EtOAc = 1:1, NH3.H2O) to afford tert-butyl 5,9-dimethyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (280 mg) as yellow oil.

[0482] Step 6. Hie racemic mixture of tert-butyl 5.9-dimethyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (280 mg) was purified by chiral HPLC to separate the enantiomers. (Column: Daicel AD-3 (30 mm x 250mm, 10pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 90% A for 6 mins; Wavelength: 214 nm; Sample Solvent: EtOH (5mL), Injection volume: 0.8 mL). Analytical chiral HPLC (Column: Daicel AD-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 90% A for 4 mins; Wavelength: 214 nm; RT1 = 2.335 min. RT2 = 2.659 min).

[0483] Eluting fraction 1 : 108 mg, 15 %, white solid; LCMS (m / z): 316.1 [M+H]+.

[0484] Eluting fraction 2: 110 mg, 15 %, white solid; LCMS (m / z): 316.2 [M+H]+.

[0485] Step 7. To a solution of tert-butyl 5.9-dimethyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (eluting fraction 1 from step 6, 108 mg. 0.34 mmol) in DCM (2 mL) was added a solution of HC1 in 1,4-dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was purified by trituration (DCM / Hexane=l / 8) to afford 5,9-dimethyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine 128BUSINESS.33510111.1410095-001WG (221124) from eluting fraction 1 (1-39) (84.6 mg HC1 salt, 98%) as a white solid. LCMS (m / z): 216.0 [M+H]+. H NMR (400 MHz, D2O) 5 7.70 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 5.11 - 5.02 (m, 1H), 4.75 - 4.67 (m, 1H), 4.08 - 3.91 (m, 2H), 3.74 (d, J = 13.8 Hz, 1H), 3.60 - 3.40 (m, 2H), 2.56 (s, 3H), 1.74 (d, J = 7.2 Hz, 3H).

[0486] The same procedure was applied to eluting fraction 2 (0.06 g) from step 3. From eluting fraction 2: 5,9-dimethyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-40) (91.2 mg HC1 salt, 96 %) as a white solid. LCMS (m / z): 216.0 [M+H]+; ’H NMR (400 MHz, D2O) 8 7.70 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 5.12 - 5.01 (m, 1H), 4.75 - 4.67 (m, 1H), 4.10 - 3.91 (m, 2H), 3.79 - 3.69 (m, 1H), 3.59 - 3.40 (m, 2H), 2.56 (s, 3H), 1.74 (d, J = 7.0 Hz, 3H).

[0487] Additional Exemplary Compounds Prepared via Example 49 Methods129BUSINESS.33510111.1

[0488] Example 50 (1-78)

[0489] Step 1. To a solution of 4-methyl-3 -nitrophenol (5 g, 33 mmol) in DCM (75 mL) was added NBS (8.72 g, 49.1 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (lOOmL), dried over Na2SC>4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.Ether to Pet.Ether: EtOAc=50: 1) to afford 2-bromo- 4-methyl-3 -nitrophenol (1.7 g, 22 %) as yellow oil. LCMS (m / z): 231.9 [M+H]+.

[0490] Step 2. To a solution of 2-bromo-4-methyl-3 -nitrophenol (1.7 g, 7.3 mmol) in acetone (8.5 mL) was added K2CO3 (2.03 g, 14.7 mmol) and Mel (2.08 g, 14.7 mmol). The reaction mixture was stirred at 65 °C overnight in a sealed tube. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. Hie mixture was purified by column chromatography on silica gel (Pet. Ether to Pet.Ether: EtOAc=70: l) to afford 2-bromo-l-methoxy-4-methyl-3 -nitrobenzene (1.2 g, 67 %) as a yellow oil. LCMS (m / z): 246.0 [M+H]+.

[0491] Step 3. A solution of 2-bromo-l -methoxy -4-methyl -3 -nitrobenzene (1.2 g, 4.9 mmol), tertbutyl 5 -oxo- 1,4-diazepane-l -carboxylate (1.25 g, 5.85 mmol), Pd(TFA)2 (130 mg, 0.390 mmol), R-BINAP (243 mg, 0.390 mmol) and CS2CO3 (2.22 g, 6.88 mmol) in toluene (12 mL) was stirred at 100 °C for 3h under microwave. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). Hie combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to afford crude tert-butyl 4-(6-methoxy-3-methyl-2-nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (225.1 mg, 12 %) as a yellow oil, which was used directly. LCMS (m / z): 378.2 [M-H]+.

[0492] Step 4. To a solution of tert-butyl 4-(6-methoxy-3-methyl-2-nitrophenyl)-5 -oxo- 1,4- diazepane-l -carboxylate (174 mg, 0.458 mmol) in toluene (1.5 mL) and AcOH (2.5 mL) was added Fe (256130BUSINESS.33510111.1410095-001WG (221124) mg, 4.59 mmol). The reaction mixture was stirred at 120 °C for 1 h. The mixture was filtered. The filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with NaHCCL (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by Prep-TLC (DCM:MeOH=20: 1) to afford tert-butyl 10-methoxy-7-methyl-l, 2,4,5- tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (70 mg. 46 %) as yellow oil. LCMS (m / z): 332.2 [M+H]+.

[0493] Step 5. To a solution of tert-butyl 10-methoxy-7-methyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (68 mg, 0.20 mmol) in 4M HCl / dioxane (2 mL) and DCM (2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The mixture was triturated with DCM / n-hexane=l: l (2 mL) and freeze-dried to afford 10- methoxy-7-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-78) (46.2 mg, HC1 salt, 97.3 %) as a white solid. LCMS (m / z): 232.2 [M+H]+. 'H NMR (400 MHz, DMSO-r / 6) 5 10. 13 (s, 2H), 7.27 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 5.16 (d, J = 6.6 Hz, 2H), 3.96 (s, 3H), 3.80 - 3.73 (m, 6H), 2.52 (d, 3H).

[0494] Example 51 (1-99)

[0495] Step 1. A solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate prepared as in example 42 (500 mg, 1.26 mmol) and Pd(dppf)C12 (92.2 mg, 0.126 mmol.) in THF (16 mL) was added ZnEt2 (1.55 g, 12.6 mmol). The mixture solution was stirred at 25 °C for 0.5 h and 70 °C for 2 h under N2. The mixture was diluted with water (300 mL) and extracted with EtOAc (2 x 80 mL). Tire combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to obtain the crude material. The crude product was purified by silica gel column (eluting with DCM: MeOH =100: 1—50: 1, v / v) to afford tert-butyl 8-ethyl-10-131BUSINESS.33510111.1methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (400 mg, 91 % yield) as a yellow solid. LCMS (m / z): 346.2 [M+H]+.

[0496] Step 2. To a solution of tert-butyl 8-cthyl-10-mcthoxy-l,2,4,5-tctrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (400 mg, 1.16 mmol) in DCM (4 mL) was added NBS (225.5 mg, 1.158 mmol). The mixture was stirred at room temperature for 1 h. Tire mixture was diluted with water (80 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated to obtain the crude compound. The crude product was purified by silica gel column (eluting with PE:EA=10: 1-5: 1, v / v) to afford tert-butyl 7-bromo- 8-etliyl-10-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (300 mg, 60 % yield) as a white solid. LCMS (m / z): 424.1 [M+H]+.

[0497] Step 3. A mixture of tert-butyl 7-bromo-8-ethyl-10-methoxy-1.2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l ,4]diazepine-3-carboxylate (200 mg, 0.47 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane (360 mg, 1.41 mmol), P(Cy)sPd G2 (27.7 mg, 0.047 mmol), and KOAc (115 mg, 1.75 mmol) in DMAc (6 mL) was stirred at 155 °C for 2 h under N2. The mixture was diluted with water (60 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4. filtered and concentrated to obtain (3-(tert-butoxycarbonyl)-8-ethyl-10- methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[L2-d][l,4]diazepin-7-yl)boronic acid (300 mg, 80% yield) as a light yellow solid. LCMS (m / z): 390.3 [M+H]+.

[0498] Step 4. To a solution of (3-(tert-butoxycarbonyl)-8-ethyl-10-methoxy-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepin-7-yl)boronic acid (300 mg, 0.771 mmol) in EtOH (3 mL) and H2O (3 mL) was added 30 % H2O2 (174.8 mg, 1.542 mmol) and NH4HCO3 (60.96 mg, 0.7711 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO , filtered and concentrated to obtain the crude product. The crude product was purified by Prep-TLC (DCM / MeOH=20: 1, v / v) to afford tert-butyl 8-ethyl-7-hydroxy-10-methoxy-l,2,4,5-tetrahydro- 3H-benzo[4.5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (300 mg. 30 % yield) as a yellow solid. LCMS (m / z): 362.2 [M+H]+.

[0499] Step 5. To a solution of tert-butyl 8-ethyl-7-hydroxy-10-methoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (80 mg, 0.22 mmol) in dry DMF (3 mL) was added NaH (60 %, 17.7 mg, 0.443mmol). Tire reaction mixture was stirred at 0 °C for 1 h before addition CH3I (62.8 mg, 0.443 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC (44% MeCN in H2O (0.1% HCOOH)) to afford tert-butyl 8-132BUSINESS.33510111.1410095-001WG (221124) ethyl-7,10-dimethoxy-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (45 mg, 54 % yield) as a grey solid. LCMS (m / z): 376.2 [M+H]+.

[0500] Step 6. To a solution of tert-butyl 8-cthyl-7,10-dimcthoxy-l,2,4,5-tctrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (45 mg, 0.12 mmol) in DCM (1 mL) was added 4 M HCl / l,4-di oxane (1 mL).The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and triturated with DCM (5 mL). The solid was collected by filtration to afford 8-ethyl-7,10- dimethoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-99) (39.8 mg, 90 % yield) as a white solid. LCMS (m / z): 276.2 [M+H]+. ’H NMR (400 MHz, DMSO-r / 6) 5 9.89 (s, 2H), 6.88 (s, 1H), 5.05 (d, J = 6.6 Hz, 2H), 3.93 (d, J = 6.4 Hz, 6H), 3.63 - 3.61 (m, 2H), 3.58 (br s, 2H), 3.45 (br s, 2H), 2.70 (q, J = 7.4 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H).[005

[0502] Step 1. A solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate prepared as in example 42 (2 g. 5 mmol). 4, 4,5,5- tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (1.02 g, 6.06 mmol), tricyclohexylphosphine (141 mg, 0.504 mmol), Pd(OAc)2 (113 mg, 0.504 mmol) and K3PO (3.21g, 15.1 mmol) in 1,4-dioxane (20 mL) and H2O (10 mL) was stirred at 100 °C overnight under N2. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). Tire combined organic layers were washed with water (50 mL) and brine (50 mL), dried over NaiSCh. The mixture was purified by column chromatography on silica gel(Pet.ether :EtOAc=3: l - 1: 1) to afford tert-butyl 10-methoxy-8-(prop-l-en-2-yl)-1.2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (1.57 g, 87%) as an off-white solid. LCMS (m / z): 358.2 [M+H]+.

[0503] Step 2. To a solution of CH2I2 (7.49 g, 28.0 mmol) in dry toluene (2.5 mL) at -78 °C was wadded Et2Zn (1 mol / L in hexane, 14 mL, 14 mmol) under N2. After stirring at -78 °C for 30 min under N2, a solution of tert-butyl 10-methoxy-8-(prop-l-en-2-yl)-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-133BUSINESS.33510111.1d][l,4]diazepine-3-carboxylate (500 mg, 1.4 mmol) in dry toluene (7.5 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers w ere washed with water (30 mL) and brine (30 mL), dried over Na2SC>4, filtered and concentrated. The mixture was purified by prep-HPLC to tertbutyl 10-methoxy-8-(l-methylcyclopropyl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (68 mg, 13 %) as a yellow oil. LCMS (m / z): 372.3 [M+H]+.

[0504] Step 3. To a solution of tert-butyl 10-methoxy-8-(l-methylcyclopropyl)-l,2,4,5-tetrahydro- 3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (1-100) (56.5 mg, 0.152 mmol) in DCM (2 mL) was added 4 M HC1 in 1,4-dioxane (6 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. Hie mixture was triturated with DCM : hexane=l: l (10 mL) and freeze-dried to afford 10-methoxy-8-(l-methylcyclopropyl)-2.3.4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine hydrochloride (43 mg, 91 %) as an off-white solid. LCMS (m / z): 272.2 [M+H]+. ’HNMR (400 MHz, DMSO-r / s) 89.92 (brs, 2H), 7.17 - 7.13 (m, 1H), 6.91 (s, 1H), 5.07 (s, 2H), 3.99 (d, J = 1.5 Hz, 3H), 3.65-3.58 (m, 2H), 3.58-3.33 (m, 2H), 3.48-3.42 (m, 2H), 1.43 (s, 3H), 0.91 (d, J = 5.0 Hz, 2H), 0.84 - 0.79 (m, 2H).

[0505] Example 53 (1-101 & 1-102)From eluting fraction 1 & 2

[0506] Step 1. A mixture of tert-butyl 8-bromo-10-methoxy-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate prepared as in example 42 (500 mg, 1.5 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-l-en-2-yl)-l,3,2-dioxaborinane (560 mg, 3.1 mmol), K2CO3 (435 mg, 3.9 mmol,) and Pd(dppf)C12 (90 mg, 0.15 mmol) in dioxanc / watcr (10 mL / 2.5 mL) was stirred at 80 °C under N2 overnight in sealed tube. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over Na2SO4, fdtered and concentrated. The mixture was purified by prep-TLC (PE / EtOAc=3: 1) to afford134BUSINESS.33510111.1410095-001WG (221124) tert-butyl 10-methoxy-8-(3,3,3-trifluoroprop-l-en-2-yl)-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (517 mg, 99 %) as colourless oil. LCMS (m / z): 412.2 [M+H]+.

[0507] Step 2. A mixture of tcrt-butyl 10-mcthoxy-8-(3,3,3-trifluoroprop-l-cn-2-yl)-l,2,4,5- tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (467 mg, 1.14 mmol) and Pd / C (200 mg, 10 %wt) in MeOH (10 mL) was stirred at room temperature overnight under H2 balloon. The reaction mixture was filtered and concentrated. The racemic mixture (200 mg) was purified by chiral-HPLC to separate the enantiomers. (Column: Daicel AD-3 (30 mm x 250mm, 10pm); Mobile Phase A: Liquid CO2, Mobile Phase B: EtOH; Flow rate: 55 mL / min; Gradient: 90% A for 6 mins; Wavelength: 214 nm; Sample Solvent: EtOH (12 mL), Injection volume: 0.35 mL). Analytical chiral HPLC (Column: Daicel AD-3 (3 mm x 100mm. 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: EtOH; Flow rate: 1 mL / min; Gradient: 90% A for 3 mins; Wavelength: 214 nm; RT1 = 1.354 min, RT2 = 1.926 min).

[0508] Eluting fraction 1 : 120 mg, colourless oil; LCMS (m / z): 414.2 [M+H]+.

[0509] Eluting fraction 2: 110 mg, colourless oil; LCMS (m / z): 414.2 [M+H]+.

[0510] Step 3. Amixture of tert-butyl 10-methoxy-8-(l,l,l-trifluoropropan-2-yl)-l,2,4,5-tetraliydro- 3H-benzo[4.5]imidazo[l,2-d][L4]diazepine-3-carboxylate eluting fraction 1 from step 2 (120 mg. 0.290 mmol) in 4M HCl / dioxane (2 mL) / DCM (4 mL) was stirred at room temperature for 1 hour. Tire mixture was directly concentrated and triturated by DCM / hexane (1 mL / 3 mL) to afford 4-(lH-pyrrolo[2,3- b]pyridin-3-yl)cyclohex-3-en-l -amine hydrochloride (1-101) (120 mg, 99 %) as a white solid. LCMS (m / z): 314.2 [M+H]+;]H NMR (400 MHz, DMSO-de) 5 10.06 (s, 2H), 7.37 (s. 1H), 7.11 (s, 1H), 5.10 (d, J = 7.0 Hz, 2H). 4.06 - 4.01 (m. 1H), 4.00 (s, 3H), 3.66 (s, 2H), 3.58 (s, 2H), 3.46 (s, 2H), 1.52 (d. J = 7.2 Hz, 3H).

[0511] The same procedure was applied to eluting fraction 2 (110 mg, 0.266 mmol) from step 2. From eluting fraction 2 4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-102) (95 mg, 99%) as a white solid. LCMS (m / z): 314.2 [M+H]+; H NMR (400 MHz, DMSO-d6) 5 9.94 (s, 2H), 7.35 (s, 1H), 7.09 (s, 1H), 5.08 (d, J = 7.2 Hz, 2H), 4.06 - 4.01 (m, 1H), 3.99 (s, 3H), 3.65-3.60 (m, 2H), 3.57 (br s, 2H), 3.44 (br s, 2H), 1.51 (d, J = 6.8 Hz. 3H).135BUSINESS.33510111.1

[0512] Example 54 (1-103 & 1-104)

[0513] Step 1. To a solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate prepared as in example 42 (850 mg, 2.14 mmol) in dioxanc / fLO (10 mL / 2 mL) was added 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (433 mg, 2.57 mmol), PCys (60 mg, 0.21 mmol), Pd(OAc)2 (49 mg, 0.21 mmol) and K3PO4 (1 .36 g, 6.43 mmol). The mixture was stirred at 100 °C overnight under an N2 atmosphere in a sealed tube. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, fdtered and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: Pet.Ether: EtOAc =5 / 1 to 1 / 1) to afford tert-butyl 10-methoxy-8-(prop-l-en-2-yl)-L2.4.5-tetrahydro-3H-benzo[4.5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (660 mg, 86 %) as ayellow oil. LCMS (m / z): 358.3 [M+H]+.

[0514] Step 2. To a solution of tert-butyl 10-methoxy-8-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (560 mg, 1.57 mmol ) in THF / H2O (6 mL / 2 mL) was added OsO4 (40 mg, 0.16 mmol) and NMO (242 mg, 3.13 mmol). The mixture was stirred at room temperature for 1 h. NalCh ( 1.35 g, 6.27 mmol) was added, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaiSiC (aq.) (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over JSfeSC filtered and concentrated under vacuum to afford tert-butyl 8-acetyl-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (510 mg, 90 %) as a yellow solid. LCMS (m / z): 360.2 [M+H]+.136BUSINESS.33510111.1410095-001WD (221124)

[0515] Step 3. To a solution of tert-butyl 8-acetyl-10-methoxy- l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (300 mg, 0.8 mmol) in anhydrous THF (4 mL) at - 78 °C was added EtMgBr (3.4 M, 1.7 mL, 5.8 mmol) drop-wise under a N2 atmosphere. The reaction was stirred at room temperature for 2 h under a N2 atmosphere. The reaction mixture was quenched with saturated NH4CI (aq . ) ( 100 mL) and extracted with EtOAc (100 mL x 2). Tire combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (DCM: MeOH=20 / l) to afford tert-butyl 8-(2-hydroxybutan-2-yl)-10-methoxy- l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (250 mg, 76.9 %) as a white solid. LCMS (m / z): 390.3 [M+H]+.

[0516] Step 4. To a solution of tert-butyl 8-(2-hydroxybutan-2-yl)-10-methoxy- 1,2,4, 5-tetrahydro- 3H-benzo[4.5Jimidazo[l,2-d][1.4Jdiazepine-3-carboxylate (530 mg, 1.36 mmol) in DCM (7 mL) was added EhSiH (4.3 mL, 27 mmol) and TFA (2.6 mL, 34 mmol). The reaction was stirred at 30 °C overnight. The reaction mixture was adjusted pH=8~9 with saturated NH4CI (aq.) (150 mL) and extracted with DCM (50 mL x 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained was dissolved with DCM (50 mL) and 4M HC1 in dioxane (10 mL). The mixture was stirred at room temperature for 1 h. The precipitate was filtered and purified by trituration (DCM) to afford (E)-8-(but-2-en-2-yl)-10-methoxy-2.3.4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine as a mixture with 8-(sec-butyl)-10-methoxy-2,3,4,5-tetrahydro- lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (350 mg, 83%, 3 / 7, HC1 salt) as a white solid, which was used directly. LCMS (m / z): 272.2[M+H]+, 374.2 [M+H]+.

[0517] Step 5. The solution of (£)-8-(but-2-en-2-yl)-10-methoxy-2,3,4,5-tetrahydro-lH- benzo[4.5]imidazo[l,2-d][1.4]diazepine as a mixture with 8-(sec-butyl)-10-methoxy-2,3,4,5-tetrahydro- lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (240 mg, 0.88 mmol, 3 / 7) in MeOH / i-PrOH (3 mL / 3 mL) was added Pd / C (43.2 mg) . The mixture was stirred at 50 °C for 4 h under a H2atmosphere . The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue obtained was diluted water (50 mL), alkalified to pH=8~9 with saturated NaHCCL (aq.) and extracted with DCM (50 mLx5). The combined organic layers were washed with brine (50 mL), dried over Na^SCU filtered and concentrated under vacuum to afford 8-(sec-butyl)-f0-methoxy-2,3,4,5-tetrahydro-tH-benzo[4,5]imidazo[L2-dJ[l,4]diazepine (235 mg, 81 %) as a white solid. LCMS (m / z): 274.2 [M+H]+.

[0518] Step 6. To a solution of 8-(sec-butyl)-10-methoxy-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine (215 mg, 0.79 mmol) in DCM (5 mL) was added B0C2C) (257 mg, 1.18 mmol), DIEA (122 mg, 0.94 mmol) and DMAP (29 mg, 0.24 mmol). Hie reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (50 mL), washed with water (20 mL x 2) and brine (20 mL), dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified137BUSINESS.33510111.1410095-001WG (221124) by prep-TLC (DCM: MeOH=20 / l) and the racemic mixture (200 mg) was purified by chiral-HPLC to separate the enantiomers (Column: Daicel IC (30 mm x 250mm, 10pm); Mobile Phase A: Liquid CCL, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 80% Afor 5 mins; Wavelength: 214 nm; Sample Solvent: MeOH (10 mL), Injection volume: 0.8 mL). Analytical chiral HPLC (Column: Daicel IC-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 80 % A for 8 mins; Wavelength: 214 nm; RT1 = 5.700 min, RT2 = 6.228 min).

[0519] Eluting fraction 1 : 95 mg, white solid: LCMS (m / z): 374.3 [M+H]+.

[0520] Eluting fraction 2: 80 mg, white solid; LCMS (m / z): 374.3 [M+H]+.

[0521] Step 7. To a solution of tert-butyl 8-(sec-butyl)-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate eluting fraction 1 from step 6 (95 mg. 0.25 mmol) in DCM (3mL) was added 4 M HO in dioxane (3 mL). The mixture was stirred at room temperature for 2 h. Tire reaction mixture was concentrated under vacuum and the residue was purified by trituration (DCM) to afford 8-(sec-butyl)-10-methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-103) (71.5 mg, yield: 90.7 %) as a white solid. LCMS (m / z): 274.2 [M+H]+; ’H NMR (400 MHz, DMSO-de) 5 9.99 (brs, 2H). 7.13 (s, 1H), 6.98 (s, 1H), 5.10 (d, J = 7.6 Hz, 2H), 3.99 (s, 3H), 3.67 - 3.63 (m, 2H). 3.59 (brs, 2H). 3.47 (brs. 2H), 2.78 (h, J = 7.0 Hz, 1H), 1.63 (p, J = 7.4 Hz, 2H), 1.25 (d, J = 6.8 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H).

[0522] Tire same procedure was applied to eluting fraction 2 (80 mg, 0.21 mmol) from step 2. From eluting fraction 24-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-104) 52.5 mg, yield: 79%) as a white solid. LCMS (m / z): 274.2 [M+H]+; H NMR (400 MHz. DMSO-dg) 3 9.89 (brs, 2H), 7.13 (s, 1H), 6.97 (s, 1H). 5.08 (d, J = 8.0 Hz, 2H), 3.99 (s. 3H), 3.64-3.61 (m. 2H), 3.61 - 3.56 (m, 2H), 3.47 (br s, 2H), 2.77 (h, J = 7.0 Hz, 1H), 1.63 (p, J = 7.4 Hz, 2H), 1.25 (d, J = 6.8 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H).138BUSINESS.33510111.1

[0523] Example 55 (1-105 & 1-106)

[0524] Step 1. A solution of tert-butyl 7-chloro-l 0-methoxy- 1,2, 4, 5 -tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate prepared as in example 45 (500 mg, 1.42 mmol), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (358 mg. 2.13 mmol), K3PO4 (904 mg, 4.26 mmol), PCy2(39 mg, 140 pmol) and Pd(OAc)2(32 mg, 140 pmol) in dioxane / H2O (5 / 2.5 mL) was stirred at 100 °C for 16 h under N2in sealed tube. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Tire residue was purified by column (Pet.ether / EtOAc=20 / 1-5 / 1) to give tert-butyl 10-methoxy-7-(prop-l-en-2-yl)-l,2,4,5-tetraliydro-3H- benzo[4.5]imidazo[l,2-d][L4Jdiazepine-3-carboxylate (203 mg, 40 % yield) as an off-white solid. LCMS (m / z): 358.2 [M+H]+.

[0525] Step 2. A solution of tert-butyl 10-methoxy-7-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (380 mg, 1.06 mmol), NMO (287 mg, 2.13 mmol) and OSO4 (27 mg, 110 pmol) in THF / H2O (12 mL / 4 mL) was stirred at room temperature for 2 h. NaKL (909 mg, 4.25 mmol) was added and tire mixture was stirred at room temperature for 1 h. The mixture was quenched with Na2S2O3 aq. solution (30 mL), diluted with water (30 mL), extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with Na2S20s (40 mL), water (40 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated. Tire residue was purified by prep-TLC (DCM / MeOH=15 / l) to give tert-butyl 7-acetyl- 10-methoxy- 1 ,2,4,5-tetrahydro-3H-benzo [4,5]imidazo [ 1 ,2-d] [ 1 ,4]diazepine-3 - carboxylate (240 mg, 62 % yield) as an off-white solid. LCMS (m / z): 360.2 [M+H]+.139BUSINESS.33510111.1

[0526] Step 3. A solution of tert-butyl 7-acetyl-10-methoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (240 mg, 0.67 mmol) in MeOH (16 mL) and NaBEL (38 mg, 1.0 mmol) was stirred at room temperature for 2 h. The reaction was quenched with water (15 mL), extracted with EtOAc (3 x 20 mL). Hie combined organic phases were washed with water (20 mL) and brine (20 mL), dried over NaiSCL and concentrated in vacuo to give tert-butyl 7-(l-hydroxyethyl)-10- methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[L2-d][l,4]diazepine-3-carboxylate (229 mg, 95% yield) as an off-white solid. LCMS (m / z): 362.9 [M+H]+.

[0527] Step 4. A solution of tert-butyl 7-(l-hydroxyethyl)-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (213 mg, 589 pmol) in HCl / dioxane (20 mL) and DCM (10 mL) was stirred at 0 °C for 1 h. The reaction was adjusted pH=7~8 with NaHCOs aq. solution at 0 °C, diluted with water ( 10 mL), and extracted with DCM (10 x 20 mL). The combined organic layers were dried over NaiSCL, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=8 / l) and the racemic isolate of 1 -(10-methoxy-2, 3, 4, 5 -tetrahydro- 1H- benzo[4,5]imidazo[l,2-d][l,4]diazepin-7-yl)ethan-l-ol (80 mg) was subjected to chiral-HPLC to separate the enantiomers (Column: Daicel IG (30 mm x 250mm, I Oum): Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 55% A for 6 mins; Wavelength: 214 nm; Sample Solvent: MeOH (7 mL), Injection volume: 0.8 mL). Analytical chiral HPLC (Column: Daicel IC-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 55 % A for 6 mins; Wavelength: 214 nm; RT1 = 3.890 min, RT2 = 4.983 min).

[0528] Eluting fraction 1 (1-105): 29 mg, 36%, white solid; LCMS (m / z): 262.2 [M+H]+. ’H NMR (400 MHz, DMSO-de) 5 7.07 (d, J = 8.0 Hz, 1H), 6.69 (d. J = 8.2 Hz, 1H), 5.27 - 5.20 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H). 4.64 - 4.58 (m. 2H), 3.86 (s, 3H), 3.09 - 3.03 (m, 2H), 2.95 - 2.90 (m, 2H), 2.88 - 2.82 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H).

[0529] Eluting fraction 2 (1-106): 29 mg, 36%, white solid; LCMS (m / z): 262.2 [M+H]+. ’H NMR (400 MHz, DMSO-de) 5 7.08 (d. J = 8.0 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.27 - 5.20 (m, 1H), 5.00 - 4.95 (m, 1H). 4.69 - 4.64 (m. 2H), 3.86 (s, 3H), 3.14 - 3.09 (m, 2H). 3.05 - 3.00 (m. 2H), 2.96 - 2.91 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H).140BUSINESS.33510111.1

[0530] Example

[0531] Step 1. To a solution of tert-butyl 8-bromo-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (200 mg, 0.546 mmol) in DMF (10 mL) was added PdC12(PPli3)2(19.16 mg, 0.02730 mmol). Cui (10.4 mg, 0.0546 mmol), TEA (110.5 mg, 1.092 mmol) and TMSCCH (107.3 mg, 1.092 mmol). The reaction mixture was stirred at 1100C for 24 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (Pet.Ether: EtOAc = 1: 1) to afford tert-butyl 8-((trimetliylsilyl)ethynyl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (47 mg. 22 %) as a yellow solid. LCMS (m / z): 384.4 [M+H]+.

[0532] Step 2. To a solution of tert-butyl 8-((trimethylsilyl)ethynyl)- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (45 mg, 0.12 mmol) in MeOH (2 mL) was added K2CO3 (32.4 mg, 0.234 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under vacuum. The mixture was purified by prep-TLC (Pet.Ether: EtOAc=l : l) to afford tert-butyl 8-ethynyl-l,2,4.5-tetrahydro-3H-benzo[4.5]imidazo[l,2-d][1.4]diazepine-3- carboxylate (20 mg, 55 %) as a white solid. LCMS (m / z): 312.1 [M+H]+.

[0533] Step 3. To a solution of tert-butyl 8-ethynyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (20 mg, 0.064 mmol) in HCl / dioxane (4M, 1 mL) and DCM (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The mixture was triturated with DCM :n-hexane=l: 1 (2 mL) and freeze-dried to afford 8-ethynyl-2, 3,4,5- tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-107) (10.9 mg HCI salt, 80.3%) as a white solid. LCMS (m / z): 212.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 10.16 (brs, 2H), 7.90 - 7.86 (m, 2H), 7.62 - 7.58 (m, 1H), 4.89 - 4.83 (m, 2H), 4.28 (s, 1H), 3.71 - 3.66 (m, 2H), 3.53 - 3.46 (m, 4H).141BUSINESS.33510111.1

[0534] Example 57 (1-83)Step 1

[0535] Step 1. To a solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate prepared as in example 42 (165 mg, 0.416 mmol) in DCM (2 mL) was added 4 M HCI in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The mixture was triturated with DCM : hexane=l: l (20mL) and freeze-dried to afford 8-bromo-10-methoxy-2,3,4,5-tetrahydro-lH- benzo[4.5]imidazo[l,2-d][1.4Jdiazepine hydrochloride (1-83) (137 mg, 99 %) as an off-white solid. LCMS (m / z): 296.0 [M+H]+. >H NMR (400 MHz, DMSO-d6) 89.89 (s, 2H), 7.51 (d, J = 1.4 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 5.02 (d, J = 8.8 Hz, 2H), 3.98 (s, 3H), 3.60-3.52 (m, 4H), 3.41 (br s, 2H).

[0536] Example 58 (1-108)

[0537] Step 1. To a solution of tert-butyl 8-acetyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate prepared as in example 41 (200 mg, 0.66 mmol) in dry THF (6 mL) at -78 °C was added MeMgBr (3 M in THF, 1.3 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 2 h under N2. Tire reaction mixture was diluted with water (60 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL). dried over Na2SO4, fdtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (DCM: MeOH=15 / l) to afford tert-butyl 8-(2-hydroxypropan-2-yl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (165 mg, 78 %) as awhite solid. LCMS (m / z): 346.1 [M+H]+.

[0538] Step 2. A solution of tert-butyl 8-(2-hydroxypropan-2-yl)- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (223 mg, 0.646 mmol) in HCOOH (2.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with MeOH (70 mL). and potassium carbonate (60 g) added. After stirring at room temperature for 2 h, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (5% MeCN in H2O (0.5% HCOOH)) to afford 2-(2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepin-8-yl)propan- 2-ol (1-108) (7.8 mg, yield: 4.9%) as a white solid. LCMS (m / z): 246.1 [M+H]+. ’H NMR (400 MHz, DMSO-de) 8 8.41 (s, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 1.6 Hz, 1H), 4.21 - 4.19 (m, 2H). 3.07 - 3.05 (m. 2H), 2.92 - 2.85 (m, 4H), 1.45 (s, 6H).142BUSINESS.33510111.1410095-001WG (221124)

[0539] Additional Exemplary Compounds Prepared via Example 58 Methods

[0540] Example 59 (1-110)

[0541] Step 1. To a solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate prepared as in example 42 (800 mg, 2 mmol), Pd / C (80 mg) and Pd(OH)2 / C (80 mg) in MeOH (20 mL) was stirred at 40 °C overnight under a H2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give tert-butyl 10-methoxy-l,2,4,5- tetrahydro-3H-benzo[4,5]imidazo[1.2-d][l,4]diazepine-3-carboxylate (630 mg, 99% yield) as a light green solid. LCMS (m / z): 318.2 [M+H]+.

[0542] Step 2. A solution of tert-butyl 10-methoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (630 mg, 2 mmol) in DCM (5 mL) and 4M HCI / dioxane (2 mL) was stirred for 2h at room temperature. The reaction mixture was concentrated to give 10-methoxy-2, 3,4,5 -tetrahydro- lH-benzo[4.5]imidazo[l,2-d][1.4]diazepine (420 mg. 99% yield) as a green solid. LCMS (m / z): 218.2 [M+H]+.143BUSINESS.33510111.1

[0543] Step 3. A solution of 10-methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l ,2- d][ 1,4] diazepine (200 mg, 0.9 mmol), CH3CH2CH2I (187 mg, 1.10 mmol), K2CO3 (508 mg, 3.68 mmol) in DMF (10 mL) was stirred overnight at room temperature. Tire reaction mixture was diluted with water (80 mL), extraction with ethyl acetate (100 mL x 2). Tire combined organic phases were washed with water (80 mL) and brine (80 mL). dried over Na2SO4, fdtered and concentrated. The residue was purified by prep- TLC (DCM:MeOH=10: 1) to give 10-methoxy-3-propyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine (1-110) (80 mg, 36 % yield) as an off-white solid. LCMS (m / z): 260.1 [M+H]+. 'HNMR (400 MHz, DMSO-de) 8 7.11 (dd, J = 8.2, 0.8 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.68 - 4.62 (m, 2H), 3.88 (s, 3H), 3.11 - 3.04 (m, 2H), 2.78 - 2.72 (m, 2H), 2.70 - 2.63 (m, 2H), 2.46 (t, J = 7.4 Hz, 2H). 1.48 (h, J = 7.4 Hz. 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0544] Example 60 (1-111) n-lodoethane

[0545] Step 1. A solution of 10-methoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2- d][ 1,4] diazepine prepared as in example 59 (200 mg, 0.92mmol), CH3CH2I (171 mg, 1.1 mmol), K2CO3 (507.8 mg, 3.68 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with water (80 mL) and brine (80 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-TLC (DCM:MeOH=10: 1) to give 3-ethyl-10-methoxy-2,3,4,5-tetrahydro-lH- benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-111) (80 mg, 35 % yield) as an off-white solid. LCMS (m / z): 246.1 [M+H]+. ’H NMR (400 MHz, DMSO-dg) 8 7.11 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.66 (dd, J = 6.4, 2.6 Hz, 2H), 3.89 (s, 3H), 3.10 - 3.05 (m, 2H), 2.78 - 2.71 (m, 2H), 2.68 - 2.63 (m. 2H), 2.56 (q, J = 7.2 Hz, 2H). 1.04 (t. J = 7.2 Hz. 3H).

[0546] Example 61 (1-112)Step 1

[0547] Step 1. A solution of t tert-butyl 10-methoxy-8-(prop-l-en-2-yl)- 1.2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l ,4]diazepine-3-carboxylate prepared as in example 54 (38 mg, 0.099 mmol) in HCOOH (3 mL) was stirred at room temperature for 4h. Tire reaction mixture was freeze-dried to afford 10-methoxy-8-(prop-l-en-2-yl)-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine formate (I-144BUSINESS.33510111.1112) (41 mg, 51%) as a yellow solid. LCMS (m / z): 258.2 [M+H]+. 'H NMR (400 MHz, DMSO-de) 5 8.21 (s, 1H), 7.20 (d, J = 1.4 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 5.40 (d, J = 1.6 Hz, 1H), 5.04 (t, J = 1.6 Hz, 1H), 4.68 - 4.62 (m, 2H), 3.93 (s, 3H), 3.12 - 3.07 (m, 2H), 3.04 - 2.99 (m, 2H), 2.96 - 2.90 (m, 2H), 2.14 (s, 3H).

[0548] Example 62 (1-113 & 1-114)Eluting fraction 1 & 2 From eluting fraction 1 & 2

[0549] Step 1. To a solution of tert-butyl 8-acetyl-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate prepared as in example 41 (300 mg, 0.9 mmol) in MeOH (5 mL) at room temperature was added NaBH (69 mg, 1.82 mmol). The reaction was stirred at room temperature for 2 h. Tire mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. Hie residue obtained was purified by prep-TLC (DCM: MeOH =15 / 1) to afford racemic tert-butyl 8-(l- hydroxyethyl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate which was subjected to chiral resolution to separate the enantiomers (Column: Daicel IG (30 mm x 250mm, 10pm); Mobile Phase A: Liquid CO2, Mobile Phase B: EtOH; Flow7rate: 55 mL / min; Gradient: 65% A for 6 mins; Wavelength: 214 nm; Sample Solvent: MeOH (4 mL), Injection volume: 0.4 mL). Analytical chiral HPLC (Column: Daicel IG (3 mm x 100mm. 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: EtOH; Flow7rate: 1 mL / min; Gradient: 65% A for 9 mins; Wavelength: 214 nm; RT1 = 6.772 min, RT2 = 7.913 min).

[0550] Eluting fraction 1 : 45 mg, yellow solid; LCMS (m / z): 332.2 [M+H]+.

[0551] Eluting fraction 2: 45 mg, yellow solid; LCMS (m / z): 332.2 [M+H]+.

[0552] Step 2. A solution of tert-butyl 8-( 1 -hydroxyethyl)- 1,2, 4,5 -tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate eluting fraction 1 from step 1 (40 mg. 0.12 mmol) in HCOOH (2mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and freeze-dried. The residue obtained was dissolved into MeOH (3 mL) and alkalified to pH=8~9 with K2CO3 solid (300 mg). The mixture was stirred at 50 °C overnight. Tire mixture was filtered, concentrated under vacuum and purified by prep-TLC (DCM: MeOH =10 / 1, 1% NH3 H2O), triturated (Et2O / DCM=50 / l) to afford l-(2,3,4.5-tetrahydro-lH-benzo[4.5]imidazo[l,2-d][l,4]diazepin-8-yl)ethan- l-ol from eluting fraction 1 (1-113) (7.2 mg. yield: 25.7 %) as a white solid. LCMS (m / z): 232.2 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 7.51 - 7.47 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.24 - 7.16 (m, 1H), 5.07 (d, J = 4.2 Hz, 1H), 4.87 - 4.78 (m, 1H), 4.36 - 4.24 (m, 2H), 3.19 - 3.09 (m, 2H), 3.02 - 2.87 (m, 4H), 1.36 (d, J = 6.4 Hz, 3H).145BUSINESS.33510111.1

[0553] The same procedure was applied to eluting fraction 2 (45 mg, 0.14 mmol) from step 1 . From eluting fraction 2 l-(2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepin-8-yl)ethan-l-ol (1-114) (5.7 mg, yield: 18.2%) as a white solid. LCMS (m / z): 232.2 [M+H]+; HNMR (400 MHz, DMSO-d6) 57.47 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.06 (d, J = 4.2 Hz, 1H), 4.85 - 4.76 (m, 1H), 4.38 - 4.25 (m, 2H), 3.21 - 3.13 (m, 2H), 3.11 - 2.99 (m, 3H). 2.95 - 2.84 (m, 1H), 1.34 (d, J = 5.8 Hz, 3H).

[0554] E

[0555] Step 1. To a solution of isoamyl nitrite (2.28 g, 19.5 mmol) in MeCN (18 mL) was added I2 (9.89 g, 39.0 mmol) and 4-bromo-5-methyl-2-nitroaniline (900 mg, 3.9 mmol). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 (50 mL), extracted with EtOAc (40 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4, filtered and concentrated. Hie mixture was purified by column chromatography silica gel (pet ether) to afford l-bromo-4-iodo-2-methyl-5-nitrobenzene ( 1.1 g, 82 %) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 8 8.21 (s, 1H), 8.13 (s, 1H), 2.38 (s, 3H).

[0556] Step 2. A solution of tert-butyl 5-oxo-l,4-diazepane-l -carboxylate (301 mg, 1.40 mmol), 1- bromo-4-iodo-2-methyl-5-nitrobenzene (400 mg, 1.17 mmol), R-BINAP (58 mg, 0.093 mmol), Pd(TFA)2(31 mg, 0.093 mmol) and CS2CO3 (534 mg, 1.64 mmol) in toluene (8 mL) was stirred at 80 °C overnight under N2. The mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. Tire mixture was purified by prep-TLC (pet ether: EtOAc=2: 1) to afford tert-butyl 4-(4- bromo-5-methyl-2-nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (320 mg, 63 %) as a yellow solid. LCMS (m / z): 374.0 [M-55]+.146BUSINESS.33510111.1410095-001WG (221124)

[0557] Step 3. To a solution of tert-butyl 4-(4-bromo-5-methyl-2-nitrophenyl)-5-oxo-l ,4-diazepane- 1-carboxylate (320 mg, 0.747 mmol) in toluene (9 mL) and AcOH (6 mL) was added Fe (417 mg, 7.47 mmol). Tire reaction mixture was stirred at 120 °C for 4 h. Tire reaction mixture was filtered. The filtrate was diluted with water (30 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were adjusted pH = 9-10 with K2CO3 solid, washed with water (30 mL) and brine (30 mL), dried over NazSCL, filtered and concentrated. The mixture was purified by prep-TLC (Pet. ether: EtOAc =1: 1) to afford tertbutyl 8-bromo-9-methyl-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (176 mg, 61 %) as an off-yellow solid. LCMS (m / z): 382.1 [M+H]+.

[0558] Step 4. To a solution of tert-butyl 8-bromo-9-methyl-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (90 mg, 0.24 mmol) in DCM (2 mL) was added 4 M HC1 in 1.4-di oxane (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The mixture was triturated with DCM : hexane=l : 1 (10 mL) and freeze-dried to afford 8-bromo-9-methyl-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (I- 115) (73 mg, 97%) as an off-white solid. LCMS (m / z): 280.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 10.10 (brs, 2H), 8.02 (s, 1H), 7.90 (s, 1H), 4.84 - 4.76 (m, 2H), 3.69 - 3.62 (m, 2H), 3.52 (brs. 2H), 3.46 (brs. 2H), 2.50 (s, 3H).

[0559] Additional Exemplary Compounds Prepared via Example 63 Methods147BUSINESS.33510111.1

[0560] Example 64 (1-117)

[0561] Step 1. A mixture of 3-amino-4-nitrobenzonitrile (1 g, 6 mmol) and NBS (1.3 g, 7.3 mmol) in MeCN ( 14 mL) was stirred at 50 °C for 3 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 5-amino-2-bromo-4-nitrobenzonitrile (1.8 g, 99 %) as ayellow solid. LCMS (m / z): 241.9 [M+H]+.

[0562] Step 2. To a stirred solution of isoamyl nitrite (4.1 g, 35 mmol) and I2(17.8 g, 70.1 mmol) in MeCN (40 mL) at 60 °C was added a solution of 5-amino-2-bromo-4-nitrobenzonitrile (1.7 g, 7.0 mmol) in MeCN (90 mL) under N2. The reaction mixture stirred at 60 °C under N2for 2 hours. The mixture was diluted with Na^SCL aq. solution (400 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SOi. filtered and concentrated. The residue was purified by column (pet ether / EtOAc=10: 1~5: 1) to afford 2-bromo-5-iodo-4-nitrobenzonitrile (1 g, 41%) as ayellow solid. 'HNMR (400 MHz, DMSO-dd) 8 8.70 (s, 1H), 8.48 (s, 1H).

[0563] Step 3. Amixture of 2-bromo-5-iodo-4-nitrobenzonitrile (500 mg, 1.4 mmol, l.Oeq.), tert-butyl 5 -oxo- L4-diazepane-l -carboxylate (365 mg, 1.75 mmol). (R)-BINAP (70 mg. 0.1 mmol). Pd(CF3COO)2(40 mg, 0.1 mmol) and CS2CO3 (1.09 g, 3.35 mmol) in toluene (12 mL) was stirred at 80 °C overnight under N2in a sealed tube. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude tert- butyl 4-(4-bromo-5-cyano-2-nitrophenyl)-5-oxo-l,4-diazepane-l-carboxylate (540 mg, 99 %) as a yellow solid. LCMS (m / z): 383.0 [M-55]1.

[0564] Step 4. A mixture of tert-butyl 4-(4-bromo-5-cyano-2-nitrophenyl)-5-oxo-l,4-diazepane-l- carboxylate (540 mg, 1.4 mmol) and Fe (790 mg, 14 mmol) in AcOH / toluene (10 mL / 6mL) was stirred at 120 °C for 0.5 hour. The mixture was concentrated, and the residue was diluted with water (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and148BUSINESS.33510111.1410095-001WG (221124) concentrated. The mixture was purified by prep-HPLC (54% MeCN in H2O (0.1% TFA)) to afford tertbutyl 8-bromo-9-cyano-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (80 mg, 14 %) as a white solid. LCMS (m / z): 393.1 [M+H]+.

[0565] Step 5. To a solution of tert-butyl 8-bromo-9-cyano- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (80 mg, 0.2 mmol) in DCM (2 mL) was added 4 M HC1 in 1,4-dioxane (6 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was triturated with DCM / hexane (1 / 10) to afford 8-bromo-2,3,4,5- tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine-9-carbonitrile hydrochloride (1-117) (60.7 mg, 99%) as a white solid. LCMS (m / z): 291.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 9.68 (brs, 2H), 8.38 (s, 1H), 8.09 (s, 1H), 4.70 (d, J = 8.6 Hz, 2H), 3.49 (d, J = 5.6 Hz, 4H), 3.38 (brs, 2H).

[0566] Example 65 (1-118)

[0567] Step 1. To a solution of tert-butyl 8-bromo-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4.5]imidazo[l,2-d][L4]diazepine-3-carboxylate prepared as in example 42 (2 g, 5 mmol). KOH (849.5 mg, 15.14 mmol), Pd2(dbaf (462.2 mg, 0.5047 mmol) and tert-butyl xphos (857.3 mg, 2.019 mmol) in 1,4-dioxane (20 mL) and H2O (20 mL) was stirred at 100 °C for 16 h under N2. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. Tire residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 100: 1—30: 1, v / v) to afford tert-butyl149BUSINESS.33510111.1410095-001WG (221124)8-hydroxy-10-methoxy-L2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (800 mg, 48 % yield) as a yellow solid. LCMS (m / z): 334.2 [M+H]+.

[0568] Step 2. To a solution of tcrt-butyl 8-hydroxy-10-mcthoxy-l,2,4,5-tctrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (800 mg, 2.4 mmol) in DMF (4 mL) at 0 °C was added NaH (60%, 192 mg, 4.80 mmol). The reaction mixture was stirred at 0 °C for 1 h. before addition of CH3I (681.3 mg, 4.80 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over ISfeSCL, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 100: 1—80: 1, v / v) to afford tertbutyl 8,10-dimethoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (580 mg, 69 % yield) as a light yellow solid. LCMS (m / z): 348.3 [M+H]1.

[0569] Step 3. To a solution of tert-butyl 8,10-dimethoxy-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (580 mg, 1.67 mmol) in MeCN (6 mL) was added NIS (450.7 mg, 2.003 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (60 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to obtain the crude product. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 100: 1—80: 1, v / v) to afford tert-butyl 7-iodo-8,10-dimethoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (410 mg, 52 % yield) as a yellow solid. LCMS (m / z): 474.1 [M+H]+.

[0570] Step 4. A solution of tert-butyl 7-iodo-8,10-dimethoxy- 1,2,4, 5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][L4]diazepine-3-carboxylate (180 mg, 0.38 mmol), 4.4.5,5-tetramethyl-2-(prop- l-en-2-yl)-l,3,2-dioxaborolane (76.7 mg. 0.456 mmol), PCy3 (10.7 mg. 0.0382 mmol). Pd(OAc)2 (8.54 mg, 0.0380 mmol), and K3PO4 (242.2 mg, 1.141 mmol) in 1,4-dioxane (4 mL) and H2O (2 mL) was stirred at 80 °C for 16 h under N? in sealed tube. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated to obtain the crude product. Hie residue obtained was purified by prep-TLC (DCM:MeOH=20: Lv / v) to afford tert-butyl 8,10-dimethoxy-7-(prop-l-en-2-yl)-l,2,4,5-tetraliydro-3H- benzo[4.5]imidazo[l,2-d][1.4Jdiazepine-3-carboxylate (65 mg. 45 % yield) as awhite solid. LCMS (m / z): 388.3 [M+H]+.

[0571] Step 5. To a solution of tert-butyl 8,10-dimethoxy-7-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H- benzo[4.5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (50 mg, 0.13 mmol) in MeOH (2 mL) was added Pd / C (10 mg). Hie reaction mixture was stirred at room temperature for 16 h under H2 balloon. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl 7-150BUSINESS.33510111.1410095-001WD (221124) isopropyl-8,10-dimethoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (24 mg, 47 % yield) as a white solid. LCMS (m / z): 390.3 [M+H]+.

[0572] Step 6. To a solution of 7-isopropyl-8,10-dimcthoxy-l,2,4,5-tctrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (36 mg, 0.092 mmol) in DCM (2 mL) was added 4 M HC1 in 1.4-dioxane (2 mL).The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and triturated with DCM (5 mL). The solid was collected by filtration to afford 7- isopropyl-8,10-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine (1-118) (25.7 mg, 85% yield, HC1 salt) as a white solid. LCMS (m / z): 290.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 9.87 (brs, 2H), 6.85 (s, 1H), 5.09 - 5.00 (m, 2H), 3.99 (s, 3H), 3.89 (s, 3H), 3.69 (brs, 2H), 3.65-3.40 (m, 5H). 1.34 (d, J = 4 Hz. 6H).

[0573] Example 66 (1-119)

[0574] Step 1. To a solution of CuCI (167 mg, 1.69 mmol), KF (98 mg, 1.69 mmol) in DMF (1.5 mL) was added TMSCF3(240 mg, 1.69 mmol) under an N3atmosphere. After stirring for Ih at room temperature, a solution oftert-butyl 7-iodo-8,10-dimethoxy-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate prepared as in example 65 (160 mg, 0.33 mmol) in DMF (1.5 mL) was added and the mixture was stirred for 16 h at 120 °C. The reaction mixture was diluted with water (80 mL), extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SCL, filtered and concentrated. The residue was purified by prep-TLC (PE: EA=1 : 1) to give tertbutyl 8,10-dimethoxy-7-(trifluoromethyl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine- 3-carboxylate (70 mg, 50% yield) as an off-white solid. LCMS (m / z): 416.1 | M+H| .

[0575] Step 2. A solution of tert-butyl 8,10-dimethoxy-7-(trifluoromethyl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (70 mg. 0.16 mmol) in DCM (1 mL) and 4 M HCl / dioxane (1 mL) was stirred for 2 h at room temperature. Tire reaction mixture was concentrated, and the residue was triturated with MeCN (3 mL) and freeze-dried to give 8,10-dimethoxy-7-(trifluoromethyl)- 2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][l,4]diazepine hydrochloride (1-119) (31 mg, 58 % yield) as an off-white solid. LCMS (m / z): 316.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 9.82 (brs. 2H), 6.86 (s, IH), 5.04 - 4.97 (m, 2H), 4.06 (s, 3H), 3.96 (s, 3H), 3.55-3.50 (m, 4H), 3.39 (brs, 2H).151BUSINESS.33510111.1

[0576] Example 67 (1-120)

[0577] Step 1. A solution of CuCl (190 mg, 1.92 mmol), KF (111 mg, 1.92 mmol) and TMSCF3 (273 mg, 1.92 mmol) in DMF (2 mL) was stirred at room temperature for 1 h under an N2 atmosphere. A solution of tert-butyl 8-bromo-7-iodo- 10-methoxy- 1 ,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[ 1 ,2-d] [ 1 ,4]diazepine- 3-carboxylate prepared as in example 42 (200 mg. 0.38 mmol) in DMF (2 mL) was added and the mixture was stirred for 16 h at 120 °C. The reaction mixture diluted with water (80 mL). extracted with EtOAc (50 mL x 2). The organic phases were washed with brine (50 mL), dried over Na-SCL. filtered and concentrated. The residue was purified by prep-TLC (PE:EA= 1: 1) to give a mixture of tert-butyl 8-bromo-10-methoxy- 7-(trifluoromethyl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate and tertbutyl 8-chloro-10-methoxy-7-(trifluoromethyl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2- d][l,4]diazepine-3-carboxylate (60 mg, 34.8% yield) as a white solid. LCMS (m / z): 420.0 [M+H]+and 467.0 [M+H]+.

[0578] Step 2. A solution of amixture oftert-butyl 8-bromo-10-methoxy-7-(trifluoromethyl)-l,2,4,5- tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate and tert-butyl 8-chloro-10- methoxy-7-(trifluoromethyl)-l,2,4,5-tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3- carboxylate (60 mg, 0.13 mmol), Pd / C (6 mg), Pd(OH)2 (6 mg) in MeOH (4 mL) was stirred for 4 h at 40 °C under an H2 balloon. The reaction mixture was filtered and concentrated. The residue was purified by prep-TLC (PE:EA=1: 1) to give tert-butyl 10-methoxy-7-(trifluoromethyl)-L2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (30 mg, 34.8%yield) as a white solid. LCMS (m / z): 386.1 [M+H]+.

[0579] Step 3. A solution of tert-butyl 10-methoxy-7-(trifluoromethyl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][1.4]diazepine-3-carboxylate (30 mg, 0.078 mmol) in DCM (1 mL) and 4 M HCl / dioxane ( 1 mL) was stirred for 2 h at room temperature. The reaction mixture was concentrated to give 10-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydro-lH-benzo[4,5]imidazo[l,2-d][ l,4]diazepine hydrochloride (1-120) (20 mg, 98 % yield) as a white solid. LCMS (m / z): 286.1 [M+H]+. 'H NMR (400152BUSINESS.33510111.1410095-001WD (221124)MHz, DMSO-dfi) 5 9.76 (brs, 2H), 7.52 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.05 - 4.98 (m, 2H), 4.00 (s, 3H), 3.51 (dd, J = 10.8, 6.2 Hz, 4H), 3.36 (d, J = 7.6 Hz, 2H).

[0580] Example 68 (1-121)As an isolated by-product

[0581] Step 1. A solution of tert-butyl 10-methoxy-8-(prop-l-en-2-yl)-l,2,4,5-tetrahydro-3H- benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate prepared as in example 54 (100 mg, 0.280 mmol), OsO4(7.11 mg, 0.0279 mmol), NMO (65.55 mg, 0.5595 mmol) and NaIO4(239.35 mg, 1.1190 mmol) in THF / H2O (3 mL / 1 mL) was stirred at room temperature for 3h. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). Tire combined organic phases were washed with water (15 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE:EA= 1 : 1) to afford tert-butyl 8-acetyl- 10-methoxy- 1 ,2,4,5-tetrahydro-3EI-benzo[4,5]imidazo[ 1 ,2-d] [ 1 ,4]diazepine-3- carboxylatc (97 mg, 96 %) as a white solid. LCMS (m / z): 360.1 [M+H]+.

[0582] Step 2. To a solution of tert-butyl 8-acetyl-10-methoxy-l,2,4,5-tetrahydro-3H- benzo[4.5]imidazo[l,2-d][L4]diazepine-3-carboxylate (107 mg. 0.298 mmol) in THF (2 mL) at -78 °C was added MeMgBr (0.2977 mL, 0.8931 mmol) under N2. After stirring at -78 °C for 2 h, the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water (20 mL x 3). dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM: MeOH= 15: 1) to afford tert-butyl 8-(2-hydroxypropan-2-yl)-10-methoxy-l, 2,4,5- tetrahydro-3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (58 mg, 52%) as a white solid. LCMS (m / z): 376.1 [M+Hf.

[0583] Step 3. To a solution of tert-butyl 8-(2-hydroxypropan-2-yl)-10-methoxy-l,2,4,5-tetrahydro- 3H-benzo[4,5]imidazo[l,2-d][l,4]diazepine-3-carboxylate (160 mg, 0.426 mmol) in DCM (...

Claims

1. CLAIMS1. A compound of formula I :I or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4; each of R1, R2, R3, or R4is independently selected from hydrogen, halogen, -CN, -OR’, -NR2, -C(O)R, - C(0)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1-6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R1and R2, R2and R3, or R3and R4may be taken together to form an optionally substituted fused ring selected from a 3- to 8-mcmbcrcd partially unsaturated carbocyclyl or hctcrocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R5is hydrogen or an optionally substituted group selected from C1-6 aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R6is hydrogen or optionally substituted C1-6 aliphatic; each R7is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic; or two R7groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R7groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged carbocyclyl or bridged heterocyclyl having 1-164BUSINESS.33510111.1410095-001WG (221124)3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently hydrogen or optionally substituted Ci-6 aliphatic; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound of claim 1, wherein X1is N.

3. The compound of claim 1, wherein X1is CR1.

4. Tire compound of any one of claims 1-3, wherein X2is N.

5. The compound of any one of claims 1-3, wherein X2is CR2.

6. The compound of any one of claims 1-5, wherein X3is N.

7. Tire compound of any one of claims 1-5, wherein X3is CR3.

8. The compound of any one of claims 1-7, wherein X4is N.

9. The compound of any one of claims 1-7, wherein X4is CR4.

10. Tire compound of claim 1, wherein the compound is of formulae Il-a, Il-b, II-c, Il-d, or Il-e:165BUSINESS.33510111.1410095-001WG (221124)11. The compound of any one of claims 1-10, wherein R6is hydrogen.

12. The compound of any one of claims 1-10, wherein R6is optionally substituted Ci .6 aliphatic.

13. Tire compound of any one of claims 1-10, wherein R6is hydrogen or methyl.

14. The compound of any one of claims 1-10, wherein the compound is of formulae Ill-a, Ill-b. III- c, Ill-d. Ill-e. IV-a. IV-b. IV-c. IV-d. or IV-e:166BUSINESS.33510111.1BUSINESS.33510111.1or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1-14, wherein n is 0 or 1.

16. Tire compound of any one of claims 1-14, w herein each R7is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Cue aliphatic.

17. The compound of any one of claims 1-16. wherein R7is hydrogen or methyl.

18. The compound of any one of claims 1-14, wherein two R7groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

19. The compound of any one of claims 1-14, wherein two R7groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged carbocyclyl or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxy gen, or sulfur.

20. The compound of any one of claims 1-18. wherein the compound is of formulae V-a. V-b, V-c. V- d, V-e, Vi a, VLb, VI-c, Vl-d, or Vl-e:168BUSINESS.33510111.1BUSINESS.33510111.1or a pharmaceutically acceptable salt thereof.

21. Tire compound of any one of claims 1-15, wherein the compound is of formulae Vll-a, VH-b, VII- c, Vll-d, VH-e, Vill a, Vlll-b, VIII-c, Vlll-d, or Vlll-e:170BUSINESS.33510111.1or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1-21, wherein each of R1, R2. R3. or R4is independently selected from hydrogen, halogen, -CN, -OR5, -NR2, -C(O)R, -C(0)NR2, -C(O)OR -NRC(O)R -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or171BUSINESS.33510111.1sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

23. Tire compound of any one of claims 1-22, wherein R1is selected from hydrogen, fluoro, chloro, - CN, -OR5, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

24. Tire compound of any one of claims 1-22, wherein R1is hydrogen.

25. The compound of any one of claims 1-22. wherein R1is fluoro, chloro, or bromo.

26. The compound of any one of claims 1-22, wherein R1is -CN.

27. Tire compound of any one of claims 1-22, wherein R1is -OR5.

28. The compound of claim 27, wherein R5is hydrogen or an optionally substituted C1-6 aliphatic.

29. The compound of any one of claims 1-22, wherein R1is -NR2.

30. Tire compound of any one of claims 1-22, wherein R1is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

31. The compound of any one of claims 1-22. wherein R1is optionally substituted Ci-6 aliphatic.

32. The compound of claim 31, wherein R1is Ci-e aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or C’u, aliphatic.

33. The compound of any one of claims 1-22, wherein R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

34. Tire compound of any one of claims 1-22, wherein R1is an optionally substituted 3- to 6-mcmbcrcd saturated or partially unsaturated carbocyclyl.172BUSINESS.33510111.

135. The compound of any one of claims 1-22, wherein R1is an optionally substituted oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

36. The compound of any one of claims 1-22, wherein R1is phenyl.

37. The compound of any one of claims 1-22, wherein R1is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

38. Tire compound of any one of claims 1-22, wherein R1is hydrogen, fluoro, chloro, bromo, -CN, - OH, -OCHs, -OCH2CH3, -OCH(CH3)2, -OCF3, -NH2, -C(0)NH2, methyl, ethyl, n-propyl, isopropyl, n-39. Tire compound of any one of claims 1-38, wherein R2is selected from hydrogen, fluoro, chloro, - CN, -OR5, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

40. Tire compound of any one of claim 1-38, wherein R2is hydrogen.

41. The compound of any one of claims 1-38. wherein R2is fluoro, chloro, or bromo.

42. The compound of any one of claims 1-38, wherein R2is -CN.

43. Tire compound of any one of claims 1-38, wherein R2is -OR5.

44. The compound of claim 43, wherein R5is hydrogen or an optionally substituted C1-6 aliphatic.173BUSINESS.33510111.

145. The compound of any one of claims 1-38, wherein R2is -NR2.

46. Tire compound of any one of claims 1-38, wherein R2is -C(0)NR2, -C(O)OR, -NRC(O)R, - OC(O)R.

47. The compound of any one of claims 1-38, wherein R2is optionally substituted Cue aliphatic.

48. Tire compound of claim 47, wherein R2is Ci-e aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Cue aliphatic.

49. The compound of any one of claims 1-38, wherein R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

50. The compound of any one of claims 1-38, wherein R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl.

51. The compound of any one of claims 1-38, wherein R2is an optionally substituted oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

52. The compound of any one of claims 1-38, wherein R2is phenyl.

53. The compound of any one of claims 1-38, wherein R2is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

54. Tire compound of any one of claims 1-38, wherein R2is hydrogen, fluoro, chloro, bromo, -CN, - OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -NH2, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n- butyl, s-butyl,2 , 2 3. 2 3,174BUSINESS.33510111.

155. The compound of any one of claims 1-54, wherein R3is selected from hydrogen, fluoro, chloro, - CN, -OR5, -NR3, -C(O)R, -C(0)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

56. The compound of any one of claim 1-54, wherein R3is hydrogen.

57. Tire compound of any one of claims 1-54, wherein R3is fluoro, chloro, or bromo.

58. The compound of any one of claims 1-54. wherein R3is -CN.

59. The compound of any one of claims 1-54, wherein R3is -OR5.

60. Tire compound of claim 59, wherein R5is hydrogen or an optionally substituted Ci-e aliphatic.

61. The compound of any one of claims 1-54. wherein R3is -NR2.

62. The compound of any one of claims 1-54, wherein R3is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

63. The compound of any one of claims 1-54, wherein R3is optionally substituted Cue aliphatic.

64. The compound of claim 63. wherein R3is Cue aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Cue aliphatic.

65. Tire compound of any one of claims 1-54, wherein R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently- selected from nitrogen, oxygen, or sulfur.175BUSINESS.33510111.1410095-001WG (221124)66. The compound of any one of claims 1-54, wherein R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl.

67. The compound of any one of claims 1-54, wherein R3is an optionally substituted oxetanyl, tetrahydrofuranyl. or tetrahydropyranyl.

68. The compound of any one of claims 1-54, wherein R3is phenyl.

69. Tire compound of any one of claims 1-54, wherein R3is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

70. The compound of any one of claims 1-54, wherein R3is hydrogen, fluoro, chloro, bromo, -CN, - OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -NH2, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n-71. The compound of any one of claims 1-70, wherein R4is selected from hydrogen, fluoro, chloro, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

72. The compound of any one of claim 1-70, wherein R4is hydrogen.

73. The compound of any one of claims 1-70, wherein R4is fluoro, chloro, or bromo.

74. Tire compound of any one of claims 1-70, wherein R4is -CN.176BUSINESS.33510111.

175. The compound of any one of claims 1-70, wherein R4is -OR5.

76. Tire compound of claim 75, wherein R5is hydrogen or an optionally substituted Ci-e aliphatic.

77. The compound of any one of claims 1-70, wherein R4is -NR2.

78. The compound of any one of claims 1-70, wherein R4is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

79. Tire compound of any one of claims 1-70, wherein R4is optionally substituted Cue aliphatic.

80. The compound of claim 79. wherein R4is Ci-6 aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Ci-e aliphatic.

81. Tire compound of any one of claims 1-70, wherein R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

82. The compound of any one of claims 1-70, wherein R4is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl.

83. The compound of any one of claims 1-70, wherein R4is an optionally substituted oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

84. The compound of any one of claims 1 -70, wherein R4is phenyl.

85. Tire compound of any one of claims 1-70, wherein R4is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

86. The compound of any one of claims 1-70, wherein R4is hydrogen, fluoro, chloro, bromo, -CN, - OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -NH2, -C(O)NH2, methyl, ethyl, n-propyl, isopropyl, n- butyl, s-butyl,2 , 2 3, 2 3,177BUSINESS.33510111.

187. Tire compound of any one of claims 1-21, wherein R1and R2may be taken together to form an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

88. The compound of any one of claims 1-21 or 87, wherein R1and R2may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

89. The compound of any one of claims 1-21 or 87-88, wherein R1and R2may be taken together to fomr an optionally substituted fused90. The compound of any one of claims 1-21 or 87-88, wherein R1and R2may be taken together to fonn an optionally substituted fused91. The compound of any one of claims 1-21, wherein R2and R3may be taken together to form an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

92. The compound of any one of claims 1-21 or 91. wherein R2and R3may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.178BUSINESS.33510111.

193. The compound of any one of claims 1-21 or 91-92, wherein R2and R3may be taken together to form an optionally substituted fused94. The compound of any one of claims 1-21 or 91-92, wherein R2and R3may be taken together to form an optionally substituted fused95. The compound of any one of claims 1-21, wherein R3and R4may be taken together to form an optionally substituted fused ring selected from a 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, benzo, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

96. The compound of any one of claims 1-21 or 95, wherein R3and R4may be taken together to form an optionally substituted fused 3- to 8-membered partially unsaturated carbocyclyl or heterocyclyl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur.

97. The compound of any one of claims 1-21 or 95-96, wherein R3and R4may be taken together to form an optionally substituted fused98. The compound of any one of claims 1-21 or 95-96, wherein R3and R4may be taken together to form an optionally substituted fused99. The compound of claim 1, wherein the compound is of Table 1, or a pharmaceutically acceptable salt thereof.

100. A pharmaceutical composition comprising a compound of any one of claims 1-99, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.179BUSINESS.33510111.1410095-001WG (221124)101. A method of activating 5-HT2AR, or a mutant thereof, in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 100.

102. A method of increasing activation of a G protein signaling pathway associated with 5 -HT2 AR over a 0-arrestin signaling pathway associated with 5-HT2AR in a biological sample, comprising administering to the biological sample a compound of any one of claims 1-99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 100.

103. A method of selectively activating 5-HT2AR, or a mutant thereof, (e.g., over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 100.

104. A method of activating 5-HT2AR, or a mutant thereof, in a patient comprising administering a compound of any one of claims 1-99, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 100.

105. A method of increasing activation of a G protein signaling pathway associated with 5 -HT2 AR over a 0-arrestin signaling pathway associated with 5-HT2AR in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-99, or a pharmacally acceptable salt thereof, or a pharmaceutical composition of claim 100.

106. A method of selectively activating 5-HT2AR, or a mutant thereof, (e.g., over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) in a patient comprising administering a compound of any one of claims 1-99, or a pharmacally acceptable salt thereof, or a pharmaceutical composition of claim 100.

107. A method for treating a 5-HT2AR-mediated disorder comprising administering to a patient a compound of any one of claims 1-99, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 100.180BUSINESS.33510111.1108. A method for treating a neurological disease, disorder, or condition comprising administering to a patient a compound of any one of claims 1-99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 100.

109. The method of claim 108, wherein neurological disease, disorder, or condition is depression, anxiety, substance abuse, and headaches.

110. The method of any one of claims 104-109, wherein the patient does not experience a hallucinogenic effect as a result of the activating or treating.181BUSINESS.33510111.1

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