F-ATP hydrolase inhibitors

Abstract

The present disclosure provides compounds and pharmaceutical compositions that inhibit F-ATP hydrolase and methods for treating a disease or condition associated with F-ATP hydrolase.

Description

Attorney Docket No.2019292-0022 F-ATP HYDROLASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 675,224, filed July 24, 2024, the entirety of which is incorporated herein by reference. BACKGROUND

[0002] Mitochondria are essential organelles to all eukaryotic cells. Mitochondria generate ATP and meet most of the cell’s energy requirements via an oxidative phosphorylation (OXPHOS) pathway. This is carried out by five protein complexes (complexes I-V).

[0003] F1F0-ATPase (also known as F-ATPase, complex V, F1F0-ATP synthase, and F1F0-ATP hydrolase) is a multi-component, membrane-associated protein complex that catalyzes the phosphorylation of ADP to ATP in the mitochondria. ATP synthases are present in all living organisms, and are located in the membranes of mitochondria, bacteria, and chloroplast thylakoids as well as on the surfaces of various cell types (e.g., endothelial cells, keratinocytes and adipocytes). F1F0-ATPase is a component of the mitochondrial electron transport chain (ETC) and utilizes a proton motive force generated by complexes I-IV to produce ATP (synthase function). Under conditions where the mitochondrial membrane potential is disrupted, such as by lack of oxygen or inhibition of Complex I, the F-ATPase attempts to restore the membrane potential by pumping protons back across the membrane at the expense of ATP (hydrolase function). This ATP wasting event is detrimental to cellular viability and is particularly harmful to neurons in deep brain regions most impacted in a variety of neurodegenerative diseases. SUMMARY

[0004] In some embodiments, the present disclosure provides the recognition that F1F0- ATP synthase is reversible, where complex V operates in the reverse direction to hydrolyze ATP to ADP with the help of F-ATP hydrolase, which can result in mitochondrial dysfunction. Because mitochondrial function is essential to human health, there remains a need to understand and treat diseases associated with mitochondrial dysfunction. For example, the broad role of mitochondria in health and disease is supported by the mitochondrial dysfunction association with a number of disorders. Such disorders include idiopathic neurodegenerative disorders, mitochondrial diseases (e.g., neuropathies, epilepsies, and cardiomyopathies), neurodegenerative 12886058v1 Page 1 of 494Attorney Docket No.2019292-0022 disorders, metabolic syndrome, cancer, and obesity. Accordingly, in some embodiments, the present disclosure provides compounds, compositions, and methods for treating a disease associated with mitochondrial dysfunction such as, for example, idiopathic neurodegenerative disorders, mitochondrial diseases (e.g., neuropathies, epilepsies, and cardiomyopathies), neurodegenerative disorders, metabolic syndrome, cancer, and obesity. Without wishing to be bound by any particular theory, a growing body of evidence suggests that mitochondrial abnormalities increase with age and in age-related diseases. Examples of such age-related diseases include Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia. In some embodiments, the present disclosure also provides compounds, compositions, and methods for inhibiting F-ATP hydrolase.

[0005] In some embodiments, the present disclosure provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, L1, L2, Rx, and m is as defined herein.

[0006] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] In some embodiments, the present disclosure provides a method of inhibiting F- ATP hydrolase, the method comprising contacting a biological sample with a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the present disclosure provides a method of treating a disease or condition associated with dysregulation of F-ATP hydrolase. In some such 12886058v1 Page 2 of 494Attorney Docket No.2019292-0022 embodiments, a disease or condition associated with dysregulation of F-ATP hydrolase is selected from Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia. In some such embodiments, a method of treating a disease or condition associated with dysregulation of F-ATP hydrolase comprises administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the present disclosure provides a method of treating a disease or condition associated with mitochondrial dysfunction. In some such embodiments, a disease or condition associated with mitochondrial dysfunction is selected from Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia. In some such embodiments, a method of treating a disease or condition associated with mitochondrial dysfunction comprises administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in medicine.

[0011] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in inhibiting F-ATP hydrolase in a biological sample. In some embodiments, the use is in vitro.

[0012] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition associated with F-ATP hydrolase.

[0013] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with F-ATP hydrolase. DETAILED DESCRIPTION Definitions 12886058v1 Page 3 of 494Attorney Docket No.2019292-0022

[0014] Aliphatic: The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. 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.

[0015] Alkyl: The term “alkyl” refers to a C1-6 straight or branched saturated aliphatic straight or branched chain. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0016] In some embodiments, an alkyl group is deuterated. In some embodiments and alkyl group is fluorinated.

[0017] Alkylene: The term “alkylene” refers to a bivalent saturated aliphatic group. In some embodiments, 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. In some embodiments, an alkylene chain can be a branched bivalent saturated aliphatic chain such as, for example, -CH(CH3)-. 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.

[0018] Alkenyl: The term “alkenyl”, as used herein, refers to a C2-6straight or branched aliphatic straight or branched chain that contains one or more double bond. Non-limiting examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0019] Alkynyl: The term “alkynyl”, as used herein, refers to a C2-6 straight or branched aliphatic straight or branched chain that contains one or more triple bond. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0020] Aryl: The term “aryl” refers to monocyclic and 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 three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present 12886058v1 Page 4 of 494Attorney Docket No.2019292-0022 disclosure, “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 wherein the point of attachment is on the aryl ring. Such groups include, for example, indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.

[0021] Biological sample: 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.

[0022] Carbocyclic: In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 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.

[0023] Cyano: The term “cyano” means a monovalent functional group, -CN, where a carbon atom is triple-bonded to a nitrogen atom.

[0024] Halogen: The term “halogen” means F, Cl, Br, or I.

[0025] Heteroaryl: The terms “heteroaryl” and “heteroar–” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π 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, and sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “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, 12886058v1 Page 5 of 494Attorney Docket No.2019292-0022 cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl. A heteroaryl group may be mono– or bicyclic. 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.

[0026] Heterocyclic: 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–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0027] 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, tetrahydroquinolinyl, and tetrahydroisoquinolinyl where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono– or bicyclic.

[0028] Heteroatom: The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic 12886058v1 Page 6 of 494Attorney Docket No.2019292-0022 ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N- substituted pyrrolidinyl)).

[0029] Optionally substituted: As described herein, compounds provided herein may contain “optionally 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 are replaced with a suitable substituent. 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 formation of stable or chemically feasible compounds. The 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 or more of the purposes disclosed herein.

[0030] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; – N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; – C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°, SC(S)SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; – P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4 straight or branched alkylene)O– N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be 12886058v1 Page 7 of 494Attorney Docket No.2019292-0022 substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 3–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and 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, and sulfur, which may be substituted as defined below.

[0031] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, – (CH ) SR^, –(CH ) SH, –(^^ ^ 2 0–2 2 0–2 CH2)0–2NH2, –(CH2)0–2NHR , –(CH2)0–2NR 2, –NO2, –SiR 3, – OSiR^3, -C(O)SR^ , –(C1–4 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0032] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =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 independent6aliphatic 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, and 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, C1–6 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, and sulfur. 12886058v1 Page 8 of 494Attorney Docket No.2019292-0022

[0033] 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^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0034] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR† 2, –C(S)NR† 2, –C(NH)NR† 2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, and 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 aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0035] 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 C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0036] “Optional cyclization”: As used herein, the term “optional cyclization” refers to formation of a ring by connecting two substituents in a molecule. The term “optional cyclization” may be used interchangeably with the term “optionally cyclize”. “Optional cyclization” may result in formation of a saturated, partially unsaturated, or aryl ring, as valency permits. In certain embodiments of the present disclosure, “optional cyclization” refers to formation of an aromatic ring system which includes, but is not limited to, phenyl, pyridinyl, and the like, which may bear one or more substituents. In other embodiments of the present disclosure, “optional cyclization” refers to formation of a saturated or partially unsaturated ring system which includes, but not limited to dioxolane, and the like, which may bear one or more 12886058v1 Page 9 of 494Attorney Docket No.2019292-0022 substituents. Also included within the scope of the term “optional cyclization”, as it is used herein, is formation of a ring which is fused to one or more rings. In some embodiments, a ring formed through “optional cyclization” may be substituted or unsubstituted. In some embodiments, a ring resulting from “optional cyclization” may be selected fro ,A compound of the present disclosure may only undergo “optional ents as defined herein. For example, in the present disclosure, a ringresulting from “optional cyclization” of R4and Rxmust be composed of substituents as defined herein for R4and Rx.

[0037] Oxo: The term “oxo” means , where an oxygen atom is connected to another atom by a double bond.

[0038] Pharmaceutically acceptable salt: As used herein, the term “pharmaceutically 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. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. It will be understood by persons skilled in the art that a “salt” as the term is used herein can include agents where the proton has been transferred from the acid to the base as well as those instances where there is incomplete proton transfer (for example, where the difference in pKa of the base and acid are similar). The term “salt” as used herein includes all examples where a provided compound is combined with a stoichiometric amount (e.g., 0.5, 1.0, 1.5, 2.0, etc.) of an acid (or base), regardless of whether proton transfer has in fact occurred. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids 12886058v1 Page 10 of 494Attorney Docket No.2019292-0022 such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0039] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0040] 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 disclosure. Unless otherwise stated, all tautomeric forms of the compounds provided herein are within the scope of the disclosure. For example, a structure drawn as one tautomer is intended to encompass another tautomer. A depiction of imidazole tautomer is intended to encompass the other tautom .12886058v1 Page 11 of 494Attorney Docket No.2019292-0022Similarly, a depiction of pyridin-2(1H)-one ( ) is intended to encompass pyridin-2-ol( ). Additionally, unless otherwise stated, structures depicted herein are also meant toinclude 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 disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0041] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0042] Patient: The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[0043] Pharmaceutically acceptable carrier: The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers that may be used in the compositions of this disclosure 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.

[0044] Spirocyclic: In some embodiments, “spirocyclic” refers to a 7- to 11-membered fused bicyclic (i.e., carbocyclic or heterocyclic) ring system, which is saturated or has one or 12886058v1 Page 12 of 494Attorney Docket No.2019292-0022 more units of unsaturation, and wherein the two rings of the ring system share one carbon atom at the ring juncture. Compounds

[0045] Compounds provided herein include those described generally above, 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 this disclosure, 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 are hereby incorporated by reference.

[0046] In some embodiments, the present disclosure provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: L1is selected from a bond, -C(O)-, or C1-4alkylene; ,12886058v1 Page 13 of 494Attorney Docket No.2019292-0022 Y is selected from NH, N-Ra, O, or S; Rais selected from C1-4 aliphatic or a 3- to 5-membered saturated carbocyclic ring; L2is selected from a bond or a C1-4 alkylene wherein one methylene unit is optionally replaced by -O- or -C(O)-; R2is selected from C1-6 aliphatic or Cy, wherein R2is substituted with 0-3 instances of Rw; Cy is selected from a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 8- to 10-membered saturated, partially unsaturated, or aryl bicyclic carbocyclic ring, a 7- to 9-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-to 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3is selected from ; each R4is indepen, , , R)2, and an optionally substituted group selected from C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10- membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5is selected from C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8- membered bridged bicyclic carbocyclic ring, phenyl, a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 7- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered 12886058v1 Page 14 of 494Attorney Docket No.2019292-0022 heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is substituted with 0-3 instances of Rz; each R6is independently hydrogen or C1-6 aliphatic; each Rwis independently selected from halogen, cyano, oxo, -OR, -SR, -N(R)2, -C(O)R, - C(O)OR, -C(O)N(R)2, -OC(O)R, -N(R)C(O)R, and an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Rxis selected from hydrogen, halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: Rxand R4optionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ryis independently selected from halogen, -N(R)2, and an optionally substituted group selected from C1-4 alkyl and a 3- to 6-membered saturated carbocyclic ring; each Rzis independently selected from halogen, cyano, -OR, and optionally substituted C1-4alkyl; each R is independently selected from hydrogen and an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; and 12886058v1 Page 15 of 494Attorney Docket No.2019292-0022 n is 0-2.

[0047] In some embodiments, the present disclosure provides a compound selected from formulae I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, I-h-ii, I-j, I-j-i, and I-j-ii:12886058v1 Page 16 of 494Attorney Docket No.2019292-0022 I-d I-d-i I-d-ii R4R4R4R412886058v1 Page 17 of 494Attorney Docket No.2019292-0022 or af the below embodiments apply equally to any one of formulae I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I- f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, I-h-ii, I-j, I-j-i, and / or I-j-ii.

[0049] As defined generally above, L1is selected from a bond, -C(O)-, or C1-4alkylene.

[0050] In some embodiments, L1is a bond.

[0051] In some embodiments, L1is -C(O)-.

[0052] In some embodiments, L1is C1-4 alkylene. In some embodiments, L1is C1-2 alkylene. In some embodiments, L1is C3-4alkylene. In some embodiments, L1is C2-3alkylene. In some embodiments, L1is -CH2-. In some embodiments, L1is -CH(CH3)-.

[0053] In some embodiments, L1is selected from a bond, -C(O)-, -CH2-, or -CH(CH3)-. .12886058v1 Page 18 of 494Attorney Docket No.2019292-0022 In some embodiments, R1is selected fro . In someembodiments, R1is selected from In some embodiments, R1ted

[0055] In some embodiments, R1i . In some embodiments, R1. In some embodiments .

[0056] In some embodiments .

[0057] In some embodiments .1 is12886058v1 Page 19 of 494Attorney Docket No.2019292-0022

[0059] In some embodiments .

[0060] In some embodiments .

[0061] In certain embodimenlae I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-d, I-d-i, I-d-ii, I-e, or I-f, R1is selected from orm:

[0063] In some embodiments, R1is selected from:12886058v1 Page 20 of 494Attorney Docket No.2019292-0022

[0064] As defined generally above, Y is selected from NH, N-Ra, O, or S. In some embodiments, Y is NH, O, or S.

[0065] In some embodiments, Y is NH.

[0066] In some embodiments, Y is N-Ra.

[0067] In some embodiments, Y is O.

[0068] In some embodiments, Y is S.

[0069] As defined generally above, Rais selected from C1-4 aliphatic or a 3- to 5- membered saturated carbocyclic ring.

[0070] In some embodiments, Rais C1-4aliphatic. In some embodiments, Rais C1-3aliphatic. In some embodiments, Rais C2-3 aliphatic. In some embodiments, Rais methyl, ethyl, isopropyl, or tert-butyl.

[0071] In some embodiments, Rais a 3- to 5-membered saturated carbocyclic ring. In some embodiments, Rais a 3- to 4-membered saturated carbocyclic ring. In some embodiments, Rais cyclopropyl.

[0072] In some embodiments, Rais selected from C1-4aliphatic or cyclopropyl. 12886058v1 Page 21 of 494Attorney Docket No.2019292-0022

[0073] As defined generally above, L2is selected from a bond or a C1-4alkylene wherein one methylene unit is optionally replaced by -O- or -C(O)-.

[0074] In some embodiments, L2is a bond.

[0075] In some embodiments, L2is C1-4alkylene wherein one methylene unit is optionally replaced by -O- or -C(O)-. In some embodiments, L2is C1-4 alkylene wherein one methylene unit is optionally replaced by -O-. In some embodiments, L2is C1-4 alkylene wherein one methylene unit is optionally replaced by -C(O)-. In some embodiments, L2is C1-4alkylene. In some embodiments, L2is C1-3 alkylene. In some embodiments, L2is -CH2CH2CH2-. In some embodiments, L2is C1-2 alkylene. In some embodiments, L2is -CH2-. In some embodiments, L2is -CH2CH2-. In some embodiments, L2is C1-2alkylene wherein one methylene unit is optionally replaced by -O-. In some embodiments, L2is C1-2alkylene wherein one methylene unit is optionally replaced by -C(O)-. In some embodiments, L2is C1-4 alkylene wherein one methylene unit is replaced by -C(O)-. In some embodiments, L2is C1-4 alkylene wherein one methylene unit is replaced by -O-. In some embodiments, L2is -CH2CH2O-. In some embodiments, L2is C1-2 alkylene wherein one methylene unit is replaced by -C(O)-. In some embodiments, L2is - CH2C(O)-. In some embodiments, L2is C1-2 alkylene wherein one methylene unit is replaced by - O-. In some embodiments, L2is -CH2O-.

[0076] In certain embodiments of any one of formulae I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, or I-e, L2is selected from -CH2-, -CH2O-, -CH2C(O)-, -CH2CH2CH2-, and -CH2CH2O-.

[0077] As defined generally above, R2is selected from C1-6aliphatic or Cy, wherein R2is substituted with 0-3 instances of Rw. In some embodiments, R2is substituted with 0-2 instances of Rw. In some embodiments, R2is substituted with 0-1 instances of Rw. In some embodiments, R2is substituted with 1-2 instances of Rw. In some embodiments, R2is substituted with 1-3 instances of Rw. In some embodiments, R2is substituted with 2-3 instances of Rw. In some embodiments, R2is unsubstituted.

[0078] In some embodiments, R2is C1-6 aliphatic substituted with 0-3 instances of Rw. In some embodiments, R2is C1-6aliphatic substituted with 0-2 instances of Rw. In some embodiments, R2is C1-6 aliphatic substituted with 1-3 instances of Rw. In some embodiments, R2is C1-6 aliphatic substituted with 1-2 instances of Rw. In some embodiments, R2is C1-2 aliphatic 12886058v1 Page 22 of 494Attorney Docket No.2019292-0022 substituted with 1 instance of Rw. In some embodiments, R2is -CH2CN. In some embodiments, R2is C1-6 aliphatic. In some embodiments, R2is C1-4 aliphatic. In some embodiments, R2is C1-2 aliphatic.

[0079] In some embodiments, R2is Cy substituted with 0-3 instances of Rw. In some embodiments, R2is Cy.

[0080] In some embodiments, R2is selected from:

[0081] In some embodiments, R2is selected from: 12886058v1 Page 23 of 494Attorney Docket No.2019292-0022

[0082] As defined generally above, Cy is selected from a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 8- to 10- membered saturated, partially unsaturated, or aryl bicyclic carbocyclic ring, a 7- to 9-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-to 9-membered bridged bicyclic heterocyclic ring 12886058v1 Page 24 of 494Attorney Docket No.2019292-0022 having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments, Cy is a 3- to 6-membered saturated carbocyclic ring. In some embodiments, Cy is a cyclohexyl ring. In some embodiments, Cy is a 3- to 5-membered saturated carbocyclic ring. In some embodiments, Cy is a cyclopropyl ring. In some embodiments, Cy is a cyclobutyl ring. In some embodiments, Cy is a cyclopentyl ring. In some embodiments, Cy is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.

[0084] In some embodiments, Cy is a 5- to 8-membered bridged bicyclic carbocyclic ring. In some embodiments, Cy is an 8-membered bridged bicyclic carbocyclic ring. In some embodiments, Cy is a 5- to 7-membered bridged bicyclic carbocyclic ring. In some embodiments, Cy is a 5-membered bridged bicyclic carbocyclic ring. In some embodiments, Cy is a 6-membered bridged bicyclic carbocyclic ring. In some embodiments, Cy is a 7-membered bridged bicyclic carbocyclic ring. In some embodiments, Cy is a 5-membered bridged bicyclic carbocyclic ring, a 6-membered bridged bicyclic carbocyclic ring, a 7-membered bridged bicyclic carbocyclic ring, or an 8-membered bridged bicyclic carbocyclic ring.

[0085] In some embodiments, Cy is phenyl.

[0086] In some embodiments, Cy is an 8- to 10-membered saturated, partially unsaturated, or aryl bicyclic carbocyclic ring. In some embodiments, Cy is an 8- to 10-membered saturated bicyclic carbocyclic ring. In some embodiments, Cy is a 9-membered saturated bicyclic carbocyclic ring. In some embodiments, Cy is a 7-membered saturated bicyclic carbocyclic ring. In some embodiments, Cy is an 8- to 10-membered partially unsaturated bicyclic carbocyclic ring. In some embodiments, Cy is a 9-membered partially unsaturated bicyclic carbocyclic ring. In some embodiments, Cy is a 10-membered aryl bicyclic carbocyclic ring. In some embodiments, Cy is a 7-membered saturated bicyclic carbocyclic ring or a 9-membered partially unsaturated bicyclic carbocyclic ring.

[0087] In some embodiments, Cy is a 7- to 9-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 7-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, 12886058v1 Page 25 of 494Attorney Docket No.2019292-0022 oxygen, and sulfur. In some embodiments, Cy is a 7-membered spirocyclic ring having 0 heteroatoms.

[0088] In some embodiments, Cy is a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 4- to 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 4- to 6-membered saturated heterocyclic ring having 1 nitrogen atom. In some embodiments, Cy is a 4- to 6-membered saturated heterocyclic ring having 1 oxygen atom. In some embodiments, Cy is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0089] In some embodiments, Cy is a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 4-membered saturated heterocyclic ring having 1 nitrogen atom. In some embodiments, Cy is a 5-membered saturated heterocyclic ring having 1 nitrogen atom. In some embodiments, Cy is a 6-membered saturated heterocyclic ring having 1 nitrogen atom. In some embodiments, Cy is a 6-membered saturated heterocyclic ring having 1 oxygen atom. In some embodiments, Cy is azetidinyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl.

[0090] In some embodiments, Cy is a 7-to 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 7-to 9-membered bridged bicyclic heterocyclic ring having 1 oxygen atom. In some embodiments, Cy is a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 7-membered bridged bicyclic heterocyclic ring having 1 oxygen atom.

[0091] In some embodiments, Cy is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 5- to 6-membered heteroaryl ring having 1 nitrogen atom. In some embodiments, Cy is a 5- 12886058v1 Page 26 of 494Attorney Docket No.2019292-0022 membered heteroaryl ring having 1 sulfur atom. In some embodiments, Cy is a 5-membered heteroaryl ring having 1 nitrogen atom. In some embodiments, Cy is a 5-membered heteroaryl ring having 1 sulfur atom. In some embodiments, Cy is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Cy is a 6-membered heteroaryl ring having 1 nitrogen atom. In some embodiments, Cy is a 6-membered heteroaryl ring having 1 sulfur atom. In some embodiments, Cy is pyridinyl or thiophenyl.

[0092] In some embodiments, Cy is selected from:

[0093] In some embodiments, Cy is selected from: 12886058v1 Page 27 of 494Attorney Docket No.2019292-002212886058v1 Page 28 of 494Attorney Docket No.2019292-0022

[0094] In some embodiments, Cy is selected fro ,.

[0095] As defined generally above, R3is selected fro ,.

[0097] In some embodiments .

[0098] In some embodiments .

[0099] In some embodiments .

[0100] In some embodiments, R is selected from:12886058v1 Page 29 of 494Attorney Docket No.2019292-002212886058v1 Page 30 of 494Attorney Docket No.2019292-0022

[0101] As defined generally above, each R4is independently selected from halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-6aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, each R4is independently selected from halogen, cyano, optionally substituted C1-6aliphatic, -OR, and -N(R)2. In some embodiments, each R4is independently selected from halogen and cyano. In some embodiments, each R4is -OR or - N(R)2. In some embodiments, each R4is a 3- to 6-membered saturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms 12886058v1 Page 31 of 494Attorney Docket No.2019292-0022 independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, each R4is independently selected from halogen, cyano, - CF3, -CHF2, -OCF3, -OMe, and cyclopropyl.

[0104] In certain embodiments of any one of formulae I-a, I-b, or I-d, each R4is independently selected from cyano, optionally substituted C1-6 aliphatic, -OR, -N(R)2, a 3- to 6- membered saturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R4and Rxoptionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0105] In certain embodiments of any one of formulae I-a-i, I-a-ii, I-b-i, I-b-ii, I-d-i, or I-d-ii, each R4is independently selected from cyano, optionally substituted C1-6 aliphatic, -OR, - N(R)2, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R4and Rxoptionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0106] In some embodiments, R4is halogen. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is bromo.

[0107] In some embodiments, R4is cyano.

[0108] In some embodiments, R4is substituted C1-6 aliphatic. In some embodiments, R4is substituted C1-2aliphatic. In some embodiments, R4is -CF3. In some embodiments, R4is - CHF2. In some embodiments, R4is -CH3. 12886058v1 Page 32 of 494Attorney Docket No.2019292-0022

[0109] In some embodiments, R4is -OR. In some embodiments, R4is -OMe. In some embodiments, R4is -OCF3. In some embodiments, R4is -OCHF2.

[0110] In some embodiments, R4is -N(R)2. In some embodiments, R4is -NHMe. In some embodiments, R4is -N(Me)2.

[0111] In some embodiments, R4is a 3- to 6-membered saturated carbocyclic ring. In some embodiments, R4is cyclopropyl.

[0112] In some embodiments, R4is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is a 5-membered heteroaryl ring having 2 nitrogen atoms. In some embodiments, R4is a 5- membered heteroaryl ring having 3 nitrogen atoms.

[0113] In some embodiments, R4is a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is oxetane. In some embodiments, R4is azetidine. In some embodiments, R4is a 6-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen and oxygen.

[0114] In some embodiments, R4is a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is a 7-membered spirocyclic ring having 2 heteroatoms independently selected from nitrogen and oxygen.

[0115] In some embodiments, each R4is independently optionally substituted C1-6aliphatic, -OR or -N(R)2, wherein Rxand R4cyclize to form an optionally substituted 5- to 6- membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0116] In some such embodiments, the ring formed by the cyclization of Rxand R4is a 6- membered aryl ring. In some such embodiments, the ring formed by the cyclization of Rxand R4is an optionally substituted 5- to 6-membered saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 12886058v1 Page 33 of 494Attorney Docket No.2019292-0022

[0117] In some such embodiments, R4and Rxcyclize to form a 6-membered aryl ring having 0 heteroatoms. In some such embodiments, R4and Rxcyclize to form a 6-membered aryl ring having 1 nitrogen atom. In some such embodiments, R4and Rxcyclize to form a 5- membered saturated ring having 2 oxygen atoms, which is substituted with halogen.

[0118] As defined generally above, R5is selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is substituted with 0-3 instances of Rz.

[0119] In some embodiments, R5is substituted with 0-2 instances of Rz. In some embodiments, R5is substituted with 0-1 instances of Rz. In some embodiments, R5is substituted with 1-2 instances of Rz. In some embodiments, R5is substituted with 1-3 instances of Rz. In some embodiments, R5is substituted with 2-3 instances of Rz. In some embodiments, R5is substituted with 3 instances of Rz. In some embodiments, R5is substituted with 2 instances of Rz. In some embodiments, R5is substituted with 1 instance of Rz. In some embodiments, R5is unsubstituted.

[0120] In some embodiments, R5is C1-6aliphatic, substituted with 0-3 instances of Rz. In some embodiments, R5is C1-2aliphatic, substituted with 0-3 instances of Rz. In some embodiments, R5is C1-2 aliphatic, substituted with 3 instances of Rz. In some embodiments, R5is C1-2 aliphatic, substituted with 3 instances of halogen. In some embodiments, R5is C1-2 aliphatic, substituted with 3 instances of fluoro. In some embodiments, R5is CF3.

[0121] In some embodiments, R5is a 3- to 6-membered saturated carbocyclic ring, substituted with 0-3 instances of Rz.

[0122] In some embodiments, R5is a 5- to 8-membered bridged bicyclic carbocyclic ring, substituted with 0-3 instances of Rz. 12886058v1 Page 34 of 494Attorney Docket No.2019292-0022

[0123] In some embodiments, R5is phenyl, substituted with 0-3 instances of Rz. In some embodiments, R5is phenyl, substituted with C1-4 alkyl. In some embodiments, R5is phenyl, substituted with substituted C1-4 alkyl. In some embodiments, R5is phenyl, substituted with substituted C1-2alkyl. In some embodiments, R5is phenyl, substituted with CF3.

[0124] In some embodiments, R5is a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with 0-3 instances of Rz.

[0125] In some embodiments, R5is a 4- to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with 0-3 instances of Rz.

[0126] In some embodiments, R5is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with 0-3 instances of Rz. In some embodiments, R5is a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with 0-3 instances of Rz.

[0127] As defined generally above, each R6is independently hydrogen or C1-6 aliphatic.

[0128] In some embodiments R6is hydrogen.

[0129] In some embodiments R6is C1-6 aliphatic. In some embodiments R6is methyl.

[0130] In some embodiments, each R6is independently hydrogen or methyl.

[0131] As defined generally above, each Rwis independently selected from halogen, cyano, oxo, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -OC(O)R, -N(R)C(O)R, and an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Rwis independently selected from halogen, cyano, oxo, -OR, and C1-6aliphatic. In some embodiments, each Rwis independently selected from fluoro, cyano, oxo, -OCH3, and methyl. 12886058v1 Page 35 of 494Attorney Docket No.2019292-0022

[0132] In some embodiments, Rwis halogen. In some embodiments, Rwis fluoro.

[0133] In some embodiments, Rwis cyano.

[0134] In some embodiments, Rwis oxo.

[0135] In some embodiments, Rwis -OR. In some embodiments, Rwis -OH. In some embodiments, Rwis -OCH3.

[0136] In some embodiments, Rwis C1-6 aliphatic. In some embodiments, Rwis methyl.

[0137] In some embodiments, each Rwis independently selected from fluoro, cyano, oxo, -OH, -OCH3, and methyl.

[0138] As defined generally above, Rxis selected from hydrogen, halogen, cyano, -OR, and an optionally substituted group selected from C1-4alkyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Rxand R4optionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0139] In some embodiments, Rxis selected from hydrogen, halogen, cyano, -OR, - N(R)2, and an optionally substituted group selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Rxand R4optionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0140] In some embodiments, Rxis selected from halogen, cyano, -OR, and an optionally substituted group selected from C1-4 alkyl, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0141] In some embodiments, Rxis selected from halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0142] In some embodiments, Rxis hydrogen. 12886058v1 Page 36 of 494Attorney Docket No.2019292-0022

[0143] In some embodiments, Rxis selected from halogen, cyano, -OR, and an optionally substituted group selected from C1-4 alkyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Rxand R4optionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] In some embodiments, Rxis selected from halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a 3- to 6- membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Rxand R4optionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0145] In some embodiments, Rxis selected from halogen, cyano, -OR, and an optionally substituted group selected from C1-4alkyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments, Rxis selected from halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a 3- to 6- membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0147] In some embodiments, Rxis halogen. In some embodiments, Rxis fluoro. In some embodiments, Rxis chloro.

[0148] In some embodiments, Rxis cyano.

[0149] In some embodiments, Rxis C1-4alkyl. In some embodiments, Rxis C1-3alkyl. In some embodiments, Rxis C1-2 alkyl. In some embodiments, Rxis CH3. In some embodiments, Rxis CH2H3. In some embodiments, Rxis (CH2)2CH3. In some embodiments, Rxis substituted C1-4 alkyl. In some embodiments, Rxis substituted C1-2alkyl. In some embodiments, Rxis CF3. 12886058v1 Page 37 of 494Attorney Docket No.2019292-0022

[0150] In some embodiments, Rxis C2-4alkenyl. In some embodiments, Rxis C2-3alkenyl. In some embodiments, Rxis . In some embodiments, Rxis substituted .

[0151] In some embodimenis C2-4 alkynyl. In some embodiments, R3 alkynyl. In some embodiments, Rxis .

[0152] In some embodiments, Rxis -OR. In some embodiments, Rxis -OMe. In some embodiments, Rxis -OH. In some embodiments, Rxis -O(CH2)2OMe. In some embodiments, Rxis -O(CH2)2OH. In some embodiments, Rxis -O(CH2)2N(Me)2. In some embodiments, Rxis - O(CH2)2NH2.

[0153] In some embodiments, Rxis -N(R)2. In some embodiments, Rxis -N(R)2, wherein each R is independently selected from hydrogen and optionally substituted C1-6 aliphatic. In some embodiments, Rxis -N(R)2, wherein each R is independently selected from hydrogen and optionally substituted C1-6aliphatic, wherein a C1-6aliphatic group is optionally substituted with –(CH2)0–4OR°. In some embodiments, Rxis -NH(CH2)2OCH3.

[0154] In some embodiments, Rxis a 3- to 6-membered saturated carbocyclic ring. In some embodiments, Rxis cyclopropyl.

[0155] In some embodiments, Rxis phenyl.

[0156] In some embodiments, Rxis a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rxis a 6-membered heteroaryl having 1 nitrogen atom. In some embodiments, Rxis pyridine.

[0157] In some embodiments, Rxis -OR or an optionally substituted group selected from C1-4 alkyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rxand R4cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0158] In some embodiments, Rxis -OR or an optionally substituted group selected from C1-4alkyl, wherein Rxand R4cyclize to form an optionally substituted 5- to 6-membered 12886058v1 Page 38 of 494Attorney Docket No.2019292-0022 saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0159] In some such embodiments, the ring formed by the cyclization of Rxand R4is a 6- membered aryl ring. In some such embodiments, the ring formed by the cyclization of Rxand R4is an optionally substituted 5- to 6-membered saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0160] In some such embodiments, R4and Rxcyclize to form a 6-membered aryl ring having 0 heteroatoms. In some such embodiments, R4and Rxcyclize to form a 6-membered aryl ring having 1 nitrogen atom. In some such embodiments, R4and Rxcyclize to form a 5- membered saturated ring having 2 oxygen atoms, and substituted with halogen.

[0161] In certain embodiments of any one of formulae I-a, I-a-i, I-b, I-b-i, I-d, I-d-i, I-e or I-f, Rxis selected from halogen, cyano, -OR, and an optionally substituted group selected from C1-4 alkyl, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0162] In certain embodiments of any one of formulae I-a, I-a-i, I-b, I-b-i, I-d, I-d-i, I-e or I-f, Rxis selected from halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] As defined generally above, each Ryis independently selected from halogen, - N(R)2, and an optionally substituted group selected from C1-4alkyl and a 3- to 6-membered saturated carbocyclic ring.

[0164] In some embodiments, each Ryis independently selected from halogen, -N(R)2, and optionally substituted C1-4 alkyl.

[0165] In some embodiments, Ryis halogen. In some embodiments, Ryis bromo. In some embodiments, Ryis chloro.

[0166] In some embodiments, Ryis N(R)2. In some embodiments, Ryis NH2.

[0167] In some embodiments, Ryis C1-4alkyl. In some embodiments, Ryis C1-2alkyl. In some embodiments, Ryis CH3. 12886058v1 Page 39 of 494Attorney Docket No.2019292-0022

[0168] In some embodiments, Ryis substituted C1-4alkyl. In some embodiments, Ryis substituted C1-2 alkyl. In some embodiments, Ryis CF3.

[0169] In some embodiments, Ryis an optionally substituted 3- to 6-membered saturated carbocyclic ring.

[0170] As defined generally above, each Rzis independently selected from halogen, cyano, -OR, and optionally substituted C1-4 alkyl.

[0171] In some embodiments, Rzis halogen. In some embodiments, Rzis fluoro. In some embodiments, Rzis chloro.

[0172] In some embodiments, Rzis cyano.

[0173] In some embodiments, Rzis -OR. In some embodiments, Rzis -OMe.

[0174] In some embodiments, Rzis substituted C1-4alkyl. In some embodiments, Rzis substituted C1-2 alkyl. In some embodiments, Rzis CF3.

[0175] In some embodiments, Rzis C1-4 alkyl. In some embodiments, Rzis tert-butyl. In some embodiments, Rzis iso-propyl. In some embodiments, Rzis C1-2alkyl. In some embodiments, Rzis CH3.

[0176] As defined generally above, each R is independently selected from hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0177] In some embodiments, each R is independently selected from hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R is independently selected from hydrogen or optionally substituted C1-2aliphatic.

[0178] In some embodiments R is hydrogen.

[0179] In some embodiments, R is C1-6 aliphatic. In some embodiments, R is C1-2 aliphatic. In some embodiments, R is CH3. 12886058v1 Page 40 of 494Attorney Docket No.2019292-0022

[0180] In some embodiments, R is substituted C1-6aliphatic. In some embodiments, each R is independently C1-6 aliphatic substituted with halogen, -(CH2)0-4OR°, or . -(CH2)0-4N(R°)2. In some embodiments, each R is independently C1-6 aliphatic substituted with halogen, -(CH2)0-2OR°, or . -(CH2)0-2N(R°)2. In some embodiments, each R is independently C1-6aliphatic substituted with halogen, -OR°, or . -N(R°)2. In some such embodiments, R° is C1-6 aliphatic. In some embodiments, R is (CH2)2OMe. In some embodiments, R is (CH2)2OH. In some embodiments, R is (CH2)2N(Me)2. In some embodiments, R is (CH2)2NH2. In some embodiments, R is substituted C1-2 aliphatic. In some embodiments, R is CF3. In some embodiments, R is CHF2.

[0181] As defined generally above, m is 0-3. In some embodiments, m is 0-2. In some embodiments, m is 0-1. In some embodiments, m is 1-3. In some embodiments, m is 1-2. In some embodiments, m is 2-3.

[0182] In some embodiments, m is 3.

[0183] In some embodiments, m is 2.

[0184] In some embodiments, m is 1.

[0185] In some embodiments, m is 0.

[0186] In certain embodiments of any one of formulae I-a, I-b, or I-d, m is 1-3.

[0187] As defined generally above, n is 0-2. In some embodiments, n is 0-1. In some embodiments, n is 1-2.

[0188] In some embodiments, n is 2.

[0189] In some embodiments, n is 1.

[0190] In some embodiments, n is 0.

[0191] In some embodiments, compounds of formula I are prepared according to the general syntheses depicted in General Schemes A-G.

[0192] General Scheme A 12886058v1 Page 41 of 494Attorney Docket No.2019292-0022 R R2O OxRx(R4L2R (R4)m)mR2RxO L2O O R

[0193] p y p p g p n General Scheme A. In this scheme, diamine i is condensed with keto ester ii at elevated temperature, for example 135 ºC, in a suitable solvent, such as toluene (Method A). The resulting product iii is then subjected to reductive hydrolytic conditions with a suitable acid, for example TFA, reducing agent, such as triethylsilane in an appropriate solvent, such as DCE at room temperature (Method B) to afford compounds of formula iv. Cyclization of iv to lactam v is then carried out using suitable hydrolysis conditions, for example NaOMe in methanol at room temperature (Method C). Reduction to diazepane vi is accomplished using a suitable reducing agent, for example LAH in an appropriate solvent, such as THF at room temperature. Alternatively, reduction can also be run using BH3.Me2S in a suitable solvent, such as toluene at elevated temperature, for example 100 ºC (Method D). Diazepane vi can then be converted to vii by standard acylation chemistry by treatment with for example appropriately substituted acyl chloride, acyl anhydride, sulfonyl chloride or sulfonyl anhydride at room temperature in a suitable solvent such as DCM (Method E). Intermediate vii is then converted to compounds of formula I by for example reductive amination by combining with imidazole carboxaldehyde in the presence of an acid such as acetic acid, solvent such as DCM and a reducing agent such as NaBH(OAc)3 at room temperature. 12886058v1 Page 42 of 494Attorney Docket No.2019292-0022

[0194] General Scheme B: 2 O R R 2 O L RxNHN 4NH2RxR4)m

[0195] An alternative exemplary method of preparing compounds of formula I is shown in General Scheme B. In this scheme, ortho-fluorobenzonitrile i undergoes SNAr substitution with amino ester ii at elevated temperature, for example 120 ºC, in a suitable solvent such as DMSO and base like DIEA (Method A). The resulting product iii is then subjected to reductive hydrogenation conditions with a suitable catalyst, for example Ni, base such as TEA, an appropriate solvent such as MeOH and under H2 at sufficient pressure (i.e., 15 PSI) at room temperature (Method B) to afford compounds of formula iv. Cyclization of iv to lactam v is then carried out using suitable conditions, for example NaOMe in methanol at room temperature (Method C). Reduction to diazepane vi is accomplished using a suitable reducing agent, for example LAH in an appropriate solvent such as THF at room temperature. Alternatively, reduction can also be run using BH3.Me2S in a suitable solvent, such as toluene at elevated 12886058v1 Page 43 of 494Attorney Docket No.2019292-0022 temperature, for example 100 ºC (Method D). Racemic vi can then be separated into individual enantiomers using methods common to the art such as by chiral chromatography (e.g., HPLC or SFC) or chral resolution with acid addition salt such as L-tartaric acid to provide the pure enantiomers S-vii or R-vii (Method E). The synthesis can also be initiated with an enantiomerically pure or enriched amino ester ii to generate the desired enantiomer S-vii or R-vii without the need for a chiral resolution. Diazepanes S-vii or R-vii can then be converted to S-viii or R-viii by standard acylation chemistry by treatment with for example appropriately substituted acyl chloride, acyl anhydride, sulfonyl chloride or sulfonyl anhydride at room temperature in a suitable solvent such as DCM (Method F). Intermediate S-viii or R-viii is then converted to compounds of formula I by for example reductive amination by combining with imidazole carboxaldehyde in the presence of an acid such as acetic acid, solvent such as DCM and a reducing agent such as NaBH(OAc)3 at room temperature (Method G).

[0196] General Scheme C: O R O Rx xR4)m

[0197] n a ternat ve exemp ary met od o preparng compounds o ormu a s shown in General Scheme C. In this scheme, ortho-halobenzonitrile i undergoes SNAr substitution with aziridine ester ii at elevated temperature, for example 110 ºC, in a suitable solvent such as toluene and base like Cs2CO3, Pd catalyst such as Pd2(dba)3and ligand such as BINAP (Method A). The resulting aziridine product iii undergoes ring opening when treated with an appropriately substituted alcohol in the presence of a Lewis acid such as BF3.Et2O in a solvent such as CHCl3 and at room temperature (Method B). The product v can then be converted to compounds of formula I as described in General Schemes A and B. 12886058v1 Page 44 of 494Attorney Docket No.2019292-0022

[0198] General Scheme D: x R3 Rx4R3 R(R4) N (R )mClR1Nm4)m[019y g shown in General Scheme D. Thus, starting with advanced intermediate i and reacting with halo analogs ii in the presence of a base such as K2CO3, source of iodide (NaI) and in a polar aprotic solvent such as DMF at elevated temperatures such as 60 °C provides analog iii as a mixture of diastereomers (Method A). These can be separated using chiral chromatography such as SFC to generate the individual isomers of compounds of formula I (Method B).

[0200] General Scheme E: OxR3 RxR3 R4(R4)mH2

[0201] An alternative exemplary method of preparing compounds of formula I is shown in General Scheme E. Late stage intermediate i undergoes reductive amination by combining with imidazolopyrimidin-3-yl carboxaldehyde ii in the presence of an acid such as acetic acid, solvent such as DCM and a reducing agent such as NaBH(OAc)3 at room temperature to give iii 12886058v1 Page 45 of 494Attorney Docket No.2019292-0022 (Method A). Treatment of iii with hydrazine in a solvent such as EtOH and stirring at elevated temperature such as 80 °C gives 2-aminoimidazole analogs iv (Method B).

[0202] General Scheme F: x R3 R x xR3R R3 RN X4N R4N R

[0203] An alternative exemplary method of preparing compounds of formula I is shown in General Scheme F. Compounds wherein X or Rxis halogen in i and can undergo cross- coupling reactions to introduce a variety of substitutions in the benzo ring to form intermediate ii. For example, Suzuki reactions enable late-stage introduction of aryl, vinyl or cyclopropyl groups, Buchwald reactions allow for the introduction of substituted amines. Reaction with Zn(CN)2, Brettphos and Pd enables introduction of cyano functionality. In turn, these newly introduced functional groups in ii can be further modified to different functional groups in iii. For example, introduction of a vinyl group, followed by oxidative hydrolysis using, for example OsO4 gives an aldehyde which in turn when treated with DAST gives R4as CHF2 (Method B). Intermediates iii are readily converted to compounds of formula I as previously described in Methods A and B.

[0204] General Scheme G: OMeR R3R4R3OHR4R3 O(R4)m

[0205] An alternative exemplary method of preparing compounds of formula I is shown in General Scheme G. Methoxy intermediate i can be hydrolyzed to phenol ii with for example HBr in AcOH at elevated temperatures such as 120 C (Method A). Alkylation reaction of ii with substituted alkylhalides, for example methoxyethyl bromide in the presence of a base such as 12886058v1 Page 46 of 494Attorney Docket No.2019292-0022 K2CO3and a polar aprotic solvent such as DMF gives intermediates iii (method B). Reductive amination with imidazole carboxaldehyde and intermediates ii or iii gives rise to compounds of formula I as described in methods A and B.

[0206] In some embodiments, a compound of formula I is selected from Table 1. Table 1 Structure Compound No12886058v1 Page 47 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 48 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 49 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 50 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 51 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 52 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 53 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 54 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 55 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 56 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 57 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 58 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 59 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 60 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 61 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 62 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 63 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 64 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 65 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 66 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 67 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 68 of 494Attorney Docket No.2019292-0022 Structure Compound No H N12886058v1 Page 69 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 70 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 71 of 494Attorney Docket No.2019292-0022 Structure Compound No H N12886058v1 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Compound No12886058v1 Page 85 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 86 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 87 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 88 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 89 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 90 of 494Attorney Docket No.2019292-0022 Structure Compound No H N12886058v1 Page 91 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 92 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 93 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 94 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 95 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 96 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 97 of 494Attorney Docket 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Structure Compound No12886058v1 Page 148 of 494Attorney Docket No.2019292-0022 Structure Compound No H N N12886058v1 Page 149 of 494Attorney Docket No.2019292-0022 Structure Compound No H N12886058v1 Page 150 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 151 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 152 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 153 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 154 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 155 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 156 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 157 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 158 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 159 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 160 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 161 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 162 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 163 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 164 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 165 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 166 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 167 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 168 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 169 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 170 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 171 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 172 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 173 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 174 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 175 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 176 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 177 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 178 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 179 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 180 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 181 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 182 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 183 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 184 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 185 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 186 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 187 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 188 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 189 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 190 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 191 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 192 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 193 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 194 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 195 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 196 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 197 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 198 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 199 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 200 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 201 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 202 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 203 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 204 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 205 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 206 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 207 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 208 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 209 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 210 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 211 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 212 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 213 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 214 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 215 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 216 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 217 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 218 of 494Attorney Docket No.2019292-0022 Structure Compound No HN12886058v1 Page 219 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 220 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 221 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 222 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 223 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 224 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 225 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 226 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 227 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 228 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 229 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 230 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 231 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 232 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 233 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 234 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 235 of 494Attorney Docket No.2019292-0022 Structure Compound No12886058v1 Page 236 of 494Attorney Docket No.2019292-0022 Structure Compound No or a pha

[0207] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Uses, Formulation, and Administration 12886058v1 Page 237 of 494Attorney Docket No.2019292-0022

[0208] F1F0-ATPase is a component of the mitochondrial electron transport chain (ETC) and utilizes a proton motive force generated by Complexes I-IV to produce ATP (synthase function). Under conditions where the mitochondrial membrane potential is disrupted, such as by lack of oxygen or inhibition of Complex I, the F-ATPase attempts to restore the membrane potential by pumping protons back across the membrane at the expense of ATP (hydrolase function in which the F1F0-ATPase catalyzes the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) or adenosine monophosphate (AMP) and inorganic phosphate ions). This ATP wasting event is detrimental to cellular viability and is particularly harmful to neurons in deep brain regions most impacted in a variety of neurodegenerative diseases. Unlike other ATPases which function to hydrolyze ATP and release energy, mitochondrial F1F0-ATPase has both hydrolytic and synthetic states. Accordingly, in some embodiments, the present disclosure provides a method of inhibiting F-ATP hydrolase, the method comprising treating a biological sample with a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the present disclosure provides a method of treating a disease or condition associated with F-ATP hydrolase. In some such embodiments, a disease or condition associated with F-ATP hydrolase is selected from Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia.

[0210] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in medicine.

[0211] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in inhibiting F-ATP hydrolase in a biological sample. In some embodiments, the use is in vitro.

[0212] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition associated with F-ATP hydrolase.

[0213] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with F-ATP hydrolase. 12886058v1 Page 238 of 494Attorney Docket No.2019292-0022 Diseases

[0214] Human therapeutic applications of inhibitors of ATP hydrolysis have been summarized in reviews by Ebanks, B. et al,. Aging, 2020, 12(16):16647-16662, Li, J-L. et al., Front. Mol. Neurosci., 2021, 14:797833, Vandoorne, T. et al., Acta Neuropathol., 2018, 135:489- 509, Lodi, R. et al., Proc. Natl. Acad. Sci. USA, 1999, 96:11492-11495, Seyfried, T. N. et al., iScience, 2020, 23:101761, Haythorne, E. et al., Nat. Commun, 2019, 10:2474, Tian, H. et al., J. Cel.l Mol. Med., 2022, 26(4):1000-1012, and Zhou, M. et al., Cardiology, 2021, 146(6):781-792. Inhibition of F-ATP hydrolase can be useful in the treatment of diseases and disorders including Alzheimer’s disease (AD), Parkinson’s Disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia.

[0215] In some embodiments, the disease or disorder is Alzheimer's disease (AD). AD is an irreversible neurodegenerative disease that is linked to mitochondrial dysfunction and is responsible for more than half of the 44 million cases of dementia globally. Without wishing to be bound by any particular theory, AD may be associated with dysfunction of mitochondrial ATP synthase, which is under-expressed in the hippocampal tissue of AD patients.

[0216] In some embodiments, the disease or disorder is Parkinson’s disease (PD). PD is linked to mitochondrial dysfunction and is the second most common neurodegenerative disorder worldwide, affecting 6.1 million patients in 2016. Without wishing to be bound by any particular theory, genetic models of PD have shown deficits in complex V, and link reduction in ATP production to the development of PD.

[0217] In some embodiments, the disease or disorder is amyotrophic lateral sclerosis (ALS). ALS is and irreversible neurodegenerative disorder that primarily affects motor neurons. Without wishing to be bound by any particular theory, motor neurons are vulnerable to ATP depletion, therefore disturbances in energy metabolism (e.g., ATP metabolism) may be linked to ALS.

[0218] In some embodiments, the disease or disorder is Friedreich’s ataxia (FRDA). FRDA is linked to mitochondrial dysfunction and is the most common form of inherited ataxia, presenting in 1 in 50,000 births. Without wishing to be bound by any particular theory, patients 12886058v1 Page 239 of 494Attorney Docket No.2019292-0022 with FRDA present with a deficit of mitochondrial ATP production, linking decreased amounts on ATP to development of the disease.

[0219] In some embodiments, the disease or disorder is cancer. Cancer is the second leading cause of death worldwide and abnormalities in mitochondrial function have been documented in all major cancers. ATP is required for mammalian cells to function properly. Without wishing to be bound by any particular theory, insufficiency of ATP (e.g., through disruption of ATP synthesis in Complex V) contributes to apoptotic resistance in cells (i.e., cancer).

[0220] In some embodiments, the disease or disorder is diabetes. Diabetes is a global health problem associated with inhibition of mitochondrial metabolism in pancreatic β-cells. Without wishing to be bound by any particular theory, downregulation of ATP synthesis resulting from oxidative phosphorylation and associated reduction of mitochondrial metabolism is linked to the failure of β-cells and the development of diabetes.

[0221] In some embodiments, the disease or disorder is stroke. Stroke is linked to mitochondrial dysfunction and causes greater than 40 million physical disabilities and 5 million deaths around the world per year. Without wishing to be bound by any particular theory, mitochondrial ATP synthesis is disrupted during stroke, resulting in downregulation of neurological promotion and cell survival. Accordingly, preserving mitochondrial function (e.g., synthesis of ATP) during and after stroke can be a promising therapeutic strategy to stroke.

[0222] In some embodiments, the disease or disorder is cardiac ischemia. Cardiovascular disease (e.g., cardiac ischemia) is linked to mitochondrial dysfunction and is the leading cause of death worldwide. Without wishing to be bound by any particular theory, this mitochondrial dysfunction and the resultant oxidative stress are the key mechanisms for the development of cardiac ischemia. In general, diseases associated with ischemic events are associated with a lack of oxygen, which leads to loss of mitochondrial membrane potential and ultimately causes F1F0- ATPase to switch to hydrolase mode.

[0223] In some embodiments, the present disclosure provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions provided 12886058v1 Page 240 of 494Attorney Docket No.2019292-0022 herein is such that is effective to measurably inhibit F-ATP hydrolase in a biological sample or in a patient. In certain embodiments, a composition provided herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0224] Compositions provided herein 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, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions provided herein 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 suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0225] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0226] Pharmaceutically acceptable compositions provided herein 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 commonly used 12886058v1 Page 241 of 494Attorney Docket No.2019292-0022 include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. 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.

[0227] Alternatively, pharmaceutically acceptable compositions provided herein may be administered in the form 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. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0228] Pharmaceutically acceptable compositions provided herein 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 formulations are readily prepared for each of these areas or organs.

[0229] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0230] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds provided herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0231] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as 12886058v1 Page 242 of 494Attorney Docket No.2019292-0022 solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0232] Pharmaceutically acceptable compositions provided herein 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 benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0233] Most preferably, pharmaceutically acceptable compositions provided herein are formulated for oral administration.

[0234] The amount of compounds of the present disclosure 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. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0235] 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 in the composition will also depend upon the particular compound in the composition. Exemplary Embodiments

[0236] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the disclosure: Embodiment 1. A compound of formula I: 12886058v1 Page 243 of 494Attorney Docket No.2019292-0022 or a pharmaceutically acceptable salt tL1is selected from a bond, -C(O)-, or C1-4 alkylene; RaN N ,, , , Rais selected from C1-4aliphatic or a 3- to 5-membered saturated carbocyclic ring; L2is selected from a bond or a C1-4 alkylene wherein one methylene unit is optionally replaced by -O- or -C(O)-; R2is selected from C1-6aliphatic or Cy, wherein R2is substituted with 0-3 instances of Rw; Cy is selected from a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 8- to 10-membered saturated, partially unsaturated, or aryl bicyclic carbocyclic ring, a 7- to 9-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-to 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 12886058v1 Page 244 of 494Attorney Docket No.2019292-0022 ;(R)2, and an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10- membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5is selected from C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8- membered bridged bicyclic carbocyclic ring, phenyl, a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 7- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is substituted with 0-3 instances of Rz; each R6is independently hydrogen or C1-6 aliphatic; each Rwis independently selected from halogen, cyano, oxo, -OR, -SR, -N(R)2, -C(O)R, - C(O)OR, -C(O)N(R)2, -OC(O)R, -N(R)C(O)R,, and an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Rxis selected from hydrogen, halogen, cyano, -OR, and an optionally substituted group selected from C1-4alkyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: 12886058v1 Page 245 of 494Attorney Docket No.2019292-0022 Rxand R4optionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ryis independently selected from halogen, -N(R)2, and an optionally substituted group selected from C1-4 alkyl and a 3- to 6-membered saturated carbocyclic ring; each Rzis independently selected from halogen, cyano, -OR, and optionally substituted C1-4 alkyl; each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; and n is 0-2. Embodiment 2. The compound according to Embodiment 1, wherein the compound is12886058v1 Page 246 of 494Attorney Docket No.2019292-0022 I-b-i I-d I-d-i or ap a aceu ca y accep a e sa e eo , w e e : Rxis selected from halogen, cyano, -OR, and an optionally substituted group selected from C1-4alkyl, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment 3. The compound according to Embodiment 1, wherein the compound isor a pharmaceutically acceptable salt thereof, wherein: each R4is independently selected from cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: 12886058v1 Page 247 of 494Attorney Docket No.2019292-0022 R4and Rxoptionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1-3. Embodiment 4. The compound according to Embodiment 1, wherein the compound isor a pharmaceutically acceptable salt thereof, wherein: each R4is independently selected from cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: 12886058v1 Page 248 of 494Attorney Docket No.2019292-0022 R4and Rxoptionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment 5. The compound according to Embodiment 1, wherein the compound is12886058v1 Page 249 of 494Attorney Docket No.2019292-0022 or a phaaceu ca y accepa e sa eeo, wee : R1is selected from12886058v1 Page 250 of 494Attorney Docket No.2019292-0022 or a phy p , L2is selected from -CH2-, -CH2O-, -CH2C(O)-, -CH2CH2CH2-, and -CH2CH2O-. Embodiment 7. The compound according to Embodiment 1, wherein the compound is selected from12886058v1 Page 251 of 494Attorney Docket No.2019292-0022or a pharmaceutically acceptable salt thereof. 12886058v1 Page 252 of 494Attorney Docket No.2019292-0022 Embodiment 8. The compound according to any one of Embodiments 1-4, 6, and 7, wherein R1is selected from . Embodiment 9. Thediments 1-5 and 7, wherein L2is a bond. Embodiment 10. The compound according to any one of Embodiments 1-5 and 7, wherein L2is -CH2CH2-. Embodiment 11. The compound according to any one of Embodiments 1-10, wherein Cy is. , is - CH2-. Embodiment 13. The compound according to Embodiment 1, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof. Embodiment 14. A pharmaceutical composition comprising a compound of any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof. Embodiment 15. A method of inhibiting F-ATP hydrolase, the method comprising contacting a biological sample with a compound of formula I, or a pharmaceutically acceptable salt thereof. Embodiment 16. A method of treating a disease or condition associated with F-ATP hydrolase comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof 12886058v1 Page 253 of 494Attorney Docket No.2019292-0022 Embodiment 17. The method according to Embodiment 16, wherein the disease or condition associated with F-ATP hydrolase is selected from Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia. Embodiment 18. A compound according to any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 14, for use in medicine. Embodiment 19. Use of a compound according to any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 14, in inhibiting F-ATP hydrolase in a biological sample, wherein the use is in vitro. Embodiment 20. Use of a compound according to any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 14, in treating a disease or condition associated with F-ATP hydrolase. Embodiment 21. Use of a compound according to any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 14, in the manufacture of a medicament for treating a disease or condition associated with F-ATP hydrolase. Embodiment 22. The use according to Embodiment 20 or 21, wherein the disease or condition is selected from Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia. EXAMPLES

[0237] As described in the 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 12886058v1 Page 254 of 494Attorney Docket No.2019292-0022 the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Table of Abbreviations Avg. average Tol. tolueneCompound characterization: LC / MS 12886058v1 Page 255 of 494Attorney Docket No.2019292-0022

[0238] 5_95AB_6min-220-254：LC / MS (The gradient was 5%B in 0.40 min and 5-95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95 - 5%B in 0.01 min, the flow rate was 1.0 ml / min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Luna C18 50*2.0 mm column (5 um particles). Detection methods are diode array (DAD) detection. MS mode was positive electrospray ionization. MS range was 100-1000. Purification by silica gel chromatography: Flash Silica(CS), 40-60μm,60A,180psi, flow rate: 75 mL / min;

[0239] Example 1. Synthesis of Exemplary Compounds

[0240] Example 1.1: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(2-cyclopentylethyl)- 6-methoxy-4-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (91) and enantiomers (91-1) and (91-2)

[0241] Step 1: methyl 2-(2-cyclopentylethyl)-5-methoxy-1,2,3,4-tetrahydroquinazoline- 2-carboxylate (91-B). A mixture of methyl 2-oxo-4-cyclopentylbutanoate (3 g, 16.28 mmol, 1 eq) and 2-(aminomethyl)-3-methoxyaniline (4.96 g, 32.57 mmol, 2 eq) in toluene (100 mL) was stirred at 130°C for 4 hrs. The reaction mixture was concentrated under reduced pressure to give methyl 2-(2-cyclopentylethyl)-5-methoxy-1,2,3,4-tetrahydroquinazoline-2-carboxylate (91- B, 3.8 g, crude) as a yellow solid. ESI [M+H] = 319.2 12886058v1 Page 256 of 494Attorney Docket No.2019292-0022

[0242] Step 2: methyl 2-((2-(aminomethyl)-3-methoxyphenyl)amino)-4- cyclopentylbutanoate (91-C). To a solution of methyl 2-(2-cyclopentylethyl)-5-methoxy-1,2,3,4- tetrahydroquinazoline-2-carboxylate (91-B, 3.75 g, 11.93 mmol, 1 eq) in DCE (30 mL) was added TFA (7.5 mL) at 0°C, followed by Et3SiH (2.55 g, 21.91 mmol, 1.7 eq). The mixture was stirred at 20°C for 4 hrs. TLC (Petroleum ether:Ethyl acetate = 1:1) showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give methyl 2-((2- (aminomethyl)-3-methoxyphenyl)amino)-4-cyclopentylbutanoate (91-C, 3.8 g, crude) as a yellow oil. ESI [M+H] = 321.2

[0243] Step 3: 2-(2-cyclopentylethyl)-6-methoxy-4,5-dihydro-1H-benzo[e][1,4]diazepin- 3(2H)-one 91-D). To a solution of methyl 2-((2-(aminomethyl)-3-methoxyphenyl)amino)-4- cyclopentylbutanoate (91-C, 3.8 g, 11.86 mmol, 1 eq) in MeOH (50 mL) was added aq. NaOH (1 M) at 0°C to adjust pH=13. The reaction was stirred at 20°C for 1 hr and then filtered. The filter cake was dried under reduced pressure to give 2-(2-cyclopentylethyl)-6-methoxy-4,5-dihydro- 1H-benzo[e][1,4]diazepin-3(2H)-one (91-D, 5 g, crude) as a yellow solid. ESI [M+H] = 289.2.

[0244] Step 4: 2-(2-cyclopentylethyl)-6-methoxy-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (91-E). To a solution of 2-(2-cyclopentylethyl)-6-methoxy-4,5-dihydro- 1H-benzo[e][1,4]diazepin-3(2H)-one (91-D, 1 g, 3.47 mmol, 1 eq) in THF (10 mL) was added LiAlH4 (171.01 mg, 4.51 mmol, 1.3 eq) at 0°C. The reaction mixture was stirred at 35°C for 20 hrs and then quenched by addition of Na2SO4·10H2O (200 mg) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hrs, then filtered. The filtrate was concentrated under reduced pressure to give 2-(2-cyclopentylethyl)-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (91-E, 500 mg, 1.82 mmol, 52.5% yield) as a brown oil. ESI [M+H] = 275.2

[0245] Step 5: 2-(2-cyclopentylethyl)-6-methoxy-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (91-F). To a mixture of 2-(2-cyclopentylethyl)-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (91- E, 500 mg, 1.82 mmol, 1 eq) in DCM (1 mL) was added TEA (368 mg, 3.64 mmol, 2 eq) and 4- (trifluoromethyl)benzene-1-sulfonyl chloride (312 mg, 1.27 mmol, 0.7 eq) at 0°C. The mixture was stirred at 20°C for 1 hr, then concentrated, diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum 12886058v1 Page 257 of 494Attorney Docket No.2019292-0022 ether:Ethyl acetate = 3:1) to give 2-(2-cyclopentylethyl)-6-methoxy-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (91-F, 500 mg, 56.75% yield) as yellow oil. ESI [M+H] = 483.2.

[0246] Step 6: 1-((1H-imidazol-4-yl)methyl)-2-(2-cyclopentylethyl)-6-methoxy-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (91). To a solution of 2-phenethyl-4-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (270 mg, 558 umol, 1 eq) and 1H-imidazole-4-carbaldehyde (107 mg, 1.12 mmol, 2 eq) in DCM (1 mL) was added AcOH (0.5 mL) at 20°C. The mixture was stirred at 20°C for 0.5 hrs, then NaBH(OAc)3 (202 mg, 0.95 mmol, 1.7 eq) was added and the mixture was stirred for additional 1.5 hrs at 20°C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC ((Phenomenex Gemini C18column (150 × 40 mm, 10 mm); flow rate: 25 mL / min; gradient: 55% – 90% B over 8 min; mobile phase A:10 mM aqueous NH4HCO3 mobile phase B: acetonitrile) to give 1-((1H-imidazol-4-yl)methyl)-2- (2-cyclopentylethyl)-6-methoxy-4-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (rac-110 mg, 35% yield). Material was separated by SFC (Instrument: Waters SFC80 preparative SFC； Column: Phenomenex-Cellulose-2 (250mm×30mm,10um); Mobile phase: A for CO2 and B for MeOH(0.1%NH3H2O); Gradient: B%=45% isocratic elution mode; Flow rate: 60g / min; Wavelength:220nm; Column temperature: 40℃； System back pressure: 100 bar) to generate the 2 chiral isomers. The peak with longer retention time, (1.49 min) 91-2.1H-NMR (400 MHz, CD3OD) δ = 8.03 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.17 (t, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.40 (br d, J = 14.0 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.36 - 4.27 (m, 1H), 3.84 (s, 3H), 3.77 (br d, J = 13.6 Hz, 1H), 3.64 (br d, J = 13.6 Hz, 1H), 3.23 (br s, 1H), 2.78 (br d, J = 12.4 Hz, 1H), 1.66 - 1.43 (m, 7H), 1.32 - 1.14 (m, 3H), 1.08 - 0.83 (m, 3H).

[0247] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 91-2 in Example 1.1, using analogous starting materials and / or intermediates. Compound #, Structure Analytical data12886058v1 Page 258 of 494Attorney Docket No.2019292-0022 (t, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.40 (br d, J = 14.0 Hz, s, 6 ), , , δ z,12886058v1 Page 259 of 494Attorney Docket No.2019292-0022 134-2 (*) ESI [M+H] = 471.1.1H-NMR (400 MHz, CD3OD) δ = 7.79 (s, 1H), 7.20 - 7.15 (m, 1H), 7.11 (s, 1H), 7.06 r ), ), δ 6 r - δ , , δ - δ -12886058v1 Page 260 of 494Attorney Docket No.2019292-0022 162 ESI [M+H] = 525.0.1H-NMR (400 MHz, CD3OD) δ , - - - =12886058v1 Page 261 of 494Attorney Docket No.2019292-0022 175 O CF3ESI [M+H] = 499.1.1H-NMR (400 MHz, CD3 S OD) δ , δ , δ 4 z, - z, ), .2 2, ,12886058v1 Page 262 of 494Attorney Docket No.2019292-0022 184-1 (*)1H-NMR (400 MHz, CD3OD) δ = 7.73 (d, J = 0.8 Hz, 1H) 7.30 - 7.25 (m 3H) 7.22 - 7.17 (m 2H) 7.15 - z, ), .2 2, , z, - z, - .2 5 ). = 5 9 8 = 6, 5 = - 3 7 , J ), = = ), z, br ), 612886058v1 Page 263 of 494Attorney Docket No.2019292-0022 197 ESI [M+H] =483.1.1HNMR (400 MHz, CD3OD) δ = 776 (d J = 12 Hz 1H) 735 - 724 (m 3H) 721 - z, d, , ), , = ), ), J , 5 = 5 4 ), d, = - δ , ), ),12886058v1 Page 264 of 494Attorney Docket No.2019292-0022 209 ESI [M+H] = 49921H-NMR (400 MHz CD3OD) δ - 4 , ), δ , .4 z, ), 0 ), ), δ ), 3 6 .2 δ = s, ), 1 2 3 = J 7 - - 5 212886058v1 Page 265 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 513.11H NMR (400 MHz, CDCl3) δ = 185-1 (*) 7.40 (s, 1 H), 7.30 (s, 1 H), 7.26 (s, 1 H), 7.21 (t, J = 47 - 3 9 .0 , - ), J ), ),12886058v1 Page 266 of 494Attorney Docket No.2019292-0022 325 (****) ESI [M+H] = 475.01H NMR (400 MHz, CD3OD) δ = 734 - 727 (m 1H) 727 - 718 (m 2H) 701 (s , = - - ), -12886058v1 Page 267 of 494Attorney Docket No.2019292-0022 509-2 (*) ESI [M+H] = 415.11H NMR (400 MHz, DMSO-d6) δ = 759 (s 1H) 725 - 710 (m 2H) 698 (s 1H) ), ) J δ 7 s, ), z, 2, ), -12886058v1 Page 268 of 494Attorney Docket No.2019292-0022 ESI [M+H] =493.21H NMR (400 MHz, CD3OD) δ = 510-1 (*) 7.25 (s, 2H), 7.18 (br d, J = 7.6 Hz, 2H), 7.09 (br - ) , ) , , - , , ), -12886058v1 Page 269 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 547.21H NMR (400 MHz, CD3OD) 313 δ = 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = , s, 5 d, , , δ δ12886058v1 Page 270 of 494Attorney Docket No.2019292-0022 ESI [M+1324 H] =477.2 H NMR (400 MHz, CD3OD) δ = 7.33 - 7.29 (m, 1H), 7.27 (d, J = 2.4 Hz, 1H), ), - - , δ ), ), d, d, .8 5 - ). ,12886058v1 Page 271 of 494Attorney Docket No.2019292-0022 164 ESI [M+H] = 421.1.1H NMR (400 MHz, DMSO-d6) = 14 1H 4 1H 2 1 H), z, 0 ), 6) - ), , ), 6) 1 , - 6) , - 1 ), - δ .2 br = 4 612886058v1 Page 272 of 494Attorney Docket No. 2019292-0022 520-1 (*) ESI [M+H] = 497.3.1H NMR (400 MHz, CD3OD) δ = 8.29 (br s, 1H), 7.77 (s, 1H), 7.31 - 7.25 (m, 1H), = ), 1 , , = ), br 6 = ), δ 4 - d, δ z, - s, - - δ ), = 4 9 , δ s, 4,12886058v1 Page 273 of 494Attorney Docket No.2019292-0022 8.4 Hz, 1H), 4.66 (br d, J = 14.4 Hz, 1H), 4.46 - 4.36 (m, 2H), 4.32 (s, 1H), 3.74 (br s, 1H), 3.73 (s, 3H), 44 δ z, 4, ), - - ), ), δ , - 3 , z, δ , 0, 7 2 812886058v1 Page 274 of 494Attorney Docket No.2019292-0022 202 ESI [M+H] = 513.2.1H NMR (400 MHz, CD3OD) δ = 758 - 755 (m 1H) 732 - 725 (m 4H) 723 - , , δ ), 1 8 9 δ , , - s, .6 ), δ , ), = .2 d, z, δ 6 z, ), ), - -12886058v1 Page 275 of 494Attorney Docket No.2019292-0022 191 ESI [M+H] = 489.1.1H NMR (400 MHz, CD3OD) δ ), 2 m, 5 6 = s, .4 6 , - ), 2 - - ), , = t, 7 2 5 z, 412886058v1 Page 276 of 494Attorney Docket No.2019292-0022 183 ESI [M+H] = 485.3.1H-NMR (400 MHz, CD3OD) δ ), .4 6 3 δ ), - 5 6 2, ), δ , .6 3 9 1 3, s, , δ ), ), J s, , ,12886058v1 Page 277 of 494Attorney Docket No.2019292-0022 173 ESI [M+H] = 505.0.1H-NMR (400 MHz, CDCl3) δ = 2, ), J z, - δ , z, 6 J z, ), δ 1 .8 = s, 9 6 = - 2 ), z, - δ ), ), 7 ,12886058v1 Page 278 of 494Attorney Docket No.2019292-0022 168 ESI [M+H] = 501.2.1H NMR (400 MHz, CD3OD) δ = ), ), 4 7 ), δ z, 0 = .4 - - δ ), 1 8 ), 6 δ 8 2 7 3 412886058v1 Page 279 of 494Attorney Docket No.2019292-0022 157 ESI [M+H] = 48911H NMR (400 MHz CD3OD) δ , - 5 , δ 1 d, , .2 , 3 - = z, - 3 , 7 ,12886058v1 Page 280 of 494Attorney Docket No.2019292-0022 486-1 (*) ESI [M+H] = 575.3.1H NMR (400 MHz, CD3OD) δ = 8.08 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), ), ), ), 4, z, - 4, ), , ), 9 , ),12886058v1 Page 281 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 519.2.1H NMR (400 MHz, CD3OD) δ 345 = 7.26 - 7.21 (m, 2H), 7.18 - 7.12 (m, 2H), 7.08 - 7.03 01 ), = ), 8 5 z, s, z, br d, ), 8 z, d, ), 1 , - 3 z, , ), 1 , ), ). δ 9 4 8 .4 3 1 412886058v1 Page 282 of 494Attorney Docket No.2019292-0022 Isolated as a single enantiomer: Peak 2 (Rt = 2.972) 312-2 ESI [M+H] = 533.1.1H-NMR (400 MHz, CD3OD) δ ), - , 9 5 9 , δ 6 9 , - ), δ .0 .4 9 ), - .0 6) - z, ), ), = 4 s, 1 s, ), 0 = = ),12886058v1 Page 283 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 449.1.1H NMR (400 MHz, CD3OD) 362 δ = 8.36 (br d, J = 5.2 Hz, 1H), 7.88 (br d, J = 3.2 Hz, br ), 9 , - δ 9 s, ), 0 0 , ) z, s, ), 8 - ), δ 0 .8 9 m, - ) - 0 , - ), 5 δ 2 br 1 -12886058v1 Page 284 of 494Attorney Docket No.2019292-0022 368 ESI [M+H] = 509.1.1H NMR (400 MHz, CD3OD) δ = 8.60 (s, 1H), 7.68 - 7.45 (m, 3H), 7.33 (d, J = 8.4 Hz, ), 9 9 δ 1 ), br 5 = ), 1 δ ), = z, , .6 4, z, 7 z, ), J 4 z, - ), 5 z, 9 z, br J 5 ,12886058v1 Page 285 of 494Attorney Docket No.2019292-0022 413 ESI [M+H] = 513.1.1H-NMR (400 MHz, CD3OD) δ = 7.75 (s, 1H), 7.59 (br d, J = 8.4 Hz, 1H), 7.52 (d, J , [0248

[0249] (**) Material was separated by SFC (Instrument: Waters SFC350 preparative SFC; Column: DAICEL CHIRALCEL OJ (250mm*50mm,10um); Mobile phase A: CO2, B: 0.1%NH3H2O in IPA; Gradient: B%=30% isocratic elution mode; Flow rate: CO2(140 g / min) and B(60 mL / min); Wavelength: 220nm; Column temperature: 40 degrees centigrade; System back pressure: 100 bar.) to afford two enantiomers. The stereochemistry was confirmed by VCD: Peak 1 (Rt=1.638 min) has (R)-configuration, Peak 2 (Rt=2.127) (S)-configuration.

[0250] (***) Racemic material was separated by SFC (Instrument: Waters SFC80 preparative SFC; Column: Phenomenex-Cellulose-2 (250mm * 30mm,10um); Mobile phase A: CO2and B: 0.1% NH3H2O in EtOH; Gradient: B%=30% isocratic elution mode; Flow rate: CO2(64.6 g / min), B(3.4 mL / min); Wavelength: 220 nm; Column temperature: 35°C.

[0251] (****) HATU / DIEA in THF was used to facilitate lactam formation following Step 3.

[0252] Example 1.2: 1-((1H-imidazol-4-yl)methyl)-2-(phenoxymethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (16) 12886058v1 Page 286 of 494Attorney Docket No.2019292-0022

[0253] ion of phenol (1 g, 10.63 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (2.94 g, 21.25 mmol, 2 eq) and ethyl oxirane-2-carboxylate (2.47 g, 21.25 mmol, 2 eq). The mixture was stirred at 50°C for 2 hrs. The reaction mixture was concentrated, diluted with H2O (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. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 20:1 to 5:1) to give methyl 2-hydroxy-3-phenoxypropanoate (16-B, 700 mg, 31.3% yield) as a colorless oil.1H-NMR (400 MHz, CDCl3) δ = 7.27 (t, J = 7.6 Hz, 2H), 7.01 – 6.87 (m, 3H), 4.51 (t, J = 3.2 Hz, 1H), 4.31 - 4.22 (m, 2H), 3.81 - 3.76 (m, 3H).

[0254] Step 2: synthesis of methyl 2-oxo-3-phenoxypropanoate (16-C). To a solution of methyl 2-hydroxy-3-phenoxypropanoate (16-B, 500 mg, 2.38 mmol, 1 eq) in DCM (6 mL) was added (1,1-diacetoxy-3-oxo-1λ5,2-benziodoxol-1-yl) acetate (2.02 g, 4.76 mmol, 2 eq). The mixture was stirred at 20°C for 2 hrs and then concentrated. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate = 20:1 to 5:1) to give methyl 2-oxo-3- phenoxypropanoate (16-C, 400 mg, 80.8% yield) as a white solid.

[0255] Steps 3-8: 1-((1H-imidazol-4-yl)methyl)-2-(phenoxymethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (16)

[0256] Steps 3-8 were carried out according to procedures 1-6 in Example 1.1 to afford 1-((1H-imidazol-4-yl)methyl)-2-(phenoxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (16). ESI [M+H] = 543.2.1H-NMR (400 MHz, 12886058v1 Page 287 of 494Attorney Docket No.2019292-0022 DMSO-d6) δ = 8.06 - 8.02 (m, 2 H), 8.02 - 8.00 (m, 1H), 7.97 - 7.92 (d, J = 8.4 Hz, 1H), 7.52 (m, 1H), 7.23 - 7.16 (m, 5H), 6.96 – 6.86 (m, 3H), 6.73 (m, 1H), 6.68 – 6.66 (m, 1H), 4.64 – 4.62 (d, J = 8.4 Hz, 1H) , 4.51 – 4.29 (m, 2 H) , 4.06 – 3.84 (m, 3 H), 3.59 – 3.46 (m, 2 H), 2.81 - 2.78 (m, 1 H).

[0257] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 16 in Example 1.2, using analogous starting materials and intermediates. Compound #, Structure Analytical data 6

[0258] (: Waters SFC80 preparative SFC； Column: Phenomenex-Cellulose-2 (250mm*30mm,10um); Mobile phase: A CO2and B 0.1%NH3H2O in EtOH; Gradient: B%=30% isocratic elution mode; Flow rate:CO2(18g / min) B(42ml / min); Wavelength:220nm; Column temperature: 40oC; System back pressure: 100 bar) to generate two enantiomers. The faster eluting was determined to have the (S)-configuration using X-ray analysis. The other was therefore (R)-enantiomer.

[0259] Example 1.3: 1-((1H-imidazol-4-yl)methyl)-2-(2-(thiophen-3-yl)ethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (20). 12886058v1 Page 288 of 494Attorney Docket No.2019292-0022

[0260] on of thiophene-3-carbaldehyde (5 g, 44.58 mmol, 1 eq) in toluene (150 mL) was added tetraethoxytitanium (14.24 g, 62.42 mmol, 1.4 eq) and ethyl 2-oxopropanoate (7.25 g, 62.42 mmol, 1.4 eq). The mixture was stirred at 40°C for 12 hrs. The mixture was concentrated in vacuum. The crude was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 20:1 to 5:1) to give (E)-ethyl 2-oxo-4-(thiophen-3-yl)but-3-enoate (20-B, 4 g, 42.67% yield) as a white solid. ESI [M+H] = 211.0.

[0261] Step 2: ethyl 2-oxo-4-(thiophen-3-yl)butanoate (20-C). To a mixture of ethyl (E)- 2-oxo-4-(3-thienyl)but-3-enoate (2 g, 9.51 mmol, 1 eq) in EtOAc (20 mL) was added Pd / C (1 g, 10% purity) . The reaction mixture was stirred at 20°C for 1 hr under H2 (15 Psi) and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 2:1 to 1:1) to give ethyl 2-oxo-4-(3-thienyl)butanoate (20-C, 400 mg, 19.81% yield) as a yellow solid.

[0262] Steps 3-8: 1-((1H-imidazol-4-yl)methyl)-2-(2-(thiophen-3-yl)ethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (20). Steps 3-8 were carried out according to procedures 1-6 in Example 1.1 to afford 1-((1H-imidazol-4-yl)methyl)- 2-(2-(thiophen-3-yl)ethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (20). ESI [M+H] = 471.2.1H-NMR (400 MHz, DMSO-d6) δ = 7.53 - 7.57 (m, 1H), 7.15 - 7.41 (m, 4H), 7.04 (br s, 3H), 6.80 - 6.75 (m, 1H), 4.55 - 4.61 (m, 1H), 4.20 12886058v1 Page 289 of 494Attorney Docket No.2019292-0022 - 4.37 (m, 3H), 3.77 (s, 1H), 3.40 (br s, 1H), 3.25 (br s, 1H), 2.57 - 2.45 (m, 2H), 1.33 (br s, 1H), 1.14 (br s, 1H).

[0263] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 20 in Example 1.3, using analogous starting materials and / or intermediates. Compound #, Structure Analytical data , 5 9 812886058v1 Page 290 of 494Attorney Docket No.2019292-0022 Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 0.8 Hz, 1H), 7.55 - 7.58 (m, , 0 812886058v1 Page 291 of 494Attorney Docket No.2019292-0022 22-2 (**) ESI [M+H] =429.0.1H-NMR (400 MHz, CD3OD) δ = 8.86 (s, 1H) 7.59 = - ,

[0264] ( ument: WatersUPCC with PDA； Column: DAICEL CHIRALCEL OD (250mm*30mm,10um); Mobile phase A: CO2. B: 0.1% IPA in EtOH, ; Gradient: B%=50% isocratic elution mode; Flow rate: CO2(3.4 g / min), B(3.4 mL / min); Wavelength:220 nm; Column temperature: 35℃.

[0265] (**) Intermediates after Step 6 were separated using preparative SFC using Waters SFC80; Column: Chiralcel-IG-3 (100mm*4.6mm, 3um); Mobile phase A: CO2, B: (0.1%NH3H2O in EtOH); Gradient: B%=10% isocratic elution mode; Flow rate: A: CO2 (30.6 g / min), B: (3.4mL / min); Wavelength: 220 nm; Column temperature: 35℃.

[0266] Example 1.4: 1-((1H-imidazol-4-yl)methyl)-2-(2,3-dihydro-1H-inden-2-yl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (23).

[0267] Step 1: 3-(2,3-dihydro-1H-inden-2-yl)-3-oxo-2- (triphenylphosphoranylidene)propanenitrile (23-B). To a solution of 2,3-dihydro-1H-indene-2- carboxylic acid (1 g, 6.17 mmol, 1 eq) in DCM (20 mL) was added DMAP (150.65 mg, 1.23 12886058v1 Page 292 of 494Attorney Docket No.2019292-0022 mmol, 0.2 eq) and 2-(triphenyl-λ5-phosphanylidene)acetonitrile (1.86 g, 6.17 mmol, 1 eq) and EDCI (1.18 g, 6.17 mmol, 1 eq). The mixture was stirred at 20°C for 2 hrs and then concentrated. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1 ) to give 3-(2,3-dihydro-1H-inden-2-yl)-3-oxo-2-(triphenyl-l5-phosphaneylidene)propanenitrile (23- B, 1.5 g, 54.61% yield) as a white solid. ESI [M+H] =446.1

[0268] Step 2: methyl 2-(2,3-dihydro-1H-inden-2-yl)-2-oxoacetate (23-C). Ozone (161.61 mg, 3.37 mmol, 1 eq) was bubbled into a solution of 3-(2,3-dihydro-1H-inden-2-yl)-3- oxo-2-(triphenyl-l5-phosphaneylidene)propanenitrile (1.50 g, 3.37 mmol, 1 eq) in DCM (10 mL) and MeOH (5 mL) at -78°C for 5 minutes. After excess O3 was purged by N2, the reaction mixture was poured into 10 mL of H2O and extracted with EtOAc (10 mL × 3). The combined organic phase was extracted with H2O (10 mL × 3), then dried with anhydrous Na2SO4, filtered and concentrated to give methyl 2-(2,3-dihydro-1H-inden-2-yl)-2-oxoacetate (500 mg, crude) as a white oil. ESI [M+H] =205.2

[0269] Steps 3-8: 1-((1H-imidazol-4-yl)methyl)-2-(2,3-dihydro-1H-inden-2-yl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (23). Steps 3-8 were carried out according to procedures 1-6 in Example 1.1 to afford 23. ESI [M+H] =477.2.1H-NMR (400 MHz, DMSO-d6) δ = 8.14 - 8.07 (m, 2H), 8.06 - 8.00 (m, 2H), 7.49 (s, 1H), 7.25 (d, J = 3.6 Hz, 2H), 7.19 (d, J = 7.2 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.06 – 6.98 (m, 2H), 6.95 - 6.85 (m, 2H), 4.63 (br d, J = 13.2 Hz, 1H), 4.52 - 4.32 (m, 2H), 3.83 (br d, J = 12.0 Hz, 1H), 3.64 (br d, J = 13.2 Hz, 1H), 3.49 (br d, J = 10.6 Hz, 1H), 2.93 (dd, J = 15.6, 7.6 Hz, 1H), 2.85 - 2.66 (m, 2H), 2.61 (br d, J = 12.4 Hz, 1H), 2.54 - 2.49 (m, 1H), 2.15 - 1.96 (m, 1H).

[0270] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 23 in Example 1.4, using analogous starting materials and / or intermediates. 12886058v1 Page 293 of 494Attorney Docket No.2019292-0022 Compound #, Structure Analytical data 7 ,12886058v1 Page 294 of 494Attorney Docket No.2019292-0022 27-2 (*) ESI [M+H] = 457.1.1H-NMR (400 MHz, DMSO-d6) δ = 11.98 (br s, 1H), , 2 612886058v1 Page 295 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 466.2.1H-NMR (400MHz, CDCl3) δ = 8.56 - 8.49 (m, 30 0 ), -12886058v1 Page 296 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 466136 .2. H-NMR (400MHz, CD3OD) δ = 8.83 (s, 1 H), 1 - 39 , 48 , J12886058v1 Page 297 of 494Attorney Docket No.2019292-0022 1 484-1 (**) H-NMR (400 MHz, DMSO-d6) δ = 11.88 (br s, 1H), 8.10 (m, J = 8.4 Hz , d, J , , , ) ,12886058v1 Page 298 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 466.3.1H-NMR 58 (400MHz, DMSO-d6) δ = 9.15 (br s, ), 3 5 - z, - 5 ), 612886058v1 Page 299 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 533.1.1H-NMR (400 MHz, CD3OD) δ = 8.76 (d, J = 1.2 Hz, 61 3 1 6 2 d, - 6 ), 512886058v1 Page 300 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 490.2.1H-NMR (400 MHz, CD3OD) δ = 8.21 (s, 1H), 8.12 = 64 ), , 6 z , 6712886058v1 Page 301 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 443.1.1H-NMR (400 269 MHz, CD3OD) δ = 7.97 (s, 1H), 7.35 - ), , 8 br , 5 -

[0271] ( nt: Waters UPCCwith PDA； Column: DAICEL CHIRALPAK AY-H (250mm*30mm,5um); Mobile phase: A: CO2, B: (0.1%NH3H2O in EtOH); Gradient: B%=33% isocratic elution mode; Flow rate: CO2: (6.9 g / min) B: (3.4mL / min); Wavelength:220nm; Column temperature: 35 C. Absolute configuration was determined using VCD.

[0272] (**) Racemic final materials were separated using chiral SFC.

[0273] Example 1.5: 1-((1H-imidazol-4-yl)methyl)-2-(2-(azetidin-1-yl)ethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (33)

[0274] Steps 1-6 were carried out according to procedures described in Example 1.1, Steps 1-6. Trifluoromethanesulfonyl anhydride was used in Step 5.

[0275] Step 7: 2-(1-((1H-imidazol-4-yl)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethanol (33-C). To a solution of 1-((1H-imidazol-4- 12886058v1 Page 302 of 494Attorney Docket No.2019292-0022 yl)methyl)-2-(2-(benzyloxy)ethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (33-B, 120 mg, 242.66 umol, 1 eq) in MeOH (10 mL) was added Pd / C (0.1 g, 10% purity). The mixture was stirred at 35°C for 12 hrs under H2 (15psi). Then filtered. The filtrate was concentrated under reduced pressure to give 2-(1-((1H-imidazol-4-yl)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethanol (80 mg, crude) as a white oil. ESI [M+H] = 405.3.

[0276] Step 8: 2-(1-((1H-imidazol-4-yl)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)acetaldehyde (33-D). To a mixture of 2-(1-((1H- imidazol-4-yl)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-2-yl)ethanol (33-C, 80 mg, 197.82 umol, 1 eq) in DCM (2 mL) was added DMP (117.47 mg, 276.95 umol, 1.4 eq). The mixture was stirred at 0°C for 1 hr. Then filtered. The filtrate was concentrated under reduced pressure to give 2-(1-((1H-imidazol-4- yl)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2- yl)acetaldehyde (33-D, 80 mg, crude) as a brown oil. ESI [M+H] = 403.2.

[0277] Step 9: 1-((1H-imidazol-4-yl)methyl)-2-(2-(azetidin-1-yl)ethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (33). To a mixture of 2-(1-((1H-imidazol-4-yl)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-2-yl)acetaldehyde (40 mg, 99.41 umol, 1 eq) and azetidine (11.35 mg, 199 umol, 2 eq) in DCM (1 mL) was added NaBH(OAc)3 (105.34 mg, 497.03 umol, 5 eq). The mixture was stirred at 20°C for 0.5 hrs. Then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18150*30mm*5um; flow rate: 25 mL / min; gradient: 1% – 30% B over 8 min; mobile phase A: 0.1% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give 1-((1H-imidazol-4-yl)methyl)-2-(2-(azetidin-1-yl)ethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (8.3 mg, 14% yield, TFA salt) as a red gum. ESI [M+H] = 444.2.1H-NMR (400MHz, CD3OD) δ = 8.79 (br s, 1H), 7.56 (s, 1H), 7.38 - 7.21 (m, 3H), 7.08 (t, J = 7.2 Hz, 1H), 4.76 - 4.64 (m, 2H), 4.52 (dd, J = 18.4, 14.8 Hz, 2H), 4.23 - 4.04 (m, 2H), 4.03 - 3.75 (m, 3H), 3.55 - 3.41 (m, 2H), 3.26 - 3.16 (m, 2H), 2.56 - 2.29 (m, 2H), 1.56 - 1.43 (m, 1H), 1.33 - 1.18 (m, 1H). 12886058v1 Page 303 of 494Attorney Docket No.2019292-0022

[0278] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 33 in Example 1.5, using analogous starting materials and / or intermediates. Compound #, Structure Analytical data 2 ), 0,

[0279] Example 1.6: 2-(1-((1H-imidazol-4-yl)methyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-1-(piperidin-1-yl)ethanone (37)

[0280] Steps - were carr ed out accord ng to procedures descrbed n xamp e 1.1, Steps 5-6, starting from 39-A (CAS #2110273-82-8). Trifluoromethanesulfonyl anhydride was used in Step 5.

[0281] Step 3: 2-(1-((1H-imidazol-4-yl)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-1-(piperidin-1-yl)ethanone (37). To a mixture of methyl 2-[1-(1H-imidazol-4-ylmethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4- benzodiazepin-2-yl]acetate (37-B, 40 mg, 92.50 umol, 1 eq), piperidine (15.75 mg, 185 umol, 2 eq) in toluene (1 mL) was added Al(CH3)3(2 M, 3 eq) at 0°C. The reaction mixture was stirred 12886058v1 Page 304 of 494Attorney Docket No.2019292-0022 at 100°C for 0.5 hrs under N2atmosphere. Then quenched by addition of saturated aqueous Na2CO3 (2 mL) at 0°C and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna 80*30mm*3um; flow rate: 25 mL / min; gradient: 15% – 50% B over 8 min; mobile phase A: 0.1% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give 2-(1-((1H-imidazol-4-yl)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-1-(piperidin-1- yl)ethanone (4.9 mg, 9% yield, TFA salt) as a white solid. ESI [M+H] = 486.2.1H-NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 7.72 (s, 1H), 7.35 - 7.27 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 4.70 - 4.54 (m, 4H), 3.88 (br s, 1H), 3.78 (br d, J = 13.6 Hz, 1H), 3.61 - 3.47 (m, 3H), 2.97 (br s, 2H), 2.23 (br dd, J = 16.8, 5.6 Hz, 1H), 1.93 (dd, J = 16.8, 7.6 Hz, 1H), 1.54 - 1.46 (m, 2H), 1.37 (br s, 2H), 1.34 - 1.23 (m, 1H), 1.22 - 1.13 (m, 1H)

[0282] Example 1.7: (1H-imidazol-4-yl)(2-phenethyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methanone (38)

[0283] To a m x ure o -p ene y - -((r uorome y )su ony )- , , ,5-tetrahydro-1H- benzo[e][1,4]diazepine (38-A, 100 mg, 260.14 umol, 0.5 eq, prepared according to procedures described in Example 1.1) and 1H-imidazole-4-carboxylic acid (58.32 mg, 520.27 umol, 1 eq) in pyridine (2 mL) was added POCl3 (159.55 mg, 1.04 mmol, 2 eq) at -30°C. The mixture was stirred at 0 °C for 2 hrs, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18150*40mm*10um; flow rate: 25 mL / min; gradient: 30% – 60% B over 8 min; mobile phase A: 10mM NH4HCO3 in 0.05%NH3H2O, mobile phase B: acetonitrile) to give (1H-imidazol-4-yl)(2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methanone (38, 8 mg, 3% yield) as a white solid. ESI [M+H] = 479.0.1H-NMR (400 MHz, DMSO-d6) δ = 7.98 12886058v1 Page 305 of 494Attorney Docket No.2019292-0022 (br s, 1H), 7.58 - 7.32 (m, 4H), 7.24 - 6.93 (m, 6H), 5.15 (s, 1H), 5.75 (s, 1H), 4.75 (t, 1H), 4.85 (s, 1H), 4.05 (s, 1H), 3.70 (t, 1H), 2.80 - 2.60 (m, 2H), 1.70 - 1.55 (m, 2H).

[0284] Example 1.8: 1-(2-(1-((1H-imidazol-4-yl)methyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethyl)piperidin-2-one (44) [02-imidazol-4- yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethanol (44-B). Intermediate 44-A (130 mg, 401 umol, 1 eq, prepared according to procedures described in Example 1.5) and 1- tritylimidazole-4-carbaldehyde (407 mg, 1.20 mmol, 3 eq), were treated according to procedure described in Example 1.1, Step 6 to afford 44-B (120 mg, 46.3% yield). ESI [M+H] = 647.4

[0286] Step 2: 2-(4-((trifluoromethyl)sulfonyl)-1-((1-trityl-1H-imidazol-4-yl)methyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethyl methanesulfonate (44-C). To a solution of 2-(4-((trifluoromethyl)sulfonyl)-1-((1-trityl-1H-imidazol-4-yl)methyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-2-yl)ethanol (50 mg, 77.31 umol, 1 eq) in DCM (2 mL) was added TEA (15.65 mg, 154.63 umol, 2 eq) and MsCl (19 mg, 165.86 umol, 2.15 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. Then concentrated, diluted with H2O (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(4-((trifluoromethyl)sulfonyl)-1-((1- trityl-1H-imidazol-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethyl methanesulfonate (40 mg, crude) as a white solid. ESI [M+H] = 725.4. 12886058v1 Page 306 of 494Attorney Docket No.2019292-0022

[0287] Step 3: 1-(2-(4-((trifluoromethyl)sulfonyl)-1-((1-trityl-1H-imidazol-4-yl)methyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethyl)piperidin-2-one (44-D). To a solution of piperidin-2-one (27.3 mg, 276 umol, 5 eq) in DMF (2 mL) was added NaH (6.62 mg, 165.56 umol, 60% purity, 3 eq). After stirring at 0°C for 1 hr, 2-(4-((trifluoromethyl)sulfonyl)-1-((1- trityl-1H-imidazol-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethyl methanesulfonate (44-C, 40 mg, 55 umol, 1 eq) was added. The reaction mixture was stirred at 20°C for 11 hrs. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and H2O (5 mL), then extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 0:1) to give 1-(2-(4- ((trifluoromethyl)sulfonyl)-1-((1-trityl-1H-imidazol-4-yl)methyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-2-yl)ethyl)piperidin-2-one (44-D, 20 mg, 42% yield) as a white solid. ESI [M+H] = 728.5.

[0288] Step 4: synthesis of 1-(2-(1-((1H-imidazol-4-yl)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethyl)piperidin-2- one (44). To a solution of 1-(2-(4-((trifluoromethyl)sulfonyl)-1-((1-trityl-1H-imidazol-4- yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)ethyl)piperidin-2-one (15 mg, 20.61 umol, 1 eq) in HCl / EtOAc (4 M, 1.00 mL) was stirred at 30°C for 4 hrs. Then concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 column (150 × 30 mm, 5um); flow rate: 25 mL / min; gradient: 5% – 45% B over 8 min; mobile phase A: 0.1% aqueous trifluoroacetic acid, mobile phase B: acetonitrile) to give 1-(2-(1-((1H-imidazol-4- yl)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2- yl)ethyl)piperidin-2-one (44, 3.3 mg, 27% yield, 100.00% purity, TFA salt) as a white solid. ESI [M+H] = 486.1.1H-NMR (400MHz, CD3OD) δ = 8.90 (d, J = 1.2 Hz, 1H), 7.59 (s, 1H), 7.39 - 7.28 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 4.75 - 4.64 (m, 2H), 4.60 - 4.47 (m, 2H), 3.97 (br d, J = 13.6 Hz, 1H), 3.72 - 3.61 (m, 1H), 3.46 - 3.36 (m, 1H), 3.28 (br dd, J = 5.2, 8.8 Hz, 2H), 3.19 - 3.03 (m, 2H), 2.37 - 2.28 (m, 2H), 1.84 - 1.74 (m, 4H), 1.59 - 1.45 (m, 1H), 1.32 - 1.21 (m, 1H). 12886058v1 Page 307 of 494Attorney Docket No.2019292-0022

[0289] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 44 in Example 1.8, using analogous starting materials and / or intermediates. Compound #, Structure Analytical data , 0 , ,

[0290] Example 1.9: 1-((1H-imidazol-4-yl)methyl)-2-cyclopentyl-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (48)

[0291] Step 1: (E)-methyl 2-((cyclopentylmethylene)amino)benzoate (48-B). To a mixture of cyclopentanecarbaldehyde (5 g, 50.95 mmol, 1 eq), methyl 2-aminobenzoate (7.70 g, 50.95 mmol, 1 eq) and ZnCl2(6.94 g, 50.95 mmol, 1 eq) in MeOH (10 mL) was stirred at -20°C for 1 hr. The reaction was warmed to room temperature and then concentrated under reduced pressure to give (E)-methyl 2-((cyclopentylmethylene)amino)benzoate (48-B, 10 g, crude) as a yellow oil. ESI [M+H] = 232.2. 12886058v1 Page 308 of 494Attorney Docket No.2019292-0022

[0292] Step 2: methyl 2-((cyano(cyclopentyl)methyl)amino)benzoate (48-C). To a mixture of (E)-methyl 2-((cyclopentylmethylene)amino)benzoate (48-B, 10 g, 43.24 mmol, 1 eq) in MeOH (10 mL) was added TMSCN (4.29 g, 43.24 mmol, 1 eq). The mixture was stirred at 65°C for 12 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give methyl 2-((cyano(cyclopentyl)methyl)amino)benzoate (48-C, 9 g, crude) as a yellow oil. ESI [M+H] = 259.2

[0293] Step 3: methyl 2-((2-amino-1-cyclopentylethyl)amino)benzoate (48-D). To a mixture of methyl 2-((cyano(cyclopentyl)methyl)amino)benzoate (48-C, 3 g, 11.61 mmol, 1 eq) in MeOH (50 mL) and H2O (5 mL) was added Ni (681.61 mg, 11.61 mmol, 1 eq), TEA (3.64 g, 35.92 mmol, 3.09 eq) under H2(15 Psi). The mixture was stirred at 20°C for 2 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Dichloromethane : Methanol = 100:1 to 10:1) to give methyl 2- ((2-amino-1-cyclopentylethyl)amino)benzoate (48-D, 800 mg, 26% yield) as a yellow solid. ESI [M+H] = 263.3

[0294] Step 4: synthesis of 2-cyclopentyl-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)- one (48-E). To a mixture of methyl 2-((2-amino-1-cyclopentylethyl)amino)benzoate (48-D, 800 mg, 3.05 mmol, 1 eq) in MeOH (15 mL) was added NaOMe (329.46 mg, 6.10 mmol, 2 eq). The mixture was stirred at 65°C for 24 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; flow rate: 25 mL / min; gradient: 27% – 57% B over 20 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-cyclopentyl-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (48-E, 200 mg, 28.48% yield) as a yellow solid. ESI [M+H] = 231.2.1H-NMR (400 MHz, CD3OD) δ = 7.29 - 7.17 (m, 1H), 7.24 – 7.21 (m, 1H), 6.80 - 6.70 (m, 2H), 3.46 - 3.41 (m, 1H), 3.40 - 3.35 (m, 1H), 3.33 - 3.30 (m, 1H), 2.09 - 2.07 (m, 1H), 1.92 – 1.72 (m, 2H), 1.71 - 1.61 (m, 4H), 1.60 – 1.43 (m, 1H), 1.25 - 1.23 (m, 1H).

[0295] Step 5: 2-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (48-F). From intermediate 48-E (100 mg, 441.96 umol, 1 eq) and LiAlH4 (247.17 mg, 6.51 mmol, 10 eq), 48-F (100 mg,crude) was made using the same procedure described in Example 1.1, Step 4. ESI [M+H] = 231.2 12886058v1 Page 309 of 494Attorney Docket No.2019292-0022

[0296] Step 6: 2-cyclopentyl-4-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepine (48-G). From intermediate 48-F (70 mg, 323.59 umol, 1 eq) and 4- (trifluoromethyl)benzene-1-sulfonyl chloride (79.16 mg, 323.59 umol, 1 eq), 48-G (50 mg, 36.40% yield) was made using the same procedure described in Example 1.1, Step 5. ESI [M+H] = 425.3

[0297] Step 7: 1-((1H-imidazol-4-yl)methyl)-2-cyclopentyl-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (48)

[0298] Using the same procedure as described in Example 1.1, Step 6, the title compound 48 (20.1 mg, 34.48% yield, TFA salt) was made from 48-G (50 mg, 94.23 umol, 1 eq) and 1H- imidazole-4-carbaldehyde (45.27 mg, 471.17 umol, 5 eq). ESI [M+H] = 505.1

[0299] 1H-NMR (400 MHz, CD3OD) δ = 8.74 (s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.50 (s, 1H), 7.25 - 7.31 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 4.86 (br s, 1H), 4.72 (dd, J = 13.6, 1.2 Hz, 1H), 4.51 (d, J = 15.2 Hz, 1H), 3.98 (dt, J = 12.4, 2.4 Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 3.10 - 3.17 (m, 1H), 2.79 (br d, J = 12.4 Hz, 1H), 1.94 - 2.03 (m, 1H), 1.75 - 1.86 (m, 1H), 1.56 - 1.72 (m , 3H), 1.33 - 1.46 (m , 3H), 1.02 - 1.15 (m , 1H).

[0300] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 48 in Example 1.9, using analogous starting materials and / or intermediates. 12886058v1 Page 310 of 494Attorney Docket No.2019292-0022 Compound #, Structure Analytical data J J12886058v1 Page 311 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 573.1.1H-NMR (400 54 MHz, CD3OD) δ 8.06 (d, J = 8.0 Hz, 0 , , - z, J 7 912886058v1 Page 312 of 494Attorney Docket No.2019292-0022 (m, 2H), 1.14 - 1.02 (m, 2H), 1.01 - 0.91 (m, 1H). 7 8 ,12886058v1 Page 313 of 494Attorney Docket No.2019292-0022 6 ESI [M+H] = 5417 7.1. H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (br s, z, s, , 5 512886058v1 Page 314 of 494Attorney Docket No.2019292-0022 1H-NMR (400 MHz, CD3OD) δ = 8.79 (s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.98 7 r 5 9 7 r 5 7 , 6 -12886058v1 Page 315 of 494Attorney Docket No.2019292-0022 79-2 (**)1H-NMR (400 MHz, CDCl3) δ = 7.62 - 7.54 (m, 4H), 7.29 (s, 1H), 7.24 J , 7 8 4 , ,12886058v1 Page 316 of 494Attorney Docket No.2019292-0022 1H-NMR (400 MHz, CD3OD) δ = 8.08 82-1 (**) (br d, J = 8.4 Hz, 2H), 7.95 (br d, J = J , 8 8 8 - ), , ,12886058v1 Page 317 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 439.2.1H-NMR (400 84 MHz, CD3OD) 7.89 (s, 1H), 7.32 - s, J 8 1 = = r 8 z, 612886058v1 Page 318 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 563.3.1H-NMR (400 88 MHz, CD3OD) δ = 8.06 (d, J = 8.4 Hz,12886058v1 Page 319 of 494Attorney Docket No.2019292-0022 94 ESI [M+H] = 435.1.1H-NMR (400 MHz, CD3OD) δ = 8.04 (br s, 1H), , 98 - ), 10 - ,12886058v1 Page 320 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 4071104 .1. H-NMR (400 MHz, CD3OD) δ = 7.84 (s, 1H), 7.33 - 4 - ), J , -12886058v1 Page 321 of 494Attorney Docket No.2019292-0022 111 ESI [M+H] = 480.3.1H-NMR (400 , 1 z, - 4 r12886058v1 Page 322 of 494Attorney Docket No.2019292-0022 127 ESI [M+H] = 525.0.1H-NMR (400 MHz, CD3OD) δ = 7.79 (s, 1H), 7.39 - z, 1 5 , , 812886058v1 Page 323 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 471.2.1H-NMR (400 129-1 (*) MHz, CD3OD) δ = 7.66 (d, J = 0.8 Hz, 1 12 5 13 - = 812886058v1 Page 324 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 475.2.1H-NMR (400 MHz, CD3OD) δ = 8.30 (s, 1H), 7.93 - = , - = z,12886058v1 Page 325 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 475.2.1H-NMR (400 133-1 (*) MHz, CD3OD) δ = 7.93 - 7.79 (m, , , r 0 , ), 412886058v1 Page 326 of 494Attorney Docket No.2019292-0022 1H-NMR (400 MHz, CD3OD) δ = 7.62 160-2 (****) (s, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), ), 4

[0301] ( ters SFC150APpreparative SFC; Column: DAICEL CHIRALCEL OD (250m * 30mm,10um); Mobile phase: A: CO2, B 0.1%NH3H2O in EtOH; Gradient: B%=20% isocratic elution mode; Flow rate:CO2(14 g / min),B(56 mL / min); Wavelength:220nm; Column temperature: 35 °C.

[0302] (**) Racemic material was separated by SFC (Instrument: Waters SFC80 preparative SFC； Column: Chiralcel CD-3 (50mm * 4.6mm,3um); Mobile phase A:CO2 and B:0.1%NH3H2O in EtOH; Gradient: B%=5% isocratic elution mode; Flow rate: CO2(3.23g / mim), B(0.17mL / min); Wavelength:220nm; Column temperature: 35 ℃.

[0303] (***) Racemic material was separated by SFC (Instrument: Waters SFC80 preparative SFC; Column: Phenomenex-Cellulose-2 (250 mm * 30 mm, 5 um); Mobile phase A: CO2 and B: 0.1% NH3H2O in EtOH; Gradient: B%=10% isocratic elution mode; Flow rate: CO2 (900 g / min), B (100 mL / min); Wavelength: 220 nm; Column temperature: 30 °C.

[0304] (****) Racemic material was separated by SFC (Instrument: Waters SFC80 preparative SFC；Column: DAICEL CHIRALPAK IG (250mm × 30mm,10um); Mobile phase A : CO2and B: 0.01%NH3.H2O in IPA; Gradient: B%=5% isocratic elution mode; Flow rate: CO2(20 g / min), B (40 mL / min); Wavelength:220nm; Column temperature: 30 °C to generate two enantiomers.

[0305] Example 1.10: 1-((1H-imidazol-4-yl)methyl)-2-((cyclopentyloxy)methyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (66) 12886058v1 Page 327 of 494Attorney Docket No.2019292-0022 [030ution of 2-iodobenzonitrile (66-A, 9.97 g, 43.5 mmol, 1.1 eq) and methyl aziridine-2-carboxylate (4 g, 39.5 mmol, 1 eq) in toluene (100 mL) was added Cs2CO3(25.78 g, 79.13 mmol, 2 eq), BINAP (4.93 g, 7.91 mmol, 0.2 eq) and Pd2(dba)3 (3.62 g, 3.96 mmol, 0.1 eq). The mixture was stirred at 110°C for 3 hrs under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.

[0307] The reaction mixture was purified by preparative HPLC (Welch Xtimate C18 column (250×70mm，10um); flow rate: 25 mL / min; gradient: 15% - 45% B over 20 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give methyl 1-(2- cyanophenyl)aziridine-2-carboxylate (66-B, 3.63 g, 45.4% yield) as a light yellow oil. ESI [M+H] = 203.1

[0308] Step 2: methyl 2-((2-cyanophenyl)amino)-3-(cyclopentyloxy)propanoate (66-C). To a solution of BF3.Et2O (1.71 g, 6.01 mmol, 50% purity, 0.5 eq) in CHCl3 (10 mL) was added methyl 1-(2-cyanophenyl)aziridine-2-carboxylate (66-B, 2.43 g, 12.02 mmol, 1 eq) and cyclopentanol (3.11 g, 36.05 mmol, 3 eq) at 0°C. The mixture was stirred at 20°C for 1 hr under N2. Then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex luna C18 column (250 × 70mm, 15 um); flow rate: 25 mL / min; gradient: 60% - 80% B over 20 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give methyl 2-((2-cyanophenyl)amino)-3-(cyclopentyloxy)propanoate (66-C, 200 mg, 6% yield) as a brown solid. ESI [M+H] = 289.0.1H-NMR (400 MHz, CD3OD) δ = 7.48 - 7.43 (m, 2H), 6.88 12886058v1 Page 328 of 494Attorney Docket No.2019292-0022 (dd, J = 4.0 Hz, 1H), 6.75 (t, J = 1.6 Hz, 1H), 4.31 - 4.15 (m, 1H), 4.12 - 4.01 (m, 1H), 3.81 - 3.73(s, 3H), 3.71 - 3.62 (m, 1H), 3.51 - 3.39 (m, 1H), 1.84 - 1.57 (m, 6H), 1.53 - 1.43 (m, 2H).

[0309] Step 3: synthesis of 2-((cyclopentyloxy)methyl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-3(2H)-one (66-D). To a mixture of methyl 2-((2-cyanophenyl)amino)-3- (cyclopentyloxy)propanoate (66-C, 180 mg, 624 umol, 1 eq) in MeOH (5 mL) was added TEA (0.5 mL) and H2O (0.6 mL) and Ni (0.2 g). The mixture was stirred at 20°C for 1 hr under the H2 (15psi). Then reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-((cyclopentyloxy)methyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (120 mg, 460.95 umol, 73.84% yield) as a brown oil. ESI [M+H] = 261.2.

[0310] Steps 4-6: 1-((1H-imidazol-4-yl)methyl)-2-((cyclopentyloxy)methyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (66)

[0311] Steps 4-6 were carried out according to procedures 4-6 in Example 1.1 to afford the title compound 66. ESI [M+H] = 535.1.1H-NMR (400 MHz, CD3OD) δ = 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.28 - 7.21 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.02 - 6.92 (m, 2H), 4.68 (br d, J = 13.6 Hz, 1H), 4.43 (br d, J = 9.6 Hz, 2H), 3.95 (d, J = 13.6 Hz, 1H), 3.85 (br d, J = 12.4 Hz, 1H), 3.54 (br d, J = 4.4 Hz, 1H), 3.48 - 3.43 (m, 1H), 3.03 (d, J = 7.2 Hz, 2H), 2.72 (dd, J = 12.8, 2.8 Hz, 1H), 1.67 - 1.54 (m, 4H), 1.53 - 1.41 (m, 3H), 1.41 - 1.34 (m, 1H)

[0312] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 66 in Example 1.10, using analogous starting materials and / or intermediates. 12886058v1 Page 329 of 494Attorney Docket No.2019292-0022 Compound #, Structure Analytical data z, 2 3 ). z,12886058v1 Page 330 of 494Attorney Docket No.2019292-0022 151 ESI [M+H] = 473.1.1H-NMR (400 MHz, CD3OD) δ = 4 J 2 , ), 5 312886058v1 Page 331 of 494Attorney Docket No.2019292-0022 152 ESI [M+H] =549.3.1H-NMR (400 MHz, CD3OD) δ = , ), , , , J12886058v1 Page 332 of 494Attorney Docket No.2019292-0022 186 ESI [M+H] = 527.0.1H-NMR (400 MHz, CD3OD) δ = = 7 , = 1 ),12886058v1 Page 333 of 494Attorney Docket No.2019292-0022 224 19 z, ), - H) 8 d, br 9 δ 7 6 8 ), .6 ), -12886058v1 Page 334 of 494Attorney Docket No.2019292-0022 239 1 74 = .0 ), z, 0 = m, z, 3 m, 0 z, ), - -12886058v1 Page 335 of 494Attorney Docket No.2019292-0022 495-1 (***) 4 = 7 - 6 4 = 0 - 9 - 2 ), m, - 2 ), m,12886058v1 Page 336 of 494Attorney Docket No.2019292-0022 505-2 1 z, ), J 0 J .8 ), 712886058v1 Page 337 of 494Attorney Docket No.2019292-0022 148 F = s, ), - 3 7 7 7 s, s, ), m 9 H) 5 - 3 H) ).12886058v1 Page 338 of 494Attorney Docket No.2019292-0022 153 ESI [M+H] = 487.2.1H NMR (400 MHz, CD3OD) δ ppm 0 6 - z, ), m, 5 ), d, z, s, 7 ), m, 7 3 ), br ), = ), 1 z, 3 br .6 2 ), m,12886058v1 Page 339 of 494Attorney Docket No.2019292-0022 405-1 SFC chiral separation of compound 405 gave Peak 2 (Rt=3.410 min) ESI [M+H] = 499.1.1H NMR (400 ), 5 = z, 4 ), [0preparative SFC； Column: Chiralcel OD-3 (50 mm × 4.6 mm, 3 um); Mobile phase A: CO2 and B: 0.1% IPA in MeOH; Gradient: B%=22% isocratic elution mode; Flow rate: A(12 g / min), B(3.4 mL / min); Wavelength: 220 nm; Column temperature: 35°C.

[0314] (**) TEA in EtOH was used to form the aziridine intermediate, HCl in EtOAc was used in Step 3 to deprotect the Boc group.

[0315] (***) Racemic material was separated by SFC (Instrument: Waters SFC80 preparative SFC； Column: Chiralcel OD (250mm × 30mm,10um); Mobile phase A: CO2 and B：0.1%NH3H2O in IPA; Gradient: B%=20% isocratic elution mode. Flow rate: CO2(14 g / min), B (56 mL / min); Wavelength: 220nm; Column temperature: 35°C.

[0316] (****) Racemic material was separated by SFC (Instrument: GX-281; Column: Phenomenex-Cellulose-2 (250mm × 30mm,10um); Mobile phase A : Heptane and B : IPA; Gradient: B%=10% ; Flow rate: Heptane (36 mL / min),B (4 mL / min); Wavelength:220 nm).

[0317] (*****) Conversion of F to OMe group after Step 1 was carried out using NaH in MeOH / THF mixture.

[0318] Example 1.11: 1-(1H-imidazol-4-yl)ethyl)-2-(2-cyclopentylethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine 12886058v1 Page 340 of 494Attorney Docket No.2019292-0022 CF3O O S N

[0319] ep : sy ess o - - y- - ao--y e ao. ue o 1- tritylimidazole-4-carbaldehyde (2 g, 5.91 mmol, 1 eq) in THF (20 mL) was added MeMgBr (3 M, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 hrs under the N2.The reaction mixture was diluted with H2O 30 mL and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate =10:1 to 1:3) to give 1- (1-trityl-1H-imidazol-4-yl)ethanol (1.2 g, 3.39 mmol, 57.28% yield) as a brown oil. ESI [M+H] = 355.2

[0320] Step 2: synthesis of 4-(1-chloroethyl)-1-trityl-1H-imidazole. A mixture of 1-(1- tritylimidazol-4-yl)ethanol, 900 mg, 2.54 mmol, 1 eq) in CHCl3(1 mL) was added thionyl 12886058v1 Page 341 of 494Attorney Docket No.2019292-0022 chloride (604.18 mg, 5.08 mmol, 2 eq). The mixture was stirred at 60 °C for 1 hr and concentrated under reduced pressure to give 4-(1-chloroethyl)-1-trityl-1H-imidazole (940 mg, crude) as a white solid. ESI [M+H] = 373.1.

[0321] Step 3: synthesis of rel-(s)-1-((r)-1-(1H-imidazol-4-yl)ethyl)-2-(2- cyclopentylethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine and rel-(s)-1-((s)-1-(1H-imidazol-4-yl)ethyl)-2-(2-cyclopentylethyl)-4- ((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine. To a mixture of 4-(1-chloroethyl)-1-trityl-imidazole (659.21 mg, 1.77 mmol, 2 eq) and 2-(2- cyclopentylethyl)-4-[4-(trifluoromethyl)phenyl]sulfonyl-1,2,3,5-tetrahydro-1,4-benzodiazepine (400 mg, 884 umol, 1 eq, prepared according to procedures in Example 1.8) in DMF (10 mL) was added K2CO3(366.50 mg, 2.65 mmol, 3 eq) and NaI (397.47 mg, 2.65 mmol, 3 eq). The mixture was stirred at 60°C for 5 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 (100 * 30mm，10um); flow rate: 25 mL / min; gradient: 20% – 90% B over 8 min; mobile phase A: 0.05%NH3H2O+10mM NH4HCO3, mobile phase B: acetonitrile) to give a mixture of two enantiomers 1-(1H-imidazol-4-yl)ethyl)-2-(2-cyclopentylethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (523-1) (71.6 mg, 14.4% yield) as a white solid. ESI [M+H] = 547.1.1H-NMR (400 MHz, CD3OD) δ = 8.07 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.59 - 7.44 (m, 1H), 7.31 - 7.23 (m, 2H), 7.18 - 7.08 (m, 1H), 6.98 (br t, J = 7.2 Hz, 1H), 4.83 (br s, 1H), 4.70 (dd, J = 13.6, 1.6 Hz, 1H), 3.87 - 3.75 (m, 2H), 3.54 - 3.38 (m, 1H), 2.77 (dd, J = 12.4, 2.4 Hz, 1H), 1.56 - 1.33 (m, 10H), 1.13 - 0.73(m, 6H).

[0322] A second mixture of enantiomers (523-2) was also isolated 1-(1H-imidazol-4- yl)ethyl)-2-(2-cyclopentylethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (59.3 mg, 12% yield) as a white solid. ESI [M+H] = 547.1.1H-NMR (400 MHz, CD3OD) δ = 8.07 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.59 - 7.44 (m, 1H), 7.31 - 7.24 (m, 2H), 7.17 - 7.08 (m, 1H), 6.98 (br t, J = 7.2 Hz, 1H), 4.83 (br s, 1H), 4.70 (dd, J = 13.6, 1.6 Hz, 1H), 3.87 - 3.75 (m, 2H), 3.65 - 3.74 (m, 1H), 2.77 (dd, J = 12.4, 2.4 Hz, 1H), 1.56 - 1.29 (m, 10H), 1.15 - 0.80 (m, 6H). 12886058v1 Page 342 of 494Attorney Docket No.2019292-0022

[0323] Compound 523-1 was further separated using SFC (Instrument: Waters SFC80 preparative SFC； Column: DAICEL CHIRALPAK IC(250mm*30mm,10um); Mobile phase: A CO2and B 0.1%NH3H2O in EtOH; Gradient: B%=35% isocratic elution mode; Flow rate: CO2(24.5 g / min) B(45.5 mL / min); Wavelength:220nm; Column temperature: 40℃；System back pressure: 100 bar. ) to generate two enantiomers.

[0324] Compound 523-2 was further separated using SFC (Instrument: Waters SFC80 preparative SFC； Column: DAICEL CHIRALPAK IC (250mm*30mm,10um); Mobile phase: A CO2and B 0.1%NH3H2O in EtOH; Gradient: B%=35% isocratic elution mode; Flow rate: CO2(24.5 g / min) B(45.5 mL / min); Wavelength:220nm; Column temperature: 40℃；System back pressure: 100 bar. ) to generate two enantiomers.

[0325] 1-(1H-imidazol-4-yl)ethyl)-2-(2-cyclopentylethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (523-2-1), 3.9 mg, 7% yield).1H-NMR (400 MHz, CD3OD) δ = 8.01 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.28 - 7.22 (m, 2H), 7.21 - 7.16 (m, 1H), 7.02 - 6.91 (m, 2H), 4.76 (q, J = 6.8 Hz, 1H), 4.64 (br d, J = 13.6 Hz, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.69 (br d, J = 12.4 Hz, 1H), 3.32 (br s, 1H), 2.24 (br d, J = 11.6 Hz, 1H), 1.69 - 1.42 (m, 10H), 1.36 - 1.28 (m, 1H), 1.27 - 1.14 (m, 2H), 1.13 - 0.88 (m, 3H).

[0326] 1-(1H-imidazol-4-yl)ethyl)-2-(2-cyclopentylethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (523-2-2), 21.9 mg, 36% yield).1H NMR (400 MHz, CD3OD) δ = 8.07 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.57 - 7.39 (m, 1H), 7.32 - 7.22 (m, 2H), 7.13 (br s, 1H), 6.97 (t, J = 7.2 Hz, 1H), 4.83 (br d, J = 6.8 Hz, 1H), 4.70 (dd, J = 13.6, 1.6 Hz, 1H), 3.85 - 3.73 (m, 2H), 3.47 - 3.35 (m, 1H), 2.77 (dd, J=12.4, 2.4 Hz, 1H), 1.54 - 1.31 (m, 9H), 1.15 - 1.02 (m, 1H), 0.98 - 0.71 (m, 6H)

[0327] 1-(1H-imidazol-4-yl)ethyl)-2-(2-cyclopentylethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (523-1-2), 5.2 mg, 9.30% yield).1H-NMR (400 MHz, CD3OD) δ = 8.01 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.30 - 7.22 (m, 2H), 7.21 - 7.16 (m, 1H), 7.02 - 6.91 (m, 2H), 4.76 (q, J = 6.8 Hz, 1H), 4.63 (br d, J = 13.6 Hz, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.69 (br d, J = 12.4 Hz, 1H), 12886058v1 Page 343 of 494Attorney Docket No.2019292-0022 3.35 (br s, 1H), 2.24 (br d, J = 11.6 Hz, 1H), 1.72 - 1.42 (m, 10H), 1.36 - 1.26 (m, 1H), 1.27 - 1.13 (m, 2H), 1.13 - 0.88 (m, 3H).

[0328] 1-(1H-imidazol-4-yl)ethyl)-2-(2-cyclopentylethyl)-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (523-1-1), (19.09 mg, 31.6% yield).1H NMR (400 MHz, CD3OD) δ = 8.04 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H) 7.57 - 7.39 (m, 1H), 7.28 - 7.20 (m, 2H), 7.10 (br s, 1H), 6.95 (t, J =7.2 Hz, 1H), 4.80 (br d, J = 6.8 Hz, 1H), 4.67 (dd, J = 13.6, 1.6 Hz, 1H), 3.85 - 3.73 (m, 2H), 3.47 - 3.35 (m, 1H), 2.75 (dd, J=12.4, 2.4 Hz, 1H), 1.54 - 1.30 (m, 9H), 1.13 - 0.99 (m, 1H), 0.98 - 0.68 (m, 6H)

[0329] Example 1.12: 1-((1H-imidazol-4-yl)methyl)-2-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (140).

[0330] Step 1: methyl 2-((diphenylmethylene)amino)-4-(tetrahydro-2H-pyran-4- yl)butanoate (140-B). To a mixture of methyl 2-((diphenylmethylene)amino)acetate (5.90 g, 23.31 mmol, 1.5 eq) in DMF (50 mL) and Tol. (50 mL) was added t-BuOK (1.74 g, 15.54 mmol, 1.5 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr, then 4-(2-bromoethyl)tetrahydro-2H- 12886058v1 Page 344 of 494Attorney Docket No.2019292-0022 pyran (3 g, 15.54 mmol, 1 eq) was added to the mixture at 0°C. The mixture was stirred at 0°C for 1 hr under N2. Then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 5:1) to give methyl 2-((diphenylmethylene)amino)-4-(tetrahydro-2H-pyran-4-yl)butanoate (140-B, 2.8 g, 7.66 mmol, 49.31% yield) as a white solid. ESI [M+H] = 366.1.1H-NMR (400 MHz, CD3OD) δ = 7.62 - 7.56 (m, 2H), 7.56 - 7.50 (m, 3H), 7.47 - 7.43 (m, 1H), 7.41 - 7.35 (m, 2H), 7.23 - 7.17 (m, 2H), 4.08 (dd, J = 8.0, 5.2 Hz, 1H), 3.89 (br dd, J = 11.2, 3.2 Hz, 2H), 3.73 (s, 3H), 3.34 - 3.39 (m, 1H), 3.28 - 3.32 (m, 1H), 1.94 - 2.04 (m, 1H), 1.92 - 1.81 (m, 1H), 1.61 - 1.51 (m, 2H), 1.36 (dtd, J = 10.0, 7.2, 7.2, 3.6 Hz, 1H), 1.26 - 1.13 (m, 4H)

[0331] Step 2: methyl 2-amino-4-(tetrahydro-2H-pyran-4-yl)butanoate (140-C). To a mixture of methyl 2-((diphenylmethylene)amino)-4-(tetrahydro-2H-pyran-4-yl)butanoate (140- B, 2 g, 5.47 mmol, 1 eq) in THF (12 mL), H2O (12 mL) and AcOH (7.2 mL). The mixture was stirred at 20°C for 2.5 hrs. Then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18 column (150 × 30mm,5um); flow rate: 25 mL / min; gradient: 1% - 30% B over 10 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give methyl 2-amino-4-(tetrahydro-2H-pyran-4-yl)butanoate (140-C, 750 mg, 3.03 mmol, 55.42% yield, FA salt) as a white solid. ESI [M+H] = 202.3.1H-NMR (400 MHz, CD3OD) δ = 3.96 - 4.03 (m, 1H), 3.89 (dd, J = 11.2, 4.0 Hz, 2H), 3.80 (s, 3H), 3.36 (td, J = 11.6, 1.6 Hz, 2H), 3.27 (dt, J = 3.2, 1.6 Hz, 1H), 1.81 - 1.99 (m, 2H), 1.56 - 1.67 (m, 2H), 1.50 (qd, J = 7.2, 3.6 Hz, 1H), 1.37 (br dd, J = 11.2, 6.0 Hz, 1H), 1.18 - 1.31 (m, 2H).

[0332] Step 3: methyl 2-((2-cyanophenyl)amino)-4-(tetrahydro-2H-pyran-4-yl)butanoate (140-D). To a mixture of methyl 2-amino-4-(tetrahydro-2H-pyran-4-yl)butanoate (140-C, 290.01 mg, 1.44 mmol, 1.1 eq) and 2-iodobenzonitrile (300 mg, 1.31 mmol, 1 eq) in Tol. (4 mL) was added Cs2CO3(853.61 mg, 2.62 mmol, 2 eq), Pd2(dba)3(119.95 mg, 130.99 umol, 0.1 eq) and BINAP (163.13 mg, 261.99 umol, 0.2 eq) at 25°C. The mixture was stirred at 110°C for 3 hrs under N2 atmosphere. Then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 3:1) to give methyl 2-((2-cyanophenyl)amino)-4-(tetrahydro-2H-pyran-4-yl)butanoate (260 mg, 859.88 umol, 65.64% yield) as a yellow solid. ESI [M+H] = 303.1.1H-NMR (400 MHz, CD3OD) δ = 7.48 - 7.38 (m, 2H), 6.80 - 6.71 (m, 2H), 4.40 - 4.19 (m, 1H), 3.95 - 3.88 (m, 12886058v1 Page 345 of 494Attorney Docket No.2019292-0022 2H), 3.74 (s, 3H), 3.43 - 3.36 (m, 2H), 2.02- 1.86 (m, 2H), 1.67 - 1.59 (m, 2H), 1.54 (ddd, J = 10.8, 7.2, 4.0 Hz, 1H), 1.45 - 1.35 (m, 2H), 1.31 - 1.21 (m, 2H).

[0333] Step 4 was carried out as described in Example 1.9, Step 3. Steps 5-7 were carried out according to procedures 4-6 in Example 1.1 to afford the Title compound 140: ESI [M+H] = 473.1.1H-NMR (400 MHz, CD3OD) δ = 7.92 (s, 1H), 7.38 - 7.29 (m, 1H), 7.28 - 7.19 (m, 3H), 7.03 (t, J = 7.2 Hz, 1H), 4.69 (br d, J = 14.4 Hz, 1H), 4.56 - 4.41 (m, 3H), 3.91 - 3.78 (m, 3H), 3.39 - 3.34(m, 2H), 3.33 - 3.28 (m, 2H), 1.54 - 1.43 (m, 2H), 1.35 - 1.03 (m, 7H).

[0334] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 140 in Example 1.12, using analogous starting materials and / or intermediates. Compound #, Structure Analytical data 5 7 0 ), 2 r ), , 0

[0335] Example 1.13: (R)-1-((1H-imidazol-4-yl)methyl)-2-(2-cyclopentylethyl)-4-((4- fluoropiperidin-1-yl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (522-1) 12886058v1 Page 346 of 494Attorney Docket No. 2019292-0022trifluoromethanesulfonate (219-B). To a solution of 1,1'-sulfonylbis(1H)-imidazole) (5 g, 25.23 mmol, 1 eq) in DCM (30 mL) was added methyl trifluoromethanesulfonate (4.14 g, 25.23 mmol, 1 eq) at 0°C. The mixture was stirred at 0°C for 4 hrs. And then concentrated under reduced pressure to give 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (219-B, 5 g, crude) as a white solid. ESI [M+H] = 213.1

[0337] Step 2: 1-((1H-imidazol-1-yl)sulfonyl)-4-fluoropiperidine (219-C). To a solution of 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (219- B, 1.24 g, 5.82 mmol, 2 eq) in ACN (20 mL) was added 4-fluoropiperidine (300 mg, 2.91 mmol, 1 eq). The mixture was stirred at 25°C for 12 hrs. Then concentrated under reduced pressure. The residue was purified by preparative HPLC (C18-1 column (75 × 30 mm, 3 um); flow rate: 50 mL / min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 1-((1H-imidazol-1-yl)sulfonyl)-4-fluoropiperidine (219-C, 290 mg, 1.04 mmol, 35.70% yield, FA salt) as a white solid. ESI [M+H] = 234.1

[0338] Step 3: 1-((4-fluoropiperidin-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (219-D). To a solution of 1-((1H-imidazol-1-yl)sulfonyl)-4- fluoropiperidine (219-C, 290 mg, 1.24 mmol, 1 eq) in DCM (2 mL) was added methyl trifluoromethanesulfonate (204.02 mg, 1.24 mmol, 1 eq) at 0°C. The mixture was stirred at 0°C for 4 hrs. And then concentrated under reduced pressure to give 1-((4-fluoropiperidin-1- 12886058v1 Page 347 of 494Attorney Docket No.2019292-0022 yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (219-D, 290 mg, crude) as a white solid. ESI [M+H] = 248.1.

[0339] Step 4: 2-(2-cyclopentylethyl)-4-((4-fluoropiperidin-1-yl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (single enantiomer) (219-E). To a solution of 1-((4- fluoropiperidin-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (219-D, 76.20 mg, 306.91 umol, 1.5 eq, crude from Step 3) in ACN (1 mL) was added 2-(2- cyclopentylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (402-B-1) (50 mg, 204.60 umol, 1 eq). The mixture was stirred at 25°C for 12 hrs. Then concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 3:1) to give 2-(2- cyclopentylethyl)-4-((4-fluoropiperidin-1-yl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (219-E, 60 mg, 146.50 umol, 71.60% yield) as a white solid. ESI [M+H] = 410.3.

[0340] Step 5: 1-((1H-imidazol-4-yl)methyl)-2-(2-cyclopentylethyl)-4-((4- fluoropiperidin-1-yl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (522-1). The title compound was made using the same procedure as in Example 1.1, Step 6. ESI [M+H] = 490.2.1H-NMR (400 MHz, CD3OD) δ = 8.41 (br s, 1H), 7.81 (s, 1H), 7.31 - 7.20 (m, 2H), 7.17 - 7.06 (m, 2H), 6.97 (t, J = 7.2 Hz, 1H), 4.87 - 4.69 (m, 1H), 4.61 - 4.44 (m, 2H), 4.41 - 4.33 (m, 1H), 4.23 (d, J = 14.0 Hz, 1H), 3.71 (br d, J = 12.8 Hz, 1H), 3.32 - 3.20 (m, 5H), 3.09 (dd, J = 13.2, 2.4 Hz, 1H), 2.09 - 1.95 (m, 1H), 1.94 - 1.81 (m, 3H), 1.75 - 1.41 (m, 7H), 1.39 - 1.18 (m, 3H), 1.14 - 0.86 (m, 3H).

[0341] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 522-1 in Example 1.13, using analogous starting materials and / or intermediates. 12886058v1 Page 348 of 494Attorney Docket No.2019292-0022 Compound #, Structure Analytical data ), , 0 ), , 5 - z, 2 z, 0 - 3 0 - ), 4 1 J z, = 4 , 0 ,12886058v1 Page 349 of 494Attorney Docket No.2019292-0022 494-1 [M+H] = 526.4.1H-NMR (400 MHz, CD3OD) δ = 7.88 (s, 1H), 7.27 - 7.18 J 9 z, 5 .4 z, 6 49 0 - 8 z, 1 8 , = ), , 0 z, 52 1 2 ), = 4, 2 4 = 2- 012886058v1 Page 350 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 512.2.1H-NMR (400 MHz, CD3OD) δ = 7.77 (d, J = 1.2 Hz, 527-1 11 2 ), = 4, 2 4 = 2 ), n e I z, ), z, ), , 5 .4 - z, ), z, =

[0342] Example 1.14: 1-((1H-imidazol-5-yl)methyl)-2-(2-cyclopentylethyl)-6-phenyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (513-1 and 513-2).12886058v1 Page 351 of 494Attorney Docket No.2019292-0022

[0343] Step 1: 2-(2-cyclopentylethyl)-6-phenyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (283-B). To a solution of 6-chloro-2-(2- cyclopentylethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine 283-A (160 mg, 389.41 umol, 1 eq) in dioxane (2 mL) and H2O (0.2 mL) was added XPHOS- PD-G2 (34 mg, 44 umol, 0.1 eq), phenylboronic acid (56.98 mg, 467.29 umol, 1.2 eq) and K3PO4 (186 mg, 480 umol, 2 eq). The mixture was stirred at 80°C for 12 hr under N2. The residue was purified by prep-TLC (Petroleum ether:EtOAc = 3:1) to give 283-B (200 mg, 486.76 umol, 27.14% yield), ESI [M+H] =453.1

[0344] Step 2 was carried out according to Step 6 in Example 1.1 to afford racemic product. Enantiomeric separation was carried out using SFC (column: DAICEL CHIRALCEL OD(250mm×30mm, 10 um) to afford two enantiomers: 513-2 ESI [M+H] = 533.21H NMR (400 MHz, CD3OD) δ = 7.72 (s, 1H), 7.42 - 7.39 (m, 1H), 7.39 - 7.34 (m, 2H), 7.34 - 7.30 (m, 1H), 7.28 - 7.19 (m, 3H), 7.09 (s, 1H), 6.93 (s, 1H), 4.68 - 4.47 (m, 1H), 4.45 (s, 2H), 4.42 - 4.33 (m, 1H), 3.70 - 3.51 (m, 1H), 3.25 (br d, J = 1.2 Hz, 2H), 1.76 - 1.63 (m, 3H), 1.62 - 1.54 (m, 2H), 1.53 - 1.39 (m, 3H), 1.35 - 1.23 (m, 2H), 1.13 - 1.03 (m, 2H), 1.02 - 0.95 (m, 1H) and 513-1 ESI [M+H] = 533.21H NMR (400 MHz, CD3OD) δ = 7.73 (d, J = 1.2 Hz, 1H), 7.42 - 7.40 (m, 1H), 7.38 (br d, J = 3.6 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.24 (s, 3H), 7.09 (s, 1H), 6.95 - 6.90 (m, 1H), 4.49 (s, 1H), 4.47 - 4.44 (m, 2H), 4.43 - 4.36 (m, 1H), 3.70 - 3.53 (m, 1H), 3.26 (br d, J = 10.4 Hz, 2H), 1.72 - 1.63 (m, 3H), 1.61 - 1.55 (m, 2H), 1.54 - 1.43 (m, 3H), 1.29 (ddd, J = 16.0, 10.0, 5.6 Hz, 2H), 1.12 - 1.03 (m, 2H), 1.02 - 0.95 (m, 1H).

[0345] Compounds in the following table were prepared according to procedures analogous to preparation of Compounds 513-1 and 513-2 in Example 1.14, using analogous starting materials and / or intermediates. 12886058v1 Page 352 of 494Attorney Docket No.2019292-0022 Compound #, Structure Analytical data 1 , 2 1 1 z,12886058v1 Page 353 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 534.21H NMR (400 498-2 MHz, CD3OD) δ = 8.58 (d, J = 5.6 Hz, 1 z, , , z, 8 4 ), ),12886058v1 Page 354 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 534.21H NMR (400 MHz, CD3OD) δ = 8.62 - 8.53 (m, 499-1 , z, 5 , 4 , r12886058v1 Page 355 of 494Attorney Docket No.2019292-0022 316-2 ESI [M+H] = 467.21H NMR (400 MHz, CDCl3) δ = 7.77 - 7.66 (m, 1H), 0 , ), , 4 ,12886058v1 Page 356 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 531.31H NMR (400 342 MHz, DMSO-d6) δ = 8.33 (br s, 1H), , 0 z, . ), , s, ,12886058v1 Page 357 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 505.21H NMR (400 MHz, CD3OD) δ = 7.77 (d, J = 0.8 Hz, 346 4 , - , ), z,12886058v1 Page 358 of 494Attorney Docket No.2019292-0022 322 ESI [M+H] = 509.21H NMR (400 MHz, CD3OD) δ = 7.24 - 7.15 (m, ), , 2 , -

[0346] Example 1.15: 2-((1-((1H-imidazol-4-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-yl)oxy)ethanamine (502-1). 12886058v1 Page 359 of 494Attorney Docket No.2019292-0022 H OCF ON CFBoc S3 OMeS3 OHO OON O NCF3O N [0, , , benzo[e][1,4]diazepin-6-ol (502-B). 6-methoxy-2-phenethyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (502-A) (100 mg, 241 umol, 1 eq), in DCM (0.8 mL) was added BBr3(0.8 mL) at 0°C. The mixture was stirred at 25°C for 1 hr. The reaction mixture was adjusted with NaHCO3 to PH 7-8 at 0°C, and then extracted with DCM (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC to give 502-B. ESI [M+H] = 401.4

[0348] Step 2: 2-(bicyclo[1.1.1]pentan-1-yl)-7-cyclopropyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (502-C).

[0349] Step 3 was carried out according to Step 6 in Example 1.1.

[0350] Step 4: 2-((1-((1H-imidazol-4-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-yl)oxy)ethanamine (502-1). To a solution of tert-butyl N-[2-[[1-(1H-imidazol-4-ylmethyl)-2-(2-phenylethyl)-4- (trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepin-6-yl]oxy]ethyl]carbamate (502-D, 40 mg, 64.13 umol, 1 eq) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 25°C for 0.1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Gemini C18 12886058v1 Page 360 of 494Attorney Docket No.2019292-0022 column (75 × 30 mm, 3 um); flow rate: 60 mL / min; gradient: 15% – 40% B over 8 min; mobile phase A:0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-((1-(1H-imidazol-4-ylmethyl)- 2-(2-phenylethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepin-6- yl)oxy)ethanamine (502-1, 30.8 mg, 57.94 umol, 90.35% yield, FA salt) as a white solid. [M+H] = 524.11H NMR (400 MHz, DMSO-d6) δ 8.95 - 8.72 (m, 1H), 8.05 - 7.76 (m, 2H), 7.47 (br d, J = 2.4 Hz, 1H), 7.31 - 7.19 (m, 3H), 7.17 - 7.09 (m, 1H), 7.02 (br d, J = 7.2 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4Hz, 1H), 5.35 (br d, J = 14.4 Hz, 1H), 4.73 - 4.56 (m, 1H), 4.40 (br d, J = 14.4 Hz, 1H), 4.31 - 4.15 (m, 2H), 4.13 - 4.02 (m, 1H), 3.86 - 3.71 (m, 1H), 3.47 (br d, J = 13.2 Hz, 1H), 3.54 - 3.44 (m, 1H), 3.52 - 3.42 (m, 1H), 3.25 - 3.16 (m, 1H), 3.24 - 3.16 (m, 1H), 2.66 - 2.52 (m, 2H), 1.49 - 1.32 (m, 1H), 1.27 - 1.11 (m, 1H)

[0351] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 502-1 in Example 1.15, using analogous starting materials and / or intermediates. Compound #, Structure Analytical data ), 2 712886058v1 Page 361 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 525.11H NMR (400 503-2 MHz, DMSO-d6) δ = 7.66 (s, 1H), 2 - ), , 1 s, - 012886058v1 Page 362 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 552.21HNMR (400 501-2 MHz, DMSO-d6) δ = 8.21 (br s, 1H), , 1 , 4 8 ,

[0352] Example 1.16: 2-cyclopropyl-1-((2,5-dimethyl-1H-imidazol-4-yl)methyl)-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (311). 12886058v1 Page 363 of 494Attorney Docket No.2019292-0022

[0353] (trifluoromethyl)phenyl)amino)-2-cyclopropylacetate (311-B). To a solution of 311-A (10 g, 40.00 mmol, 1 eq) and methyl 2-amino-2-cyclopropyl-acetate; hydrochloride (5.30 g, 32.00 mmol, 0.8 eq) in toluene (300 mL) was added SPhos Pd G3 (1.56 g, 2.00 mmol, 0.05 eq) and Cs2CO3(26.06 g, 80.00 mmol, 2 eq). The mixture was stirred at 90 °C for 2hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE:EtOAc = 1:0 to 1:1) based on TLC (Plate 1：PE： EA=5:1). to give 311-B (2.2 g, 7.38 mmol, 18.44% yield) as a light yellow solid. ESI [M+H] = 299.3.

[0354] Step 2: 2-cyclopropyl-7-(trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin- 3(2H)-one (311-C). To the mixture of methyl 2-((2-cyano-4-(trifluoromethyl)phenyl)amino)-2- cyclopropylacetate (365-B, 2.2 g, 7.38 mmol, 1 eq) in MeOH (50 mL) was added TEA (5 mL) and H2O (6 mL) and Ni (2 g). The mixture was stirred at 20°C for 1 hr under H2 (15psi) atmosphere, and then reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 311-C (1.42 g, 5.25 mmol, 71% yield). ESI [M+H] = 272.1

[0355] Steps 3-5 were carried out according to Steps 4-6 in Example 1.1 to afford the Title compound 311. ESI [M+H] = 497.21H NMR (400 MHz, CD3OD) δ = 7.62 (br d, J = 8.4 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.79 (br d, J = 14.4 Hz, 1H), 4.59 - 4.34 (m, 3H), 3.88 (br d, J = 13.2 Hz, 1H), 3.28 (br s, 1H), 2.68 - 2.51 (m, 1H), 2.34 (s, 3H), 2.21 12886058v1 Page 364 of 494Attorney Docket No.2019292-0022 (s, 3H), 0.67 - 0.55 (m, 1H), 0.49 (br dd, J = 3.2, 4.4 Hz, 1H), 0.38 (br dd, J = 4.8, 7.6 Hz, 2H), 0.10 (br dd, J = 5.6, 9.3 Hz, 1H).

[0356] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 311 in Example 1.16, using analogous starting materials and / or intermediates. ESI [M+H1310 ] = 483.1 H NMR (400 MHz, CD3OD) δ = 8.44 (br s, 1H), 7 3 z, 812886058v1 Page 365 of 494Attorney Docket No.2019292-0022

[0357] Example 1.17: 1-((1H-imidazol-4-yl)methyl)-4-(azepan-1-ylsulfonyl)-2-(2- cyclopentylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (490-1).

[0358] . e (200 mg, 2.02 mmol, 227.27 uL, 1 eq) was added sulfuryl chloride (326.63 mg, 2.42 mmol, 241.95 uL, 1.2 eq) at 0°C, the reaction mixture was stirred at 25°C for 1hr. TLC (Petroleum ether: Ethyl acetate = 5:1) showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give azepane-1-sulfonyl chloride (194-A).

[0359] Step 2: 4-(azepan-1-ylsulfonyl)-2-(2-cyclopentylethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (490-C).194-B (123.62 mg, 505.86 umol, 1 eq) was dissolved in DCM (3mL) and DIEA (80 mg) was added followed by azepane-1-sulfonyl chloride (100 mg, 505.86 umol, 1 eq) at 0°C, the reaction mixture was stirred at 25°C for 1hr. Then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 column (75 × 30mm, 3 um); flow rate: 25 mL / min; gradient: 55% - 95% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 490-C (20 mg, 49.31 umol, 9.75% yield). ESI [M+H] = 406.2.

[0360] Step 3 was carried out according to Step 6 in Example 1.1 to afford the Title compound 490-1 (9.4 mg, 17.68 umol.). ESI [M+H] = 486.3.1H-NMR (400 MHz, CD3OD) δ = 8.17 (s, 1H), 7.28 (br d, J = 1.2 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.23 - 7.19 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.01 – 6.94 (m, 1H), 4.57 (d, J = 14.4 Hz, 1H), 4.48 - 4.36 (m, 2H), 4.17 (d, J = 12886058v1 Page 366 of 494Attorney Docket No.2019292-0022 13.6 Hz, 1H), 3.69 (br d, J = 12.4 Hz, 1H), 3.36 (t, J = 5.6 Hz, 4H), 3.27 - 3.22 (m, 1H), 3.07 (dd, J = 13.2, 2.4 Hz, 1H), 1.79 - 1.72 (m, 4H), 1.70 - 1.61 (m, 7H), 1.59 - 1.45 (m, 4H), 1.39 - 1.23 (m, 3H), 1.16 – 0.93 (m, 3H).

[0361] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 490-1 in Example 1.17, using analogous starting materials and / or intermediates. 490-2 ESI [M+H] = 486.2.1H NMR (400 MHz, CDCl3) δ = 7.65 - 7.59 (m, 1H), 7.19 - 7.14 (m, 1H), 7.08 (br 1 m, m, z, .0 D) = ), ), 1 - 3 m, 9 D) m, z, ), 9 3 - m,12886058v1 Page 367 of 494Attorney Docket No.2019292-0022 120 ESI [M+H] = 48031H-NMR (400 MHz CD3OD) = H) H) H) 6 H) 10 ) , 87 D) .0 5 1 br 8 812886058v1 Page 368 of 494Attorney Docket No.2019292-0022 521-1 ESI [M+H] = 504.2.1H NMR (400 MHz, CD3OD) δ = 834 (s 1H) 773 (s 1H) 729 - 717 (m 2H), 9 0 z, 2 4 m, δ J s, z, ), br 6 ).

[0362] Example 1.18: 1-(1-((1H-imidazol-4-yl)methyl)-2-(2-cyclopentylethyl)-2,3- dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-2-(4-(trifluoromethyl)phenyl)ethenone (178)

[0363] To a solution of 1-((1H-imidazol-4-yl)methyl)-2-(2-cyclopentylethyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (100 mg, 308.20 umol, 1 eq) and 2-[4- (trifluoromethyl)phenyl]acetic acid (94.38 mg, 462.30 umol, 1.5 eq) in DMF (2 mL) was added HOBt (45.81 mg, 339.02 umol, 1.1 eq) and DMAP (7.53 mg, 61.64 umol, 0.2 eq) and DIEA (199.17 mg, 1.54 mmol, 268.42 uL, 5 eq) and 3-(ethyliminomethyleneamino)-N,N-dimethyl- 12886058v1 Page 369 of 494Attorney Docket No.2019292-0022 propan-1-amine;hydrochloride (59.08 mg, 308.20 umol, 1 eq) at 0°C. The mixture was stirred at 25°C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (75 × 30 mm, 3 um); flow rate: 25 mL / min; gradient: 40% – 80% B over 8 mins; mobile phase A:0.2% aqueous FA, mobile phase B: acetonitrile) to give 1-(1-((1H-imidazol-4-yl)methyl)-2-(2- cyclopentylethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-2-(4- (trifluoromethyl)phenyl)ethanone (38.9 mg, 75.96 umol, 24.6% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.60 (br d, J = 8.0 Hz, 2H), 7.53 (d, J = 0.8 Hz, 1H), 7.42 (br d, J = 7.6 Hz, 2H), 7.32 - 7.11 (m, 3H), 6.96 - 6.79 (m, 2H), 5.08 - 4.65 (m, 1H), 4.43 - 4.22 (m, 3H), 4.13 - 3.92 (m, 1H), 3.87 (br d, J = 14.4 Hz, 2H), 3.36 (br s, 1H), 3.09 - 2.74 (m, 1H), 1.63 - 1.32 (m, 7H), 1.28 - 1.07 (m, 3H), 0.98 - 0.78 (m, 3H).

[0364] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 178 in Example 1.18, using analogous starting materials and / or intermediates. 177 - 8

[0365] Example 1.19: 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-6-(2- methoxyethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (471) 12886058v1 Page 370 of 494Attorney Docket No.2019292-0022

[0366] tep : synt es s o tert- uty -tert- utoxycar ony - -[ - uoro- - (trifluoromethyl)phenyl]carbamate (471-B)

[0367] To a solution of 3-fluoro-4-(trifluoromethyl)aniline (50 g, 279.15 mmol, 1 eq) in DCM (700 mL) was added TEA (141.23 g, 1.40 mol, 194.27 mL, 5 eq) and DMAP (3.41 g, 27.92 mmol, 0.1 eq) and Boc2O (213.23 g, 977.03 mmol, 224.46 mL, 3.5 eq). The mixture was stirred at 25°C for 6 hrs. The reaction mixture was quenched by addition sat. aq. H2O 700 mL at 0°C, and then extracted with DCM 1500 mL (500 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 1:0 to 10:1) to give tert-butyl N- tert-butoxycarbonyl-N-[3-fluoro-4-(trifluoromethyl)phenyl]carbamate (80 g, 210.89 mmol, 75.55% yield) as a yellow oil. 12886058v1 Page 371 of 494Attorney Docket No.2019292-0022

[0368] Step 2: synthesis of tert-butyl (3-fluoro-4-(trifluoromethyl)phenyl)carbamate (471-C)

[0369] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-fluoro-4- (trifluoromethyl)phenyl]carbamate (79 g, 208.25 mmol, 1 eq) in MeOH (1000 mL) was added K2CO3 (143.91 g, 1.04 mol, 5 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture was poured into 1000 mL of H2O and extracted with Ethyl acetate (1000 mL × 3). The combined organic phase dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (3-fluoro-4-(trifluoromethyl)phenyl)carbamate (53 g, 189.81 mmol, 91.14% yield) as a white solid.

[0370] Step 3: synthesis of tert-butyl (3-fluoro-2-iodo-4- (trifluoromethyl)phenyl)carbamate (471-D)

[0371] To a solution of tert-butyl (3-fluoro-4-(trifluoromethyl)phenyl)carbamate (20 g, 71.63 mmol, 1 eq) in THF (500 mL) was added n-BuLi (2.5 M, 85.95 mL, 3 eq) at -78°C under N2. The mixture was stirred at -78°C for 1 hr under N2, then was added I2(72.72 g, 286.50 mmol, 57.71 mL, 4 eq) at -78°C under N2. The mixture was stirred at 25°C for 1 hr under N2. The reaction mixture was quenched by addition of sat.aq. NH4Cl 1000 mL at 0°C under N2, and then extracted with Ethyl acetate 3000 mL (1000 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate =100 / 1 to 1 / 1) to give tert-butyl (3- fluoro-2-iodo-4-(trifluoromethyl)phenyl)carbamate (25 g, 61.71 mmol, 86.16% yield) as a yellow solid.

[0372] Step 4: synthesis of tert-butyl (2-cyano-3-fluoro-4- (trifluoromethyl)phenyl)carbamate (471-E)

[0373] To a solution of tert-butyl (3-fluoro-2-iodo-4-(trifluoromethyl)phenyl)carbamate (23 g, 56.77 mmol, 1 eq) in DMF (150 mL) was added CuCN (10.17 g, 113.54 mmol, 24.80 mL, 2 eq). The mixture was stirred at 130°C for 2 hrs. The reaction mixture was quenched by addition H2O 300 mL at 0°C, and then extracted with Ethyl acetate 600 mL (200 mL × 3). The combined organic layers were washed with sat.aq. NaCl 600 mL (200 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column 12886058v1 Page 372 of 494Attorney Docket No.2019292-0022 chromatography on silica gel (Petroleum ether / Ethyl acetate=20 / 1 to 3 / 1) to give tert-butyl (2- cyano-3-fluoro-4-(trifluoromethyl)phenyl)carbamate (7 g, 23.01 mmol, 40.53% yield) as a pale yellow solid.

[0374] 1H-NMR (400 MHz, CHLOROFORM-d) δ = 8.25 (d, J = 9.2 Hz, 1H), 7.75 (t, J = 8.6 Hz, 1H), 7.19 (br s, 1H), 1.56 (s, 9H).

[0375] Step 5: synthesis of tert-butyl (2-cyano-3-methoxy-4- (trifluoromethyl)phenyl)carbamate (471-F)

[0376] To a solution of tert-butyl (2-cyano-3-fluoro-4- (trifluoromethyl)phenyl)carbamate (6.8 g, 22.35 mmol, 1 eq) in MeOH (60 mL) was added NaOMe (4.02 g, 22.35 mmol, 50 mL, 30% purity, 1 eq). The mixture was stirred at 60°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give tert-butyl (2-cyano-3- methoxy-4-(trifluoromethyl)phenyl)carbamate (7 g, crude) as a yellow oil. ESI [M+H] = 317.1

[0377] Step 6: synthesis of 6-amino-2-methoxy-3-(trifluoromethyl)benzonitrile (471-G)

[0378] A mixture of tert-butyl (2-cyano-3-methoxy-4- (trifluoromethyl)phenyl)carbamate (7 g, 22.13 mmol, 1 eq, crude from Step 5) in HCl / MeOH (100 mL) (4M) was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 150 mL and extracted with Ethyl acetate 300 mL (100 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1) to give 6-amino-2-methoxy-3- (trifluoromethyl)benzonitrile (4.6 g, 21.28 mmol, 96.15% yield) as a pale yellow solid.

[0379] Step 7: synthesis of 2-(aminomethyl)-3-methoxy-4-(trifluoromethyl)aniline (471- H)

[0380] To a solution of 6-amino-2-methoxy-3-(trifluoromethyl)benzonitrile (4.5 g, 20.82 mmol, 1 eq) in THF (50 mL) was added BH3.THF (1 M, 45.00 mL, 2.16 eq) at 0°C under N2. The mixture was stirred at 60°C for 1 hr under N2. The reaction mixture was quenched by addition MeOH 40 mL at 0°C under N2, the mixture was stirred at 60°C for 2 hrs under N2. and then was added HCl (1M) 20 mL at 0°C, the mixture was stirred at 20°C for 0.5 hr, concentrated 12886058v1 Page 373 of 494Attorney Docket No.2019292-0022 under reduced pressure to give a residue. The reaction mixture was quenched by addition 4 M NaOH 20 mL at 0°C, and then extracted with EtOAc 300 mL (100 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(aminomethyl)-3-methoxy-4- (trifluoromethyl)aniline (4.3 g, 19.53 mmol, 93.81% yield) as a yellow gum. ESI [M-H] = 219.0

[0381] Step 8: synthesis of methyl 2-(bicyclo[1.1.1]pentan-1-yl)-5-methoxy-6- (trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2-carboxylate (471-I)

[0382] To a solution of 2-(aminomethyl)-3-methoxy-4-(trifluoromethyl)aniline (4.3 g, 19.53 mmol, 1 eq) in Tol. (100 mL) was added methyl 2-(bicyclo[1.1.1]pentan-1-yl)-2- oxoacetate (3.01 g, 19.53 mmol, 1 eq). The mixture was stirred at 130°C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate=8 / 1 to 5 / 1) to give methyl 2- (bicyclo[1.1.1]pentan-1-yl)-5-methoxy-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2- carboxylate (4.7 g, 13.19 mmol, 67.54% yield) as a pale yellow solid. ESI [M+H] = 357.1

[0383] Step 9: synthesis of methyl 2-((2-(aminomethyl)-3-methoxy-4- (trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1-yl)acetate (471-J)

[0384] To a solution of methyl 2-(bicyclo[1.1.1]pentan-1-yl)-5-methoxy-6- (trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2-carboxylate (4.5 g, 12.63 mmol, 1 eq) in DCE (45 mL) and TFA (15 mL) was added triethylsilane (2.94 g, 25.26 mmol, 4.03 mL, 2 eq) at 0°C. The mixture was stirred at 60°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give methyl 2-((2-(aminomethyl)-3-methoxy-4- (trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1-yl)acetate (4.5 g, 9.53 mmol, 75.44% yield, TFA salt) as a yellow oil. ESI [M+H] = 359.2

[0385] Step 10: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7- (trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (471-K)

[0386] To a solution of methyl 2-((2-(aminomethyl)-3-methoxy-4- (trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1-yl)acetate (4.4 g, 9.31 mmol, 1 eq, TFA) in MeOH (40 mL) was added DIEA (3.61 g, 27.94 mmol, 4.87 mL, 3 eq) and NaOMe (5.03 g, 93.15 mmol, 10 eq). The mixture was stirred at 70°C for 1 hr. The reaction mixture was 12886058v1 Page 374 of 494Attorney Docket No.2019292-0022 filtered and concentrated under reduced pressure to remove solvent. The residue was diluted with 1N HCl 20 mL and extracted with EtOAc 60 mL (20 mL × 3). The combined organic layers were washed with NaCl sat.aq.30 mL (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate=5 / 1 to 2 / 1) to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7- (trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (2.6 g, 7.97 mmol, 85.54% yield) as a yellow gum. ESI [M+H] = 327.1

[0387] Step 11: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (471-L)

[0388] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7-(trifluoromethyl)- 4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (1.5 g, 4.60 mmol, 1 eq) in THF (10 mL) was added BH3.THF (1 M, 13.79 mL, 3 eq) at 0°C under N2. The mixture was stirred at 40°C for 1 hr under N2. The reaction mixture was quenched by addition MeOH 20 mL at 0°C under N2, the mixture was stirred at 40°C for 0.5 hr under N2, and then was added 1N HCl 10 mL at 0°C, the mixture was stirred at 40°C for 0.5 hr, concentrated under reduced pressure to give a residue. The reaction mixture was quenched by addition sat.aq. Na2CO320 mL at 0°C, and then extracted with EtOAc 60 mL (20 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate=3 / 1 to 0 / 1) to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (850 mg, 2.72 mmol, 59.20% yield) as a yellow oil. ESI [M+H] = 313.2

[0389] Step 12: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (471-M)

[0390] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7-(trifluoromethyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (400 mg, 1.28 mmol, 1 eq) and DIEA (827.59 mg, 6.40 mmol, 1.12 mL, 5 eq) in DCM (4 mL) was added Tf2O (397.47 mg, 1.41 mmol, 232.44 μL, 1.1 eq) at -78°C under N2. The mixture was stirred at -78°C for 1 hr under N2. The reaction mixture was filtered. The residue was purified by column chromatography (Petroleum 12886058v1 Page 375 of 494Attorney Docket No.2019292-0022 ether / Ethyl acetate=100 / 1 to 10 / 1) to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (400 mg, 900.11 μmol, 70.28% yield) as a pale yellow solid. ESI [M-H] = 442.9

[0391] Step 13: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (471-N)

[0392] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (280 mg, 630.08 μmol, 1 eq) in DCM (2 mL) was added BBr3 (2 M, 1 mL, 3.17 eq) at 0°C, the reaction was stirred at 20°C for 2 hrs. The reaction mixture was quenched by H2O (3 mL) at 20°C and extracted with DCM (3 mL × 3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18100×40mm×5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (60 mg, 139.42 μmol, 22.13% yield) as a brown solid. ESI [M+H] = 431.1

[0393] Step 14: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-methoxyethoxy)-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (471-O)

[0394] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (30 mg, 69.71 μmol, 1 eq) in DMF (1 mL) was added K2CO3(11.56 mg, 83.65 μmol, 1.2 eq) and 1-bromo-2- methoxyethane (10.66 mg, 76.68 μmol, 7.21 μL, 1.1 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition H2O 2 mL at 0°C, and then extracted with EtOAc 6 mL (2 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (Petroleum ether: Ethyl acetate=5:1) to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-methoxyethoxy)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (20 mg, 40.95 μmol, 58.74% yield) as a pale red gum. ESI [M+H] = 489.2 12886058v1 Page 376 of 494Attorney Docket No.2019292-0022

[0395] Step 15: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 6-(2-methoxyethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (471)

[0396] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-methoxyethoxy)-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (20 mg, 40.95 μmol, 1 eq) and 1H-imidazole-4-carbaldehyde (19.67 mg, 204.73 μmol, 5 eq) in DCM (1 mL) and HOAc (0.5 mL) was added NaBH(OAc)3(43.39 mg, 204.73 μmol, 5 eq). The mixture was stirred at 40°C for 48 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100×30mm×3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%- 45% B over 8.0 min) to give 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-6-(2- methoxyethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (5.9 mg, 9.48 μmol, 23.14% yield, 98.714% purity, FA salt) as a white solid. ESI [M+H] = 511.1

[0397] 1H-NMR (400 MHz, CD3OD) δ = 7.69 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H), 7.11 (s, 1H), 5.47 (br d, J = 15.4 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.32 - 4.25 (m, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.98 - 3.78 (m, 3H), 3.75 - 3.69 (m, 1H), 3.50 - 3.42 (m, 4H), 3.24 - 3.15 (m, 1H), 2.30 (s, 1H), 1.70 (dd, J = 1.2, 9.3 Hz, 3H), 1.45 (d, J = 8.4 Hz, 3H).

[0398] Example 1.20: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (466)12886058v1 Page 377 of 494Attorney Docket No.2019292-0022

[0399] Step 1: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 6-methoxy-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (466)

[0400] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (80 mg, 180.02 μmol, 1 eq) and 1H-imidazole-4-carbaldehyde (86.49 mg, 900.11 μmol, 5 eq) in HOAc (1 mL) and DCM (1 mL) was added NaBH(OAc)3(190.77 mg, 900.11 μmol, 5 eq). The mixture was stirred at 40°C for 12 hrs. The reaction solution is blow-dried with N2. The residue was purified by preparative HPLC(column: Phenomenex Luna C18100*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:20%-50% B over 8.0 min ) to give 1-((1H-imidazol-4- yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (466) (37.5 mg, 65.60 μmol, 36.44% yield, 99.8% purity, FA salt) as a white solid. ESI [M-H] = 525.1

[0401] 1H NMR (400 MHz, CD3OD) δ = 7.75 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.18 - 7.12 (m, 2H),2 - 4.53 (m, 1H), 4.48 - 4.40 (m, 1H), 4.12 (br d, J = 14.0 Hz, 1H), 3.89 (s, 4H), 3.48 (br s, 1H), 3.20 (br d, J = 12.8 Hz, 1H), 2.29 (s, 1H), 1.70 (d, J = 9.2 Hz, 3H), 1.45 (br d, J = 9.2 Hz, 3H)

[0402] Example 1.21: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-6-ol (473)

[0403] Step 1: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6- ol (473)

[0404] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (10 mg, 23.24 12886058v1 Page 378 of 494Attorney Docket No.2019292-0022 μmol, 1 eq) and 1H-imidazole-4-carbaldehyde (11.16 mg, 116.18 μmol, 5 eq) in AcOH (1 mL) was added NaBH(OAc)3 (24.62 mg, 116.18 μmol, 5 eq). The mixture was stirred at 40°C for 48 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:45%-80% B over 8.0 min) to give 1-((1H-imidazol-4- yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (3.3 mg, 5.80 μmol, 24.96% yield, 97.8% purity, FA salt) as a pale yellow solid. ESI [M-H] = 511.1

[0405] 1HNMR (400 MHz, CD3OD) δ = 7.76 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.49 (br d, J = 14.2 Hz, 1H), 4.57 (br d, J = 13.6 Hz, 2H), 4.48 - 4.42 (m, 1H), 4.15 (br d, J = 14.4 Hz, 1H), 3.85 (br d, J = 12.8 Hz, 1H), 3.40 (br s, 1H), 3.20 (br d, J = 12.8 Hz, 1H), 2.30 (s, 1H), 1.74 (br d, J = 9.2 Hz, 3H), 1.46 (br d, J = 9.2 Hz, 3H)

[0406] Example 1.22: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(3- methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (470) 12886058v1 Page 379 of 494Attorney Docket No.2019292-0022 [0407p y - - y y . . p - -y - - - - (triphenylphosphoranylidene)propanenitrile (470-B)

[0408] To a solution of 3-methoxybicyclo[1.1.1]pentane-1-carboxylic acid (4.9 g, 34.47 mmol, 1 eq) in DCM (120 mL) was added DMAP (842.24 mg, 6.89 mmol, 0.2 eq), 2- (triphenylphosphoranylidene)acetonitrile (10.39 g, 34.47 mmol, 1 eq) and EDCI (6.61 g, 34.47 mmol, 1 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 1:0 to 7:3) to give 3-(3- methoxybicyclo[1.1.1]pentan-1-yl)-3-oxo-2-(triphenylphosphoranylidene)propanenitrile (13.6 g, 31.97 mmol, 92.73% yield) as a white solid. ESI [M+H] = 426.0

[0409] Step 2: synthesis of methyl 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-2-oxoacetate (470-C) 12886058v1 Page 380 of 494Attorney Docket No.2019292-0022

[0410] OZONE was bubbled into a solution of 3-(3-methoxybicyclo[1.1.1]pentan-1-yl)- 3-oxo-2-(triphenylphosphoranylidene)propanenitrile (13.6 g, 31.97 mmol, 1 eq) in DCM (160 mL) and MeOH (80 mL) at -78°C for 3 hrs. After excess O3 was purged by N2, the reaction mixture was poured into 100 mL of MTBE and stirred at 25°C for 3 hrs. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 2- (3-methoxybicyclo[1.1.1]pentan-1-yl)-2-oxoacetate (7.4 g, crude) as a yellow oil.

[0411] Step 3: synthesis of methyl 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-6- (trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2-carboxylate (470-D)

[0412] To a solution of methyl 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-2-oxoacetate (7 g, 38.00 mmol, 1 eq) in Tol. (280 mL) was added 2-(aminomethyl)-4-(trifluoromethyl)aniline (4.34 g, 22.80 mmol, 0.6 eq). The mixture was stirred at 135°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 100:0 to 19:1) to give methyl 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-1,2,3,4- tetrahydroquinazoline-2-carboxylate (4.2 g, 11.79 mmol, 31.01% yield) as a white solid. ESI [M+H] = 357.2

[0413] Step 4: synthesis of methyl 2-((2-(aminomethyl)-4- (trifluoromethyl)phenyl)amino)-2-(3-methoxybicyclo[1.1.1]pentan-1-yl)acetate (470-E)

[0414] To a solution of methyl 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-6- (trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2-carboxylate (3.1 g, 8.70 mmol, 1 eq) in DCM (60 mL) was added TFA (15 mL) and Et3SiH (2.02 g, 17.40 mmol, 2.78 mL, 2 eq) at 0°C. The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue purified by preparative HPLC (column: Phenomenex luna C18250*150mm*15um; mobile phase: [H2O(0.1%TFA)- ACN]; gradient: 20%-50% B over 20.0 min) to give methyl 2-((2-(aminomethyl)-4- (trifluoromethyl)phenyl)amino)-2-(3-methoxybicyclo[1.1.1]pentan-1-yl)acetate (2.2 g, 6.14 mmol, 70.57% yield) as a white solid. ESI [M-NH2] = 342.1

[0415] Step 5: synthesis of 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)- 4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (470-F) 12886058v1 Page 381 of 494Attorney Docket No.2019292-0022

[0416] To a solution of methyl 2-((2-(aminomethyl)-4-(trifluoromethyl)phenyl)amino)- 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)acetate (2.1 g, 5.86 mmol, 1 eq) in MeOH (40 mL) was added DIEA (2.27 g, 17.58 mmol, 3.06 mL, 3 eq) and NaOMe (3.17 g, 58.60 mmol, 10 eq) at 0°C. The mixture was stirred at 60°C for 0.5 hr. The reaction mixture was diluted with H2O 50 mL and extracted with EtOAc (55 mL * 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-3(2H)-one (1.1 g, crude) as a white solid. ESI [M+H] = 327.1

[0417] Step 6: synthesis of 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (470-G)

[0418] To a solution of 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4,5- dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (1 g, 3.06 mmol, 1 eq) in THF (200 mL) was added BH3.THF (1 M, 15.32 mL, 5 eq) at 0°C. The mixture was stirred at 60°C for 1 hr under N2. The reaction mixture was quenched by addition saturated aqueous MeOH (300 mL) at 0°C slowly under N2 and stirred at 60oC for 1 hr, then the reaction mixture was concentrated under reduced pressure to give 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (1.2 g, crude) as a white solid. ESI [M+H] = 313.1

[0419] Step 7: synthesis of 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)- 4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (470-H)

[0420] To a solution of 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (1.1 g, 3.52 mmol, 1 eq) in DCM (20 mL) was added DIEA (1.37 g, 10.57 mmol, 1.84 mL, 3 eq) and Tf2O (1.49 g, 5.28 mmol, 871.64 μL, 1.5 eq) at -78°C. The mixture was stirred at -78 °C for 0.5 hr under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 100:0 to 3:1) to give 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (1.4 g, 3.15 mmol, 89.45% yield) as a white solid. ESI [M+H] = 445.1 12886058v1 Page 382 of 494Attorney Docket No.2019292-0022

[0421] Step 8: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(3- methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (470)

[0422] A mixture of 2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (100 mg, 225.03 μmol, 1 eq), 1H-imidazole-4-carbaldehyde (108.11 mg, 1.13 mmol, 5 eq) , NaBH(OAc)3 (238.46 mg, 1.13 mmol, 5 eq) , in DCM (2 mL) and AcOH (1 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 40 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue purified by preparative HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O(0.2% FA)-ACN]; gradient:30%-60% B over 8.0 min) to give 1-((1H- imidazol-4-yl)methyl)-2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (8.1 mg, 13.05 μmol, 5.80% yield, 91.9% purity, FA salt) as a white solid. ESI [M+H] = 525.1

[0423] 1H NMR (400 MHz, CD3OD) δ = 7.72 (s, 1H), 7.67 - 7.60 (m, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 4.78 (br d, J = 14.4 Hz, 1H), 4.57 (s, 1H), 4.54 - 4.44 (m, 2H), 4.00 - 3.82 (m, 1H), 3.72 (br s, 1H), 3.35 (br d, J = 2.4 Hz, 1H), 3.11 (s, 3H), 1.75 (d, J = 9.2 Hz, 3H), 1.42 (d, J = 9.2 Hz, 3H).

[0424] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 470 in Example 1.22, using analogous starting materials and / or intermediates. 447 1 D) 9 6 , z, ), ,12886058v1 Page 383 of 494Attorney Docket No.2019292-0022 468 ESI [M+H] = 509.1.1H-NMR (400 MHz,CD3OD) δ = 774 1 H 767 761 1 H 754 d J = J J = J ) ) 2 , 6 , 4 - ) ), , 0 , ) = ), = ), 3 8 z, ), z, z, , .212886058v1 Page 384 of 494Attorney Docket No.2019292-0022 Isolated as a single enantiomer: Peak 1 (Rt=2.930 424-1 min). ESI [M+H] = 519.0.1H-NMR (400 MHz, = = = br ), .4 ), ) 0 = , .2 .8 = 4 z, ), br 1 = 0, 6 z,12886058v1 Page 385 of 494Attorney Docket No.2019292-0022 421-2 Isolated as a single enantiomer: Peak 2 (Rt=3.202 min). ESI [M+H] = 466.1.1H-NMR (400 MHz, ), br 1 = .4 = ) 1 7 , .2 .2 ), 2 0 ), ), ), 4 J Rt 0 ), ), ), 3 J12886058v1 Page 386 of 494Attorney Docket No.2019292-0022 Isolated as a single enantiomer: Peak 1 (Rt = 3.268 min) ESI [M+H] = 505.0 / 507.0. , 3 6 = z, 6 - z, 7 z, ), z, z, ), d, 7 z, .6 = = br ),12886058v1 Page 387 of 494Attorney Docket No.2019292-0022 411-1 Isolated as a single enantiomer: Peak 2 (Rt = 3.804 min) ESI [M+H] = 511.2.1H NMR (400 MHz, ), d, J .6 9 7 z, = .3 ), = - z, 1) ) - ), 2 ), 4) ) - = ), 912886058v1 Page 388 of 494Attorney Docket No.2019292-0022 459 ESI [M+H] = 519.0.1H NMR (400 MHz, CD3OD) δ = 7.69 (s, 1H), 7.62 (br d, J = 8.8 Hz, 1H), 7.56 7 z, = br 2 ) = ), ), ), 5 6 0 , ), = - d, = ), ) .4 0 , z, s, )12886058v1 Page 389 of 494Attorney Docket No.2019292-0022 ESI [M+H] = 495.1.1H NMR (400 MHz,CD3OD) δ = 7.82 (s, 1H), 7.60 (br d, J = 8.4 Hz, 1H), 7.51 18 , z, .4 ), al - d, - .0 = ), ) - z, br 3 J br - ). ) - z, z, 4, 2,12886058v1 Page 390 of 494Attorney Docket No.2019292-0022 347-2 Isolated as a single enantiomer: Peak 2 (Rt = 0.869). ESI [M+H] = 461.1.1H NMR (400 MHz, CD3OD) m, 2 = 4, = - 3 ), ), z, .8 6 ), ) 1 8 , z, .4 ), al ) 8 0 ), 3 br12886058v1 Page 391 of 494Attorney Docket No.2019292-0022 380 ESI [M+H] = 457.2.1H NMR (400 MHz, CD3OD) δ = 7.67 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.05 (s, .8 ), - 1 ) 1 = z, 0 3 = ) 2 ), ), , = z, - ), = , = 2, z, ) ), ), ), z, ), z,12886058v1 Page 392 of 494Attorney Docket No.2019292-0022 ESI [M+1411 H] = 523.2. H NMR (400 MHz, METHANOL-d4) δ = 7.79 (s, 1H), 7.37 - 7.30 (m, 7 - br z, ), ) 7 4 ), , ) ) = ), 2 , , 1 ),12886058v1 Page 393 of 494Attorney Docket No.2019292-0022 423 ESI [M+H] = 505.0.1H-NMR (400 MHz, CD3OD) δ = 8.30 (s, 1H), 7.83 (s, 1H), 7.47 - 7.41 (m, 1H), ), - , 7 ) ), ), .4 3 ), ) - 2 - 4 ), ) 3 7 ), ), ), ) z, ), ), ), ), 8 br12886058v1 Page 394 of 494Attorney Docket No.2019292-0022 435 ESI [M+H] = 573.1.1H-NMR (400 MHz,CD3OD) δ = 7.72 - 7.62 (m, 2H), 7.56 (d, J = 1.2 Hz, 1H), z, br = 6,

[0425] Example 1.23: Synthesis of 1-((1H-imidazo[1,2-a]imidazol-6-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-6-methyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (460)

[0426] Step 1: synthesis of (E)-trimethyl((4-phenylbuta-1,3-dien-2-yl)oxy)silane (460-B)

[0427] To a solution of LDA (2 M, 34.89 mL, 1.02 eq) in THF (120 mL) was added dropwise a solution of (E)-4-phenylbut-3-en-2-one (10 g, 68.41 mmol, 1 eq) was added dropwise at -78°C. TMSCl (7.58 g, 69.77 mmol, 8.86 mL, 1.02 eq) was added dropwise at - 78°C. The mixture was stirred at 25°C for 12 hrs under N2. The reaction mixture was quenched by addition saturated aqueous NH4Cl (500 mL) at 0°C slowly under N2and stirred at 25oC for 15 mins. Then THF was removed under vacuum. The resulting solution was extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine (20 mL×1), dried over 12886058v1 Page 395 of 494Attorney Docket No.2019292-0022 Na2SO4, filtered and concentrated under reduced pressure to give (E)-trimethyl((4-phenylbuta- 1,3-dien-2-yl)oxy)silane (10 g, crude) as a white solid.

[0428] Step 2: synthesis of (E)-1-bromo-4-phenylbut-3-en-2-one (460-C)

[0429] To a solution of (E)-trimethyl((4-phenylbuta-1,3-dien-2-yl)oxy)silane (10 g, 45.79 mmol, 1 eq) in THF (100 mL) was added NBS (8.88 g, 49.92 mmol, 1.09 eq). The mixture was stirred at -40°C for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:7) to give (E)-1-bromo-4- phenylbut-3-en-2-one (7 g, 31.10 mmol, 67.91% yield) as a yellow oil.

[0430] 1H NMR (400 MHz, CD3OD) δ = 7.74 (d, J = 16.0 Hz, 1H), 7.69 - 7.64 (m, 2H), 7.46 - 7.41 (m, 3H), 7.00 (d, J = 16.0 Hz, 1H), 4.90 (s, 1H), 4.30 (s, 2H), 2.01 (s, 1H), 1.24 (t, J = 7.2 Hz, 1H).

[0431] Step 3: synthesis of 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (460-E)

[0432] To a solution of 2-nitro-1H-imidazole (6.4 g, 56.60 mmol, 1 eq) in THF (70 mL) was added NaH (2.72 g, 67.92 mmol, 60% purity, 1.2 eq) in portions at 0°C under N2 atmosphere, the mixture was stirred at 0°C for 0.5 hr. Then SEM-Cl (11.32 g, 67.92 mmol, 12.02 mL, 1.2 eq) was added the above mixture. The mixture was stirred at 25°C for 1 hr. The reaction mixture was quenched by addition sat. aq. NH4Cl 50 mL at 0°C under N2 atmosphere, and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with sat. aq. NaCl (50 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:1 to 7:3) to give 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (13 g, 53.42 mmol, 94.39% yield) as a white oil.

[0433] 1H NMR (400 MHz, CD3OD) δ = 7.60 (d, J = 1.2 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 5.78 (s, 2H), 3.71 - 3.63 (m, 2H), 0.97 - 0.90 (m, 2H), 0.01 - -0.06 (m, 10H)

[0434] Step 4: synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2(3H)- imine (460-F) 12886058v1 Page 396 of 494Attorney Docket No.2019292-0022

[0435] To a solution of 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (13 g, 53.42 mmol, 1 eq) in EtOAc (200 mL) was added Pd / C (6.25 g, 10% Pd on carbon) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2(15 Psi) at 25°C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 2(3H)-imine (11 g, crude) as a white solid. ESI [M+H] = 214.1

[0436] Step 5: synthesis of (E)-6-styryl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazo[1,2-a]imidazole (460-G)

[0437] To a solution of (E)-6-styryl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazo[1,2-a]imidazole (5.5 g, 25.78 mmol, 1 eq) in THF (70 mL) was added tetraisopropoxytitanium (7.33 g, 25.78 mmol, 7.61 mL, 1 eq) and (E)-1-bromo-4-phenylbut-3- en-2-one (2.90 g, 12.89 mmol, 0.5 eq) at 0°C. The mixture was stirred at 40°C for 12 hrs. The reaction solution is adjusted to PH = 8 with sat. aq. NaHCO3 at 0°C. The residue was diluted with H2O 50 mL and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 100:1 to 17:3) to give (E)-6-styryl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazo[1,2-a]imidazole (2.38 g, 7.01 mmol, 27.19% yield) as a white solid. ESI [M+H] = 340.2

[0438] 1H NMR (400 MHz, CD3OD) δ = 7.48 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.22 - 7.14 (m, 3H), 7.09 - 7.00 (m, 2H), 5.37 (s, 2H), 3.67 - 3.60 (m, 2H), 0.91 (t, J = 8.0 Hz, 2H), -0.01 - -0.08 (m, 9H).

[0439] Step 6: synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[1,2- a]imidazole-6-carbaldehyde (460-H)

[0440] To a solution of (E)-6-styryl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazo[1,2-a]imidazole (1.48 g, 4.36 mmol, 1 eq) in dioxane (80 mL) and H2O (16 mL) and 2- methylbutan-2-ol (16 mL) was added NaIO4(2.80 g, 13.08 mmol, 724.67 μL, 3 eq) and tetraoxoosmium (110.82 mg, 435.93 μmol, 22.62 μL, 0.1 eq) at 0°C. The mixture was stirred at 20°C for 2 hrs. The reaction mixture was extracted with EtOAc (40 mL×3). The combined 12886058v1 Page 397 of 494Attorney Docket No.2019292-0022 organic layers were washed with sat. aq. NaCl (40 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The water phase was quenched by addition sat.aq.Na2SO3 (40 mL) at 0°C. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (250 × 70 mm, 10 um); flow rate: 25 mL / min; gradient: 35% – 65% B over 17 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[1,2-a]imidazole-6-carbaldehyde (30 mg, 113.04 μmol, 2.59% yield) as a white solid. ESI [M+H] = 266.2

[0441] Step 7: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[1,2-a]imidazol- 6-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (460-I)

[0442] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (18 mg, 49.95 μmol, 1 eq) in AcOH (2 mL) was added NaBH(OAc)3 (63.51 mg, 299.67 μmol, 6 eq) and 1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazo[1,2-a]imidazole-6-carbaldehyde (26.51 mg, 99.89 μmol, 2 eq). The mixture was stirred at 40°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC(column: XPT C18150*307u;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:70%-98% B over 8.0 min ) to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[1,2-a]imidazol- 6-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (10 mg, 16.40 μmol, 32.83% yield) as a white solid. ESI [M+H] = 610.1

[0443] Step 8: synthesis of 1-((1H-imidazo[1,2-a]imidazol-6-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-6-methyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (460)

[0444] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[1,2-a]imidazol- 6-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (7 mg, 11.48 μmol, 1 eq) in DCM (1 mL) was added TFA (0.1 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue 12886058v1 Page 398 of 494Attorney Docket No.2019292-0022 was purified by preparative HPLC (column: Phenomenex Luna C18100*30mm*5um; mobile phase: [H2O(0.2% FA)-ACN]; gradient:30%-60% B over 8.0 min) give 1-((1H-imidazo[1,2- a]imidazol-6-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-6-methyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (1.8 mg, 3.34 μmol, 29.06% yield, 97.4% purity, FA salt) as a white solid. ESI [M+H] = 480.2

[0445] 1H NMR (400 MHz, CD3OD) δ = 7.60 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.28 - 7.14 (m, 2H), 6.98 (d, J = 7.2 Hz, 1H), 5.14 - 5.01 (m, 1H), 4.82 - 4.75 (m, 1H), 4.51 (d, J = 14.4 Hz, 1H), 4.37 (br d, J = 14.4 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.43 - 3.35 (m, 2H), 2.49 (s, 3H), 2.29 (s, 1H), 1.73 (dd, J = 9.2, 1.2 Hz, 3H).

[0446] Example 1.24: Synthesis of (R)-1-((1H-imidazol-4-yl)methyl)-2-(tert-butyl)-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine and (S)-1-((1H-imidazol-4-yl)methyl)-2-(tert-butyl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine 12886058v1 Page 399 of 494Attorney Docket No.2019292-0022

[0447] Step 1: synthesis of (R)-methyl 2-((2-cyano-4-(trifluoromethyl)phenyl)amino)- 3,3-dimethylbutanoate (479-B)

[0448] To a mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (458.04 mg, 2.42 mmol, 0.8 eq) and methyl (R)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride (550 mg, 3.03 mmol, 1 eq) in DMSO (1 mL) was added DIEA (2.15 g, 16.65 mmol, 2.90 mL, 5.5 eq), the mixture was stirred at 120°C for 12 hrs. The reaction mixture was quenched by addition H2O (10 mL) at 0°C, and then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 3:1) to give (R)-methyl 2-((2-cyano-4-(trifluoromethyl)phenyl)amino)-3,3- dimethylbutanoate (210 mg, 668.15 μmol, 22.07% yield) as a white solid. ESI [M+H] = 315.3 12886058v1 Page 400 of 494Attorney Docket No.2019292-0022

[0449] Step 2: synthesis of (R)-methyl 2-((2-(aminomethyl)-4- (trifluoromethyl)phenyl)amino)-3,3-dimethylbutanoate (479-C)

[0450] To a mixture of methyl (R)-methyl 2-((2-cyano-4- (trifluoromethyl)phenyl)amino)-3,3-dimethylbutanoate (160 mg, 509.06 μmol, 1 eq) in MeOH (2 mL), H2O (0.2 mL), TEA (0.2 mL) was added Ni (509.06 μmol), the mixture was stirred at 25°C for 1 hr under H2 (15 psi). The suspension was filtered through a pad of silica gel and filter cake was washed with MeOH (5 mL × 2), the filtrate was concentrated under reduced pressure to give a residue. And the filter cake was collected and handled safely. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1) to give (R)-methyl 2-((2-(aminomethyl)-4- (trifluoromethyl)phenyl)amino)-3,3-dimethylbutanoate (140 mg, 439.79 μmol, 86.39% yield) as a yellow solid. ESI [M+H] = 319.3

[0451] Step 3: synthesis of (R)-2-(tert-butyl)-7-(trifluoromethyl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-3(2H)-one (479-D)

[0452] To a mixture of methyl (R)-methyl 2-((2-(aminomethyl)-4- (trifluoromethyl)phenyl)amino)-3,3-dimethylbutanoate (140 mg, 439.79 μmol, 1 eq) in MeOH (3 mL) was added DIEA (284.20 mg, 2.20 mmol, 383.02 μL, 5 eq), then NaOMe (237.59 mg, 4.40 mmol, 10 eq) was added to the mixture reaction, the mixture was stirred at 70°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Then the reaction mixture was quenched by H2O (5 mL) at 0°C, and then extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1) to give (R)-2-(tert-butyl)-7-(trifluoromethyl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-3(2H)-one (60 mg, 209.58 μmol, 47.65% yield) as a white solid. ESI [M+H] = 287.3

[0453] Step 4: synthesis of 2-(tert-butyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (479-E peak 1 and enantiomer 479-E peak 2)

[0454] To a mixture of (R)-2-(tert-butyl)-7-(trifluoromethyl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-3(2H)-one (60 mg, 209.58 μmol, 1 eq) in THF (2 mL) was added BH3.THF (1 M, 628.73 μL, 3 eq) at 0°C, the mixture was stirred at 40°C for 1 hr under N2. The 12886058v1 Page 401 of 494Attorney Docket No.2019292-0022 reaction mixture was quenched by addition MeOH (2 ml) at 0°C and stirred at 60°C for 0.5 hr. Then the reaction mixture was concentrated under reduced pressure to give a residue, after that dioxane (2mL) and 1 N HCl (2 mL) was added to the mixture reaction, the mixture reaction was stirred at 60°C for 0.5 hr, then the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 column (75 × 30 mm, 3 um); flow rate: 25 mL / min; gradient: 25% – 55% B over 8 min; mobile phase A: 0.2% aqueous FA , mobile phase B: acetonitrile) and the product was separated by SFC (Instrument: Gilson 281 Semi-preparative HPLC system; Column: DAICEL CHIRALPAK IG (250mm × 30mm,10um);Mobile phase A: CO2 and B:0.1%NH3H2O in MeOH; Gradient: B%=10% isocratic elution mode; Flow rate:CO2(63 g / min) and B (7 g / min);Wavelength: 220&254nm;Column temperature: 40℃;System back pressure: 100 bar) to generate two enantiomers.

[0455] Peak 1 (Rt =1.141) 2-(tert-butyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (479-E peak 1) (13 mg, 47.74 μmol, 22.78% yield) as a yellow solid. ESI [M+H] = 273.1

[0456] Step 5: synthesis of 2-(tert-butyl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (479-G)

[0457] To a mixture of 2-(tert-butyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (479-E peak 1) (13 mg, 47.74 μmol, 1 eq) and DIEA (18.51 mg, 143.22 μmol, 24.95 μL, 3 eq) in DCM (1 mL) was added trifluoromethanesulfonic anhydride (14.82 mg, 52.51 μmol, 8.66 μL, 1.1 eq) at -78°C, the mixture was stirred at -78°C for 1 hr under N2. The reaction mixture was filtered. The residue was purified by flash column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 3:1) to give 2-(tert-butyl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (479-G-1) (19 mg, 46.99 μmol, 98.42% yield) as a yellow solid. ESI [M+H] = 405.1

[0458] Step 6: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(tert-butyl)-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (479-1) 12886058v1 Page 402 of 494Attorney Docket No.2019292-0022

[0459] To a mixture of 2-(tert-butyl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (479-G-1) (19 mg, 46.99 μmol, 1 eq) and 1H- imidazole-4-carbaldehyde (22.57 mg, 234.93 μmol, 5 eq) in DCM (0.3 mL), AcOH (1 mL) was added NaBH(OAc)3(49.79 mg, 234.93 μmol, 5 eq), the mixture was stirred at 40°C for 5 days. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (10 mL) at 0°C, and then extracted with DCM (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 column (100 × 30 mm, 3 um); flow rate: 25 mL / min; gradient: 30% – 60% B over 8 min; mobile phase A: 0.2% aqueous FA , mobile phase B: acetonitrile) to give 1-((1H-imidazol-4-yl)methyl)-2-(tert-butyl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (479-1) (1 mg, 1.88 μmol, 3.99% yield, 99.466% purity, FA salt) as a white solid. ESI [M+H] = 485.1

[0460] 1H-NMR (400 MHz,CD3OD) δ = 7.67 (s, 1 H), 7.63 - 7.56 (m, 1 H), 7.48 (br s, 2 H), 7.07 (br s, 1 H), 4.77 (br d, J = 14.4 Hz, 2 H), 4.60 (br d, J = 2.8 Hz, 2 H), 4.46 - 4.39 (m, 1 H), 4.28 - 4.13 (m, 1 H), 3.29 (br s, 1 H), 0.85 (s, 9 H)

[0461] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 479-1 in Example 1.24, using analogous starting materials and / or intermediates. Single enantiomer prepared from (479-E peak 2): 479-2 ESI M+H = 48511H NMR 400 MH CD OD) 6 2 br s, ) z, br , 2 , ),12886058v1 Page 403 of 494Attorney Docket No.2019292-0022 1.33 - 1.24 (m, 1H), 0.58 - 0.52 (m, 1H), 0.51 - 0.45 (m, 3H). ) z, br 4 ), s, z, ) J z, 2 , 3 ), ) br .0 ), ), ) 3 br ), z,12886058v1 Page 404 of 494Attorney Docket No.2019292-0022 1 H), 4.22 - 4.02 (m, 1 H), 3.30 (br s, 2 H), 2.54 (s, 3 H), 0.82 (s, 9 H).

[0462] (bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-6-yl)oxy)ethanol (464) 12886058v1 Page 405 of 494Attorney Docket No.2019292-0022

[0463] Step 1: synthesis of tert-butyl (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2- cyano-4-(trifluoromethyl)phenyl)carbamate (464-B)

[0464] To a solution of NaH (474.83 mg, 11.87 mmol, 60% purity, 3 eq) in THF (20 mL) was added 2-((tert-butyldimethylsilyl)oxy)ethanol (1.05 g, 5.94 mmol, 1.5 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr, then added tert-butyl N-tert-butoxycarbonyl-N-[2-cyano-3- 12886058v1 Page 406 of 494Attorney Docket No.2019292-0022 fluoro-4-(trifluoromethyl)phenyl]carbamate (see Example 1.19) (1.6 g, 3.96 mmol, 1 eq) at 0°C. The mixture was stirred at 40°C for 12 hrs under N2. The reaction mixture was quenched by addition sat. aq. NH4Cl 20 mL at 0°C under N2, and then extracted with EtOAc (20 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 1:0 to 10:1) to give tert-butyl (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyano-4- (trifluoromethyl)phenyl)carbamate (1 g, 2.17 mmol, 54.87% yield) as a white solid. ESI [M-H] =459.3

[0465] Step 2: synthesis of 6-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3- (trifluoromethyl)benzonitrile (464-C)

[0466] To a solution of tert-butyl (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyano-4- (trifluoromethyl)phenyl)carbamate (0.7 g, 1.52 mmol, 1 eq) in DMF (15 mL) was added CsF (692.63 mg, 4.56 mmol, 3 eq). The mixture was stirred at 40°C for 12 hrs. The reaction mixture was poured into 15 mL of H2O and extracted with DCM (15 mL × 3). The combined organic phase dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1) to give 6-amino-2-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-3-(trifluoromethyl)benzonitrile (520 mg, 1.50 mmol, 98.80% yield) was obtained as a yellow oil. ESI [M-H] = 345.0

[0467] Step 3: synthesis of 6-amino-2-(2-hydroxyethoxy)-3-(trifluoromethyl)benzonitrile (464-D)

[0468] The mixture of 6-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3- (trifluoromethyl)benzonitrile (520 mg, 1.50 mmol, 1 eq) in TFA (3 mL) and DCM (6 mL) was stirred at 20°C for 1 hr. To the reaction mixture was added sat.aq. Na2CO3 (10 ml) portion wise until it was basified to pH > 7, then reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL), the water phase was extracted with EtOAc (10 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated to give 6-amino-2-(2- hydroxyethoxy)-3-(trifluoromethyl)benzonitrile (450 mg, crude) as a white solid. ESI [M-H] =245.2 12886058v1 Page 407 of 494Attorney Docket No.2019292-0022

[0469] Step 4: synthesis of 2-(3-amino-2-(aminomethyl)-6- (trifluoromethyl)phenoxy)ethanol (464-E)

[0470] To a solution of 6-amino-2-(2-hydroxyethoxy)-3-(trifluoromethyl)benzonitrile (450 mg, 1.83 mmol, 1 eq) in THF (10 mL) was added BH3.THF (1 M, 5.48 mL, 3 eq) at 0°C under N2. The mixture was stirred at 60°C for 2 hrs under N2. The reaction mixture was quenched by addition MeOH 10 mL at 0°C under N2, the mixture was stirred at 60°C for 2 hrs under N2. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(3-amino-2-(aminomethyl)-6-(trifluoromethyl)phenoxy)ethanol (500 mg, crude) as a yellow oil. ESI [M-H] =249.2

[0471] Step 5: synthesis of methyl 2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-hydroxyethoxy)-6- (trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2-carboxylate (464-F)

[0472] The mixture of methyl 2-(bicyclo[1.1.1]pentan-1-yl)-2-oxoacetate (308.06 mg, 2.00 mmol, 1 eq) and 2-(3-amino-2-(aminomethyl)-6-(trifluoromethyl)phenoxy)ethanol (500 mg, 2.00 mmol, 1 eq) in Tol. (10 mL) was stirred at 135°C for 1 hr under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 1:0 to 0:1) to give methyl 2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-hydroxyethoxy)-6-(trifluoromethyl)-1,2,3,4- tetrahydroquinazoline-2-carboxylate (400 mg, 1.04 mmol, 51.81% yield) as a white solid. ESI [M+H] =387.2

[0473] Step 6: synthesis of methyl 2-((2-(aminomethyl)-3-(2-hydroxyethoxy)-4- (trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1-yl)acetate (464-G)

[0474] To a solution of methyl 2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-hydroxyethoxy)-6- (trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2-carboxylate (300 mg, 776.47 μmol, 1 eq) in TFA (1 mL) and DCM (3 mL) was added Et3SiH (180.57 mg, 1.55 mmol, 248.04 uL, 2 eq) at 0°C. The mixture was stirred at 40°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give methyl 2-((2-(aminomethyl)-3-(2-hydroxyethoxy)-4- (trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1-yl)acetate (220 mg, crude) as a yellow solid. ESI [M+H] =389.2 12886058v1 Page 408 of 494Attorney Docket No.2019292-0022

[0475] Step 7: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxyethoxy)-7- (trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (464-H)

[0476] To a solution of methyl 2-((2-(aminomethyl)-3-(2-hydroxyethoxy)-4- (trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1-yl)acetate (220 mg, 566.45 umol, 1 eq) in MeOH (3 mL) was added DIEA (219.63 mg, 1.70 mmol, 296.00 uL, 3 eq) and NaOMe (306.02 mg, 5.66 mmol, 10 eq) at 0°C. The mixture was stirred at 70°C for 1 hr. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 2:1) to give 2-(bicyclo[1.1.1]pentan-1- yl)-6-(2-hydroxyethoxy)-7-(trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (80 mg, 224.51 umol, 39.63% yield) as a yellow oil. ESI [M+H] =357.1

[0477] Step 8: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin- 3(2H)-one (464-I)

[0478] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxyethoxy)-7- (trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (80 mg, 224.51 umol, 1 eq) in DCM (2 mL) was added IMIDAZOLE (30.57 mg, 449.01 umol, 2 eq) and TBSCl (50.76 mg, 336.76 umol, 41.43 uL, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1) to give 2-(bicyclo[1.1.1]pentan-1- yl)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-3(2H)-one (50 mg, 106.25 μmol, 47.33% yield) as a white solid. ESI [M+H] =471.3

[0479] Step 9: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (464-J)

[0480] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin- 3(2H)-one (50 mg, 106.25 umol, 1 eq) in THF (2 mL) was added BH3.THF (1 M, 318.74 uL, 3 eq) at 0°C under N2. The mixture was stirred at 60°C for 1 hr under N2. The reaction mixture 12886058v1 Page 409 of 494Attorney Docket No.2019292-0022 was quenched by addition MeOH 2 mL at 0°C under N2, the mixture was stirred at 60°C for 2 hrs under N2. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (30 mg, crude) as a white solid. ESI [M+H] =457.2

[0481] Step 10: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (464-K)

[0482] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (30 mg, 65.70 umol, 1 eq) and DIEA (25.47 mg, 197.10 umol, 34.33 μL, 3 eq) in DCM (1 mL) was added Tf2O (20.39 mg, 72.27 umol, 11.92 uL, 1.1 eq) at -78°C under N2. The mixture was stirred at -78°C for 10 min under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 5:1) to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (20 mg, 33.97 μmol, 51.71% yield) as a white solid. ESI [M+H] =589.3

[0483] Step 11: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (464-L)

[0484] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (20.00 mg, 33.97 umol, 1 eq) and 1H-imidazole-4- carbaldehyde (16.32 mg, 169.87 umol, 5 eq) in DCM (0.5 mL) and AcOH (0.5 mL) was added NaBH(OAc)3 (36.00 mg, 169.87 umol, 5 eq). The mixture was stirred at 40°C for 24 hrs. The reaction mixture was concentrated under reduced pressure to give 1-((1H-imidazol-4- yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-7- 12886058v1 Page 410 of 494Attorney Docket No.2019292-0022 (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (10 mg, 14.95 umol, 44.01% yield) as a yellow oil. ESI [M+H] =669.3

[0485] Step 12: synthesis of 2-((1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1- yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-6-yl)oxy)ethanol (464)

[0486] The mixture of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-6-(2- ((tert-butyldimethylsilyl)oxy)ethoxy)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (10 mg, 14.95 umol, 1 eq) in HCl / MeOH (4 M, 1 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 column (100 × 30 mm, 3 um); flow rate: 25 mL / min; gradient: 15% – 45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-((1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-6-yl)oxy)ethanol (464)) (4.6 mg, 7.48 umol, 50.05% yield, 97.7% purity, FA salt) as a white solid. ESI [M+H] =555.1

[0487] 1H NMR (400 MHz, CD3OD) δ = 7.86 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 4.4 Hz, 2H), 5.47 (br d, J = 14.0 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.52 - 4.42 (m, 1H), 4.27 - 4.21 (m, 1H), 4.16 (br d, J = 14.0 Hz, 1H), 3.99 - 3.85 (m, 4H), 3.49 (t, J = 2.8 Hz, 1H), 3.24 (br d, J = 12.9 Hz, 1H), 2.32 (s, 1H), 1.73 (dd, J = 1.5, 9.4 Hz, 3H), 1.52 - 1.44 (m, 3H).

[0488] Example 1.26 Synthesis of： (R)4-((2-(bicyclo[1.1.1]pentan-1-yl)-6- cyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)-1H-imidazol-2-amine and (S)-4-((2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H- imidazol-2-amine 12886058v1 Page 411 of 494Attorney Docket No.2019292-0022

[0489] Step 1: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-1-(imidazo[1,2- a]pyrimidin-3-ylmethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (418)

[0490] To a solution of 2-(1-bicyclo[1.1.1]pentanyl)-6-cyclopropyl-4- (trifluoromethylsulfonyl)-1,2,3,5-tetrahydro-1,4-benzodiazepine (120 mg, 310.53 μmol, 1 eq) and imidazo[1,2-a]pyrimidine-3-carbaldehyde (228.45 mg, 1.55 mmol, 5 eq) in AcOH (3 mL) was added NaBH(OAc)3 (394.89 mg, 1.86 mmol, 6 eq). The mixture was stirred at 40°C for 2 hrs. The reaction mixture was adjusted PH to 6-7 by NaHCO3 (1 mL) at 0°C, and then extracted with EtOAc(1mL × 3). The combined organic layers were washed with sat. aq. NaCl (1mL× 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (100 × 30 mm, 3 mm); flow rate: 25 mL / min; gradient: 25% – 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-(1-bicyclo[1.1.1]pentanyl)-6-cyclopropyl-4- (trifluoromethylsulfonyl)-1,2,3,5-tetrahydro-1,4-benzodiazepine (130 mg, 229.28 μmol, 73.83% yield, 99.4% purity, FA salt) as a yellow solid. ESI [M+H] = 518.2

[0491] 1H-NMR (400 MHz, CD3OD) δ = 8.74 (dd, J = 1.6, 6.8 Hz, 1H), 8.61 (dd, J = 2.0, 4.0 Hz, 1H), 7.81 (s, 1H), 7.39 - 7.23 (m, 2H), 7.13 (dd, J = 4.0, 6.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.64 - 5.38 (m, 1H), 5.03 (br d, J = 14.4 Hz, 1H), 4.79 (s, 1H), 4.20 - 4.03 (m, 1H), 3.98 - 3.60 (m, 1H), 3.43 - 3.36 (m, 1H), 3.11 - 2.85 (m, 1H), 2.29 (s, 2H), 1.75 (br d, J = 9.2 Hz, 3H), 1.44 (br d, J = 8.8 Hz, 3H), 1.04 - 0.83 (m, 3H), 0.43 - 0.24 (m, 1H) 12886058v1 Page 412 of 494Attorney Docket No.2019292-0022

[0492] Step 2: synthesis of 4-((2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H- imidazol-2-amine (419)

[0493] To a solution of 2-(1-bicyclo[1.1.1]pentanyl)-6-cyclopropyl-1-(imidazo[1,2- a]pyrimidin-3-ylmethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepine (100 mg, 158.33 μmol, 1 eq, FA) in EtOH (2 mL) was added hydrazine;hydrate (198.15 mg, 3.17 mmol, 192.01 μL, 80% purity, 20 eq) at 0°C under N2. The mixture was stirred at 80°C for 2 hrs under N2. The reaction mixture was added to H2O (2 mL) under N2, then the reaction mixture was partitioned between EtOAc (2 mL) and H2O (2 mL), the water phase was extracted with EtOAc (2 mL× 2), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (WePure Biotech XP tC18column (150 × 40 mm, 7 mm); flow rate: 25 mL / min; gradient: 50% – 85% B over 10 min; mobile phase A: 10 mM aqueous NH4HCO3 , mobile phase B: acetonitrile) to give 4-((2- (bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-1-yl)methyl)-1H-imidazol-2-amine (25.9 mg, 51.20 μmol, 32.34% yield, 95.2% purity) as a white solid. ESI [M+H] = 482.1

[0494] 1H-NMR (400 MHz, CD3OD) δ = 7.24 - 7.15 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 5.53 (br d, J = 14.0 Hz, 1H), 4.38 - 4.19 (m, 3H), 3.92 - 3.82 (m, 1H), 3.42 - 3.39 (m, 1H), 3.24 - 3.14 (m, 1H), 2.39 - 2.26 (m, 1H), 2.23 (s, 1H), 1.65 (d, J = 8.8 Hz, 3H), 1.34 (br d, J = 8.8 Hz, 3H), 1.05 - 0.87 (m, 3H), 0.34 - 0.21 (m, 1H)

[0495] Step 3: Chiral separation to give (R)-4-((2-(bicyclo[1.1.1]pentan-1-yl)-6- cyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)-1H-imidazol-2-amine and (S)-4-((2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H- imidazol-2-amine

[0496] 4-((2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H-imidazol-2-amine (20 mg) was separated by SFC (Instrument: Waters SFC80 preparative SFC；Column: DAICEL CHIRALCEL OZ (250mm× 20mm,10um); Mobile phase: A for CO2and B for 12886058v1 Page 413 of 494Attorney Docket No.2019292-0022 MeOH(0.1%NH3H2O); Gradient: B%=45% isocratic elution mode to generate the 2 chiral isomers.

[0497] Peak 1 (Rt=1.322) 4-((2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H- imidazol-2-amine (419-1), 4.7 mg, 9.34 μmol, 22.49% yield, 95.7% purity). ESI [M+H] = 482.1

[0498] 1H-NMR (400 MHz, CD3OD) δ = 7.14 - 7.05 (m, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.42 (s, 1H), 5.43 (br d, J = 14.0 Hz, 1H), 4.29 - 4.09 (m, 3H), 3.75 (br d, J = 12.0 Hz, 1H), 3.31 (br s, 1H), 3.09 (br d, J = 12.4 Hz, 1H), 2.29 - 2.15 (m, 1H), 2.13 (s, 1H), 1.55 (br d, J = 9.4 Hz, 3H), 1.24 (br d, J = 9.2 Hz, 3H), 0.88 - 0.78 (m, 3H), 0.25 - 0.11 (m, 1H)

[0499] Peak 2 (Rt=1.502) 4-((2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H- imidazol-2-amine (419-2), 3.8 mg, 7.69 μmol, 18.52% yield, 97.5% purity). ESI [M+H] = 482.1

[0500] 1H-NMR (400 MHz, CD3OD) δ = 7.26 - 7.14 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 5.53 (br d, J = 14.0 Hz, 1H), 4.44 - 4.12 (m, 3H), 3.85 (br d, J = 12.0 Hz, 1H), 3.41 (br s, 1H), 3.20 (br d, J = 12.4 Hz, 1H), 2.41 - 2.27 (m, 1H), 2.23 (s, 1H), 1.76 - 1.58 (m, 3H), 1.34 (br d, J = 9.2 Hz, 3H), 1.01 - 0.88 (m, 3H), 0.38 - 0.19 (m, 1H)

[0501] Compounds in the following table were prepared according to procedures analogous to preparation of Compounds 419, 419-1, and 419-2 in Example 1.26, using analogous starting materials and / or intermediates. ESI [M+H] = 496.1.1H NMR (400 MHz, CD3OD) 0, 2 9 ), br s, 512886058v1 Page 414 of 494Attorney Docket No.2019292-0022 ESI [M+H] =456.2.1H NMR (400 MHz, CD3OD) 415 δ = 7.20 - 7.14 (m, 1H), 7.08 (br d, J = 8.0 Hz, 1H), br ), s, 2 = ) 0, 6 5 ), ), s, 3 ) ), br ), s, 2 =

[0502] Example 1.27: Synthesis of (R)-1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (480-1) 12886058v1 Page 415 of 494Attorney Docket No.2019292-0022

[0503] Step 1: synthesis of 6-amino-2-fluoro-3-(trifluoromethyl)benzonitrile (480-B)

[0504] To a solution of 3-fluoro-2-iodo-4-(trifluoromethyl)aniline (10 g, 32.79 mmol, 1 eq) in DMF (300 mL) was added Pd(PPh3)4(1.89 g, 1.64 mmol, 0.05 eq) and CuCN (29.36 g, 327.86 mmol, 71.62 mL, 10 eq). The mixture was stirred at 110°C for 12 hrs under N2.TLC (Petroleum ether: Ethyl acetate = 1:1) showed the reaction was completed. The residue was diluted with H2O (300 mL) and extracted with EtOAc 900 mL (300 mL×3), dried over Na2SO4, 12886058v1 Page 416 of 494Attorney Docket No.2019292-0022 filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 1:0 to 1:1) to give 6-amino-2- fluoro-3-(trifluoromethyl)benzonitrile (5 g, 12.93 mmol, 39.45% yield, 60% purity) as a yellow oil. ESI [M-H] = 203.0

[0505] Step 2: synthesis of tert-butyl N-tert-butoxycarbonyl-N-[2-cyano-3-fluoro-4- (trifluoromethyl)phenyl]carbamate (480-C)

[0506] To a solution of 6-amino-2-fluoro-3-(trifluoromethyl)benzonitrile (5 g, 24.49 mmol, 1 eq) in DCM (100 mL) was added tert-butoxycarbonyl tert-butyl carbonate (10.69 g, 48.99 mmol, 11.25 mL, 2 eq), TEA (7.44 g, 73.48 mmol, 10.23 mL, 3 eq) and DMAP (598.51 mg, 4.90 mmol, 0.2 eq), The mixture was stirred at 20°C for 1 hr. The residue was diluted with H2O 150 mL and extracted with EtOAc 300 mL(100 mL ×3).The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 100:1 to 5:1) to give tert-butyl N-tert-butoxycarbonyl-N-[2-cyano-3-fluoro-4- (trifluoromethyl)phenyl]carbamate (8.2 g, crude) as a yellow oil. ESI [M-H] = 303.1

[0507] Step 3: synthesis of tert-butyl (3-azido-2-cyano-4- (trifluoromethyl)phenyl)carbamate (480-D)

[0508] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[2-cyano-3-fluoro-4- (trifluoromethyl)phenyl]carbamate (3.8 g, 9.40 mmol, 1 eq) in DMF (30 mL) was added NaN3 (672.04 mg, 10.34 mmol, 1.1 eq). The mixture was stirred at 60°C for 1 hr. To the reaction mixture was added sat. aq. Na2CO3(60 ml) portionwise until it was basified to pH > 10 at 0°C, then reaction mixture was partitioned between EtOAc (60 mL) and H2O (60 mL), the water phase was extracted with EtOAc (60 mL×3), the combined organic phase was used directly to give tert-butyl (3-azido-2-cyano-4-(trifluoromethyl)phenyl)carbamate (3.8 g, crude) as a yellow oil. ESI [M-H] = 326.1

[0509] Step 4: synthesis of tert-butyl (3-amino-2-cyano-4- (trifluoromethyl)phenyl)carbamate (480-E)

[0510] To a solution of tert-butyl (3-azido-2-cyano-4- (trifluoromethyl)phenyl)carbamate (3.8 g, 11.61 mmol, 1 eq, crude from Step 2) in EtOAc (60 12886058v1 Page 417 of 494Attorney Docket No.2019292-0022 mL) was added Pd / C (2.47 g, 10% Pd on carbon). The mixture was stirred at 20°C for 1 hr under H2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (3-amino-2-cyano-4-(trifluoromethyl)phenyl)carbamate (3.8 g, crude) as a yellow solid. ESI [M-H] = 300.1

[0511] Step 5: synthesis of tert-butyl (3-chloro-2-cyano-4- (trifluoromethyl)phenyl)carbamate (480-F)

[0512] To a solution of tert-butyl (3-azido-2-cyano-4- (trifluoromethyl)phenyl)carbamate (3.8 g, 12.61 mmol, 1 eq, crude from Step 3) in ACN (100 mL) was added t-BuONO (3.90 g, 37.84 mmol, 4.50 mL, 3 eq), CuCl (3.75 g, 37.84 mmol, 904.88 μL, 3 eq), CuCl2(3.39 g, 25.23 mmol, 2 eq), the mixture was stirred at 60°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 100:1 to 5:1) to give tert-butyl (3-chloro-2-cyano-4-(trifluoromethyl)phenyl)carbamate (3.4 g, crude) as a yellow solid. ESI [M-H] = 319.1

[0513] Step 6: synthesis of 6-amino-2-chloro-3-(trifluoromethyl)benzonitrile (480-G)

[0514] A mixture of tert-butyl (3-chloro-2-cyano-4-(trifluoromethyl)phenyl)carbamate (3.4 g, 10.60 mmol, 1 eq) in THF (25 mL) and HCl (25 mL). The mixture was stirred at 20°C for 24 hrs. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (100 mL) at 0°C, and then extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1 ) to give 6-amino-2-chloro-3- (trifluoromethyl)benzonitrile (2.1 g, 9.52 mmol, 89.80% yield) as a yellow solid. ESI [M-H] = 219.1

[0515] Step 7: synthesis of 2-(aminomethyl)-3-chloro-4-(trifluoromethyl)aniline (480-H)

[0516] To a solution of 6-amino-2-chloro-3-(trifluoromethyl)benzonitrile (2.1 g, 9.52 mmol, 1 eq) in THF (15 mL) was added BH3.THF (1 M, 19.04 mL, 2 eq) at 0°C under N2. The mixture was stirred at 60°C for 2 hrs under N2. The reaction mixture was quenched by addition MeOH (50 mL) at 0°C under N2, and then the reaction was stirred at 60°C for 0.5 hr, after that the reaction mixture was concentrated under reduced pressure to give a residue, then dioxane (10 12886058v1 Page 418 of 494Attorney Docket No.2019292-0022 mL) and 1 N HCl 10 mL) was added to the mixture reaction , the mixture was stirred at 60°C for 0.5 hr, then the residue was diluted with NaOH solution 50mL and extracted with EtOAc 120 mL(40 mL ×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(aminomethyl)-3-chloro-4-(trifluoromethyl)aniline (1.92 g, crude) as a yellow solid. ESI [M-H] = 223.1

[0517] Step 8: synthesis of methyl 2-(bicyclo[1.1.1]pentan-1-yl)-5-chloro-6- (trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2-carboxylate (480-I)

[0518] To a solution of methyl 2-(1-bicyclo[1.1.1]pentanyl)-2-oxo-acetate (1.3 g, 8.43 mmol, 1 eq) and 2-(aminomethyl)-3-chloro-4-(trifluoromethyl)aniline (1.89 g, 8.43 mmol, 1 eq) in Tol. (20 mL). The mixture was stirred at 135°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 100:1 to 3:1) to give methyl 2- (bicyclo[1.1.1]pentan-1-yl)-5-chloro-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2- carboxylate (3 g, 8.32 mmol, 98.61% yield) as a yellow solid. ESI [M+H] = 361.1

[0519] Step 9: synthesis of methyl 2-((2-(aminomethyl)-3-chloro-4- (trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1-yl)acetate (480-J)

[0520] To a solution of methyl 2-(1-bicyclo[1.1.1]pentanyl)-5-chloro-6- (trifluoromethyl)-3,4-dihydro-1H-quinazoline-2-carboxylate (2.9 g, 8.04 mmol, 1 eq) in DCM (20 mL) and TFA (7 mL) was added Et3SiH (1.59 g, 13.67 mmol, 2.18 mL, 1.7 eq) at 0°C. The mixture was stirred at 40°C for 24 hrs. The residue was diluted with H2O 100 mL and extracted with EtOAc 300 mL (100 mL ×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 100:1 to 0:1) to give methyl 2- ((2-(aminomethyl)-3-chloro-4-(trifluoromethyl)phenyl)amino)-2-(bicyclo[1.1.1]pentan-1- yl)acetate (710 mg, 1.96 mmol, 24.35% yield) as a yellow solid. ESI [M+H] = 363.1

[0521] Step 10: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)- 4,5-dihydro-1H-benzo[e][1,4]diazepin-3(2H)-one (480-K)

[0522] To a mixture of methyl 2-[2-(aminomethyl)-3-chloro-4- (trifluoromethyl)anilino]-2-(1-bicyclo[1.1.1]pentanyl)acetate (700 mg, 1.93 mmol, 12886058v1 Page 419 of 494Attorney Docket No.2019292-0022 1 eq) in MeOH (10 mL), DIEA (1.25 g, 9.65 mmol, 1.68 mL, 5 eq) was added to adjust PH = 7 at 0°C, then NaOMe (1.04 g, 19.30 mmol, 10 eq) was added to the mixture reaction at 0°C, the mixture was stirred at 50°C for 1 hr. The residue was diluted with H2O 50 mL and extracted with EtOAc 120 mL (40 mL ×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 100:1 to 1:1) to give 2- (bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-3(2H)-one (520 mg, 1.57 mmol, 81.48% yield) as a yellow solid. ESI [M+H] = 331.0

[0523] Step 11: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (480-L)

[0524] To a solution of 2-(1-bicyclo[1.1.1]pentanyl)-6-chloro-7-(trifluoromethyl)- 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (520 mg, 1.57 mmol, 1 eq) in THF (5 mL) was added BH3.THF (1 M, 7.86 mL, 5 eq) at 0°C under N2. The mixture was stirred at 40°C for 1 hr under N2. The reaction mixture was quenched by addition MeOH (20 mL) at 0°C under N2, and then the reaction was stirred at 60°C for 0.5 hr, after that the reaction mixture was concentrated under reduced pressure to give a residue, then dioxane (5 mL) and 1 N HCl (5 mL) was added to the mixture reaction , the mixture was stirred at 60°C for 0.5 hr, then the reaction mixture was concentrated under reduced pressure to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7- (trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (220 mg ) as a yellow solid. ESI [M+H] = 317.1

[0525] Step 12: synthesis of (R)-2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7- (trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (480-M) and (S)-2- (bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (439-M).

[0526] 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepine (220 mg) was separated by SFC (Instrument: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm×30mm,10um); Mobile phase A: CO2 and B: 0.1%NH3H2O in IPA; Gradient: B%=15% isocratic elution mode; Flow rate: 12886058v1 Page 420 of 494Attorney Docket No.2019292-0022 CO2(210 g / min) and B (70 g / min); Wavelength: 220&254nm; Column temperature: 40℃; System back pressure: 100 bar) to generate two enantiomers (480-M peak 1 and 480-M peak 2).

[0527] Peak 1 (Rt = 1.487) 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (480-M peak 1) (80 mg, 252.57 μmol, 16.06% yield). ESI [M+H] = 317.1.

[0528] Peak 2 (Rt = 1.652) 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin (480-M peak 2) (70 mg, 221.00 μmol, 14.06% yield). ESI [M+H] = 317.1.

[0529] Step 13: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)- 4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (480-N-1)

[0530] To a mixture of 2-(1-bicyclo[1.1.1]pentanyl)-6-chloro-7-(trifluoromethyl)-2,3,4,5- tetrahydro-1H-1,4-benzodiazepine (480-M peak 1) (75.00 mg, 236.78 μmol, 1 eq) in DCM (2 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (80.17 mg, 284.14 μmol, 46.88 μL, 1.2 eq) and DIEA (91.81 mg, 710.34 μmol, 123.73 μL, 3 eq) at -78°C, the mixture was stirred at -78°C for 0.5 hr under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate =5:1) to give 2-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (90 mg, 200.53 μmol, 84.69% yield) as a yellow oil. ESI [M+H] = 449.2

[0531] Step 14: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-7- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (480-O-1)

[0532] To a solution of 2-(1-bicyclo[1.1.1]pentanyl)-6-chloro-7-(trifluoromethyl)-4- (trifluoromethylsulfonyl)-1,2,3,5-tetrahydro-1,4-benzodiazepine (480-N-1) (20 mg, 44.56 μmol, 1 eq) in Tol. (1 mL) and H2O (0.1 mL) was added ditert-butyl(cyclopenta-1,4-dien-1- yl)phosphane;dichloropalladium;iron (2.90 mg, 4.46 μmol, 0.1 eq) and K3PO4 (18.92 mg, 89.12 μmol, 2 eq) and cyclopropylboronic acid (19.14 mg, 222.81 μmol, 5 eq). The mixture was stirred at 90°C for 12 hrs under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC 12886058v1 Page 421 of 494Attorney Docket No.2019292-0022 (Petroleum ether: Ethyl acetate =5:1 ) to give (R)-2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl- 7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (20 mg, crude) as a yellow oil. ESI [M+H] = 455.1

[0533] Step 15: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 6-cyclopropyl-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (480-1)

[0534] To a mixture of (2R)-2-(1-bicyclo[1.1.1]pentanyl)-6-cyclopropyl-7- (trifluoromethyl)-4-(trifluoromethylsulfonyl)-1,2,3,5-tetrahydro-1,4-benzodiazepine (480-O-1) (20 mg, 44.01 μmol, 1 eq) and 1H-imidazole-4-carbaldehyde (21.14 mg, 220.06 μmol, 5 eq) in DCE (1 mL), AcOH (3 mL)was added NaBH(OAc)3(46.64 mg, 220.06 μmol, 5 eq), the mixture was stirred at 40°C for 12 hrs. The reaction mixture was quenched by addition saturated aqueous NaHCO3 (30 mL) at 0°C, and then extracted with EtOAc (30 mL ×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 column (100×30 mm, 3um); flow rate: 25 mL / min; gradient: 40% –75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (480-1) (11.5 mg, 19.81 μmol, 45.01% yield, 100.000% purity, FA salt) as a white solid. ESI [M+H] = 535.2

[0535] 1H NMR (400 MHz, CD3OD) δ = 7.77 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 5.92 (br d, J = 13.2 Hz, 1H), 4.58 - 4.49 (m, 2H), 4.42 (br d, J = 14.0 Hz, 1H), 3.92 - 3.63 (m, 1H), 3.41 (t, J = 3.6 Hz, 1H), 3.26 (br s, 1H), 2.32 (s, 1H), 2.22 - 2.11 (m, 1H), 1.74 (dd, J = 9.2, 1.6 Hz, 3H), 1.44 (br d, J = 9.2 Hz, 3H), 1.21 - 1.10 (m, 2H), 0.93 - 0.85 (m, 1H), 0.48 - 0.39 (m, 1H)

[0536] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 480-1 in Example 1.27, using analogous starting materials and / or intermediates. 12886058v1 Page 422 of 494Attorney Docket No.2019292-0022 Step 14 (Suzuki reaction) was slightly modified by 481-2 using 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane = s, z, z, ), - 7 ) z, br 5 ), ), 6 ) 7 , 1 ), 6, 7 ) 9 z, , z, ), 312886058v1 Page 423 of 494Attorney Docket No.2019292-0022 482-1 Chiral SFC afforded the pure enantiomers : Peak 1 (Rt = 1.624). ESI [M+H] = 531.3.1H NMR (400 2 ), , 1 , 3 - , 2 0 ), J , z, z, 9 ), - , ) br d, br 7 ). ) z, .4 .4 = 9 ) ) s,12886058v1 Page 424 of 494Attorney Docket No.2019292-0022 1H), 5.06 (br s, 1H), 4.53 - 4.42 (m, 3H), 3.85 (br d, J = 12.8 Hz, 1H), 3.37 (br s, 1H), 3.21 (br d, J = d, ) .0 .6 1 2 1 3 6 ) = ), 3 ), s, 0

[0537] Example 1.28: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-6-ol (469)

[0538] Step 1: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (469-B) 12886058v1 Page 425 of 494Attorney Docket No.2019292-0022

[0539] A solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6-methoxy-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (250 mg, 562.57 μmol, 1 eq) in HBr (2 mL) - AcOH (0.5 mL) was stirred at 120°C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:45%- 80% B over 8.0 min) give 2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (10 mg, 23.24 μmol, 4.13% yield) as a brown solid. ESI [M-H] = 431.1

[0540] Step 2: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6- ol (469)

[0541] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (10 mg, 23.24 μmol, 1 eq) and 1H-imidazole-4-carbaldehyde (11.16 mg, 116.18 μmol, 5 eq) in AcOH (1 mL) was added NaBH(OAc)3 (24.62 mg, 116.18 μmol, 5 eq). The mixture was stirred at 40°C for 48 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:45%-80% B over 8.0 min) to give 1-((1H-imidazol-4- yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-7-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (3.3 mg, 5.80 μmol, 24.96% yield, 97.8% purity, FA salt) as a pale yellow solid. ESI [M-H] = 511.1

[0542] 1HNMR (400 MHz, CD3OD) δ = 7.76 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.49 (br d, J = 14.2 Hz, 1H), 4.57 (br d, J = 13.6 Hz, 2H), 4.48 - 4.42 (m, 1H), 4.15 (br d, J = 14.4 Hz, 1H), 3.85 (br d, J = 12.8 Hz, 1H), 3.40 (br s, 1H), 3.20 (br d, J = 12.8 Hz, 1H), 2.30 (s, 1H), 1.74 (br d, J = 9.2 Hz, 3H), 1.46 (br d, J = 9.2 Hz, 3H)

[0543] Example 1.29: Synthesis of (R)-1-((1H-imidazol-4-yl)methyl)-2,6-dicyclopropyl- 4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine and (S)-1-((1H- imidazol-4-yl)methyl)-2,6-dicyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine 12886058v1 Page 426 of 494Attorney Docket No.2019292-0022 [0544p y - - - y p py -

[0545] To intermediate 483-A (70 g, 268.29 mmol, 1 eq) and cyclopropylboronic acid (27.65 g, 321.95 mmol, 1.2 eq), in H2O (40 mL) and Tol. (400 mL) was added tricyclohexylphosphane (11.4 g, 40.60 mmol, 13.2 mL, 0.2 eq), tripotassium; phosphate (150.8 g, 710 mmol, 3.5 eq) and diacetoxypalladium (4.1 g, 18.2 mmol, 0.09 eq). The mixture was stirred at 100°C for 5hr under N2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 100 : 0 to 20:1) to give 483-B (28 g, 104.44 mmol, 38.93% yield, FA salt).

[0546] Step 2: synthesis of tert-butyl (2-cyano-3-cyclopropylphenyl)carbamate (483-C)

[0547] A mixture of 2-bromo-6-cyclopropylbenzonitrile (7 g, 31.52 mmol, 1 eq), tert- butyl carbamate (9.23 g, 78.80 mmol, 2.5 eq), Cs2CO3(20.54 g, 63.04 mmol, 2 eq), SPhos Pd 12886058v1 Page 427 of 494Attorney Docket No.2019292-0022 G3 (1.23 g, 1.58 mmol, 0.05 eq) in Tol. (250 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2. The reaction mixture was filtered and concentrated. The crude product was purified by re-crystallization from DMF (50 mL) at 20oC to give tert-butyl (2-cyano-3-cyclopropylphenyl)carbamate (6 g, 23.23 mmol, 73.69% yield) as a white solid. ESI [M+H] = 259.3

[0548] 1H NMR (400 MHz, MeOD) δ = 7.50 (d, J = 4.4 Hz, 2H), 6.84 (t, J = 4.4 Hz, 1H), 2.25 (ddd, J = 8.4, 5.2, 3.2 Hz, 1H), 1.57 (s, 9H), 1.27 - 1.03 (m, 2H), 0.84 (dd, J = 4.8, 1.6 Hz, 2H).

[0549] Step 3: synthesis of ethyl 2-((tert-butoxycarbonyl) (2-cyano-3- cyclopropylphenyl)amino)-2-cyclopropylacetate (483-D)

[0550] To a solution of tert-butyl (2-cyano-3-cyclopropylphenyl)carbamate (5.4 g, 20.90 mmol, 1 eq) in DMF (100 mL) was added Cs2CO3 (13.62 g, 41.81 mmol, 2 eq) under 20°C for 0.5hr, followed by addition of ethyl 2-bromo-2-cyclopropylacetate (6.49 g, 31.36 mmol, 1.5 eq). The mixture was stirred at 100°C for 0.5hr and then filtered to give ethyl 2-((tert- butoxycarbonyl)(2-cyano-3-cyclopropylphenyl)amino)-2-cyclopropylacetate (5 g, crude) as a white solid. ESI [M+H] = 385.4

[0551] Step 4: synthesis of tert-butyl 2,6-dicyclopropyl-3-oxo-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine-1-carboxylate (483-E)

[0552] To a solution of ethyl 2-((tert-butoxycarbonyl) (2-cyano-3- cyclopropylphenyl)amino)-2-cyclopropylacetate (1.2 g, 3.12 mmol, 1 eq) in MeOH (15 mL) and THF (15 mL) was added NH3 / MeOH (5 mL) and Ni. The mixture was stirred at 25°Cfor 12 hrs under H2. The suspension was filtered through a pad of silica gel and the pad was washed with MeOH (10 mL×3), the filtrate was concentrated under reduced pressure to give to give tert-butyl 2,6-dicyclopropyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-1-carboxylate (950 mg, crude) as a white solid and used directly into the next step ESI [M+H] = 343.1

[0553] Steps 5 (483-E) to step 8 (483-J) were performed in a manner consistent with those described in Example 1.1 12886058v1 Page 428 of 494Attorney Docket No.2019292-0022

[0554] Step 9: synthesis of 1-((1H-imidazol-4-yl)methyl)-2,6-dicyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (343) and (S)-1-((1H- imidazol-4-yl)methyl)-2,6-dicyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (483-1)

[0555] Racemic target 483J (20 mg) was separated by SFC (Instrument : Waters SFC80 preparative SFC; Column: REGIS (s,s) WHELK-O1(250mm × 30mm,10um);Mobile phase A: CO2and B:0.1%NH3H2O in IPA; Gradient: B% = 20% isocratic elution mode; Flow rate : CO2(280 g / min) and B (70 g / min);Wavelength: 220&254nm; Column temperature: 40oC; System back pressure: 100 bar) to generate two enantiomers.

[0556] Peak 1 (Rt = 0.985 min) 1-((1H-imidazol-4-yl)methyl)-2,6-dicyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (483-1), 7.3 mg, 16.27 μmol, 11.73% yield, 98.166% purity). ESI [M+H] =361.2

[0557] 1H NMR (400 MHz, CD3OD) δ = 7.61 (s, 1H), 7.23 - 7.18 (m, 1H), 7.16 - 7.12 (m, 1H), 6.98 s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 5.50 (br d, J = 14.4 Hz, 1H), 4.61 - 4.43 (m, 3H), 3.70 (br s, 1H), 3.37 - 3.33 (m, 1H), 2.65 - 2.51 (m, 1H), 2.36 - 2.17 (m, 1H), 0.97 - 0.86 (m, 3H), 0.59 (qd, J = 4.6, 9.3 Hz, 1H), 0.50 - 0.31 (m, 4H), 0.09 - -0.02 (m, 1H).

[0558] Peak 2 (Rt = 1.057 min) 1-((1H-imidazol-4-yl)methyl)-2,6-dicyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (483-2), 8.7 mg, 19.69 μmol, 14.19% yield, 99.687% purity). ESI [M+H] = 361.2.

[0559] 1H NMR (400 MHz, CD3OD ) δ = 7.57 (s, 1H), 7.19 - 7.15 (m, 1H), 7.12 - 7.08 (m, 1H), 6.94 (br s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.45 (br d, J = 14.4 Hz, 1H), 4.58 - 4.37 (m, 3H), 3.79 - 3.55 (m, 1H), 3.37 - 3.28 (m, 1H), 2.62 - 2.49 (m, 1H), 2.21 (br d, J = 4.4 Hz, 1H), 0.96 - 0.80 (m, 3H), 0.55 (br dd, J = 9.6, 4.8 Hz, 1H), 0.47 - 0.27 (m, 4H), -0.01 (qd, J = 9.6, 4.8 Hz, 1H).

[0560] Example 1.30: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine-7-carbonitrile (369) 12886058v1 Page 429 of 494Attorney Docket No.2019292-0022

[0561] Schloro-2,3-dihydro- 1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (369)

[0562] To a mixture of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-7- chloro-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (30 mg, 65.09 μmol, 1 eq) in THF (2 mL) was added BRETTPHOS (6.99 mg, 13.02μmol, 0.2 eq), BrettPhos Pd G3 (11.80 mg, 13.02 μmol, 0.2 eq) and Zn(CN)2 (76.43 mg, 650.90 μmol, 41.31 μL, 10 eq) at 25°C under N2, the reaction mixture was stirred at 80°C for 1 hr under N2. To the reaction mixture was added sat. aq. Na2CO3 (2 ml) portion wise until it was basified to pH > 10 at 0°C, then reaction mixture was partitioned between EtOAc (3 mL) and H2O (3 mL), the water phase was extracted with EtOAc (3 mL×3), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Instrument: Gilson 281 Semi-preparative HPLC system; Column: Phenomenex Luna C18100×30mm×3um; Mobile phase: A: H2O(0.2% FA); B: ACN; Gradient: B from 30.00% to 60.00% in 8.00 min; Flow rate: 25.00ml / min; Monitor wavelength: 220&254nm) to give 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine-7-carbonitrile ((7.5 mg, 15.03 μmol, 23.09% yield, 99.7% purity, FA salt) as a yellow solid. ESI [M+H] = 452.1

[0563] 1H NMR (400 MHz, DMSO-d6) δ = 12.49 - 11.71 (m, 1H), 7.76 (br d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.53 (br d, J = 8.4 Hz, 1H), 7.12 (br s, 1H), 4.75 (br d, J = 14.8 Hz, 1H), 4.56 (br d, J = 14.4 Hz, 1H), 4.39 (br d, J = 14.4 Hz, 2H), 3.85 (br d, J = 13.2 Hz, 1H), 3.60 (br s, 1H), 3.33 (br s, 1H), 2.27 (s, 1H), 1.60 (br d, J = 8.4 Hz, 3H), 1.29 (br d, J = 9.2 Hz, 3H). 12886058v1 Page 430 of 494Attorney Docket No.2019292-0022

[0564] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 382 in Example 1.30, using analogous starting materials and / or intermediates. ESI [M+H] = 470.1.1H NMR (400 MHz, CD3OD) 434 δ = 769 (d J = 08 Hz 1H) 763 (t J = 81 Hz 1H), J 3 .5 1 ) ), - = = z, ) ), J , 2 ,

[0565] Example 1.31: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-7-(oxetan-3-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (381) 12886058v1 Page 431 of 494Attorney Docket No.2019292-0022 [0566n-1-yl)- 7-bromo-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (381-B)

[0567] From intermediate 381-A (100 mg, 235.15 μmol, 1 eq) and 1H-imidazole-5- carbaldehyde (112.97 mg, 1.18 mmol, 5 eq), 381-B (115 mg, 227.56 μmol, 96.77% yield) was made using the same procedure described in Example 1.1 for the reductive amination. ESI [M+H] = 505.1

[0568] Step 2: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 7-(oxetan-3-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (381)

[0569] To a solution of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-7- bromo-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (40 mg, 79.15 μmol, 1 eq) and 3-bromooxetane (13.01 mg, 94.98 μmol, 1.2 eq) in DMA (1.5 mL) was added Manganese (17.39 mg, 316.61 μmol, 17.24 μL, 4 eq) and NiCl2∙glyme (1.74 mg, 7.92 μmol, 0.1 eq) and 1,10-phenanthroline (1.43 mg, 7.92 μmol, 0.1 eq) and TBAI (43.85 mg, 118.73 μmol, 1.5 eq). The mixture was stirred at 100°C for 0.5 hrs under Ar. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL), the water phase was extracted with EtOAc (10 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 × 30 mm, 10 um); flow rate: 25 mL / min; gradient: 45% – 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give crude product. The crude product was purified by preparative HPLC (Waters xbridge column (150 × 25 mm, 10 um); flow rate: 60 mL / min; gradient: 35% – 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-7-(oxetan-3-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- 12886058v1 Page 432 of 494Attorney Docket No.2019292-0022 benzo[e][1,4]diazepine (8.8 mg, 17.82 μmol, 22.51% yield, 97.7% purity) as pale yellow solid. ESI [M+H] = 483.2

[0570] 1H NMR (400 MHz, CD3OD) δ = 7.65 (d, J = 1.2 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 – 7.24 (m, 2H), 7.06 (s, 1H), 5.08 (dd, J = 8.4, 6.0 Hz, 2H), 4.73 (q, J = 6.4 Hz,2H), 4.68 (br d, J = 14.0 Hz, 1H), 4.57 – 4.41 (m, 3H), 4.31 – 4.21 (m, 1H), 3.86 (br d, J = 13.2 Hz, 1H), 3.30 (br s, 1H), 3.21 (dd, J = 13.2, 2.4 Hz, 1H), 2.24 (s, 1H), 1.69 (dd, J = 9.2, 1.6 Hz, 3H), 1.40 – 1.33 (m, 3H).

[0571] Example 1.32: Synthesis of 1-((1H-imidazol-4-yl)methyl)-7-(433zetidine-1-yl)- 2-(bicyclo[1.1.1]pentan-1-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (382)

[0572] Step 1: synthesis of 2-(bicyclo[1.1.1]pentan-1-yl)-7-bromo-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (382-B)

[0573] From intermediate 382-A (1 g, 3.41 mmol, 1 eq), which was prepared in a similar manner as shown in Example 1.21, and trifluoromethanesulfonic anhydride (1.06 g, 3.75 mmol, 619.00 μL, 1.1 eq), 382-B (960 mg, 2.26 mmol, 66.19% yield) was made using the same procedure described in Example 1.21. ESI [M+H] = 425.1

[0574] Step 2: synthesis of 7-(433zetidine-1-yl)-2-(bicyclo[1.1.1]pentan-1-yl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (382-C) 12886058v1 Page 433 of 494Attorney Docket No.2019292-0022

[0575] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-7-bromo-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (50 mg, 117.57 μmol, 1 eq) and azetidine (33.56 mg, 587.87 μmol, 39.67 μL, 5 eq) in dioxane (1 mL) was added JohnPhos (3.51 mg, 11.76 μmol, 0.1 eq) and Pd2(dba)3(5.38 mg, 5.88 μmol, 0.05 eq) and NaOtBu (16.95 mg, 176.36 μmol, 1.5 eq). The mixture was stirred at 90°C for 1 hr under N2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (Petroleum ether : Ethyl acetate = 2:1 ) to give 7-(434zetidine-1-yl)-2-(bicyclo[1.1.1]pentan-1-yl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (40 mg, 99.64 μmol, 84.75% yield) as yellow oil. ESI [M+H] = 402.2

[0576] Step 3: synthesis of 1-((1H-imidazol-4-yl)methyl)-7-(434zetidine-1-yl)-2- (bicyclo[1.1.1]pentan-1-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (382)

[0577] Using the same reductive amination procedure as described in Example 1.21, the title compound 382 (7.4 mg, 14.03 μmol, 14.08% yield, 100.0% purity, FA salt) was made from 382-C (40 mg, 99.64 μmol, 1 eq) and 1H-imidazole-5-carbaldehyde (47.87 mg, 498.20 μmol, 5 eq), and purified by preparative HPLC (Waters Xbridge BEH C18column (100 × 30 mm, 10 um); flow rate: 60 mL / min; gradient: 45% – 75% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3 , mobile phase B: acetonitrile) to give crude product. The crude product was purified by preparative HPLC (Phenomenex Luna C18 column (100 × 30 mm, 3 um); flow rate: 25 mL / min; gradient: 15% – 45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). ESI [M+H] = 482.1

[0578] 1H NMR (400 MHz, CD3OD) δ = 7.75 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.51 (dd, J = 8.8, 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 4.60 – 4.53 (m, 1H), 4.52 – 4.37 (m, 3H), 3.85 (br t, J = 7.2 Hz, 5H), 3.27 – 3.17 (m, 2H), 2.37 (quin, J = 7.2 Hz, 2H), 2.28 (s, 1H), 1.71 (dd, J = 9.6, 1.6 Hz, 3H), 1.41 (br d, J = 9.2 Hz, 3H).

[0579] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 382 in Example 1.32, using analogous starting materials and / or intermediates. 12886058v1 Page 434 of 494Attorney Docket No.2019292-0022 383 ESI [M+H] = 512.2.1H NMR (400 MHz, CD3OD) δ = 766 (d J = 08 Hz 1H) 718 (d J = 88 Hz, ), - 8 1 )12886058v1 Page 435 of 494Attorney Docket No.2019292-0022 389 ESI [M+H] = 524.2.1H-NMR (400 MHz, CD3OD) δ = 781 (d J = 08 Hz 1H) 715 - 707 (m 2H), z, 4 , ), e th 2- ) z, .8 .8 br br 6 4 e s ) ), 5 s, 1 - 712886058v1 Page 436 of 494Attorney Docket No.2019292-0022 In step 2, the triazole is introduced by replacing the Johnphos Pd2(dba)3, tBuONa / dioxane with 392 D) .4 .8 ), br ), br D) s, .4 J m, s, 6

[0580] Example 1.33: Synthesis of 4-((6-methyl-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H- imidazol-2-amine (384) 12886058v1 Page 437 of 494Attorney Docket No.2019292-0022 [0581- carbaldehyde (384-B)

[0582] To a solution of 1H-imidazole-4-carbaldehyde (5 g, 52.04 mmol, 1 eq) in DCM (50 mL) was added SEM-Cl (13.01 g, 78.05 mmol, 13.81 mL, 1.5 eq) and DIEA (20.18 g, 156.11 mmol, 27.19 mL, 3 eq) at 0°C. The mixture was stirred at 40°C for 2 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (250 × 100 mm, 10 um); flow rate: 25 mL / min; gradient: 25% – 55% B over 20 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazole-4-carbaldehyde (2.5 g, 11.04 mmol, 21.23% yield) as yellow oil. ESI [M+H] = 227.1

[0583] Step 2: synthesis of 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 4-carbaldehyde (384-C)

[0584] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4- carbaldehyde (1 g, 4.42 mmol, 1 eq) in CCl4 (30 mL) was added NBS (864.97 mg, 4.86 mmol, 12886058v1 Page 438 of 494Attorney Docket No.2019292-0022 1.1 eq) and AIBN (72.55 mg, 441.80 μmol, 0.1 eq). The mixture was stirred at 50 °C for 2 hr under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE: EtOAc = 100:1 / 20:1) to give 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4- carbaldehyde (300 mg, 982.82 μmol, 22.25% yield) as white solid. ESI [M+H] = 305.1

[0585] Step 3: synthesis of 1-((2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)methyl)-6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepine (384-D)

[0586] From intermediate 384-B (300 mg, 982.82 μmol, 1 eq) and 6-methyl-2- phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (469.92 mg, 1.18 mmol, 1.2 eq), 384-D (420 mg, 610.74 μmol, 62.14% yield) was made using the same procedure described in the reductive amination step in Example 1.1. ESI [M+H] = 687.3

[0587] Step 4: synthesis of 4-((6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-2-amine (384-E)

[0588] To a solution of 1-((2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4- yl)methyl)-6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (200 mg, 290.83 μmol, 1 eq) and tert-butyl carbamate (51.10 mg, 436.25 μmol, 1.5 eq) in 2-methylbutan-2-ol (1 mL) was added [2-(2- aminophenyl)phenyl]- methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (23.10 mg, 29.08 μmol, 0.1 eq) and t-BuONa (2 M, 290.83 μL, 2 eq). The mixture was stirred at 90 °C for 1 hr under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (100 × 30 mm, 3 um); flow rate: 25 mL / min; gradient: 45% – 80% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 4-((6-methyl-2- phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amine (50 mg, 69.07 μmol, 23.75% yield) as white oil. ESI [M+H] = 624.3 12886058v1 Page 439 of 494Attorney Docket No.2019292-0022

[0589] Step 5: synthesis of (2-amino-4-((6-methyl-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H- imidazol-1-yl)methanol (384-F)

[0590] To a solution of 4-((6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-amine (50 mg, 69.07 μmol, 1 eq) in TFA (1 mL). The mixture was stirred at 25°C for 12 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a (2-amino-4-((6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H-imidazol-1-yl)methanol (50 mg, crude) as white solid. ESI [M+H] = 524.2

[0591] Step 6: synthesis of 4-((6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H-imidazol-2-amine (384)

[0592] To a solution of (2-amino-4-((6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H-imidazol-1-yl)methanol (50 mg, 95.50 μmol, 1 eq, crude from Step 5) in EtOH (2 mL) was added KOAc (93.72 mg, 954.98 μmol, 10 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (100 × 30 mm, um); flow rate: 25 mL / min; gradient: 20% – 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 4-((6-methyl-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-1-yl)methyl)-1H-imidazol-2-amine (7.8 mg, 14.24 μmol, 14.91% yield, 98.5% purity, FA salt) as white solid. ESI [M+H] = 494.1

[0593] 1H-NMR (400 MHz, CD3OD) δ = 8.54 (s, 1H), 7.30 - 7.13 (m, 4H), 7.12 - 7.00 (m, 3H), 6.97 - 6.85 (m, 1H), 6.32 (s, 1H), 5.04 (br d, J = 14.4 Hz, 1H), 4.37 (br d, J = 14.4 Hz, 1H), 4.29 - 4.19 (m, 1H), 4.08 (d, J = 14.0 Hz, 1H), 3.95 - 3.84 (m, 1H), 3.29 (br d, J = 2.8 Hz, 2H), 2.73 - 2.61 (m, 1H), 2.53 - 2.47 (m, 1H), 2.46 (s, 3H), 1.48 (br d, J = 7.2 Hz, 1H), 1.35 - 1.17 (m, 1H). 12886058v1 Page 440 of 494Attorney Docket No.2019292-0022

[0594] Example 1.34: Synthesis of 1-(1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)- 2,2,2-trifluoroethanone (349) and enantiomers (349-1 and 349-2)

[0595] p y - y . . p - -y - - y p py - , ,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (349-B)

[0596] From intermediate 349-A (300 mg, 1.02 mmol, 1 eq) and cyclopropylboronic acid (439.44 mg, 5.12 mmol, 5 eq), 349-B (230 mg, 904.20 μmol, 88.37% yield) was made using the same procedure described in Example 1.26 for production of 349-O. ESI [M+H] = 255.2

[0597] Step 2: Synthesis of tert-butyl 2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-2,3- dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (349-C)

[0598] To a mixture of 2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepine (220 mg, 864.88 μmol, 1 eq) in MeOH (3 mL) was added Boc2O (188.76 mg, 864.88 μmol, 198.69 μL, 1 eq) at 25°C, the reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1:0 to 3:1) to give tert-butyl 2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-2,3-dihydro- 12886058v1 Page 441 of 494Attorney Docket No.2019292-0022 1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (270 mg,761.67 μmol, 88.07% yield) as a yellow solid. ESI [M+H] = 355.2

[0599] Step 4: Synthesis of tert-butyl 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)- carboxylate (349-D)

[0600] From intermediate 349-C (260 mg, 733.46 μmol, 1 eq) and 1H-imidazole-4- carbaldehyde (352.38 mg, 3.67 mmol, 5 eq), 349-D (300 mg, 690.33 μmol, 94.12% yield) was made using the same procedure described in the reductive amination step in Example 1.1.

[0601] Step 5: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- 6-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (349-E)

[0602] The mixture of tert-butyl 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan- 1-yl)-6-cyclopropyl-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (280 mg, 644.31 μmol, 1 eq) in DCM (2 mL) and TFA (2 mL) was stirred at 25°C for 30 mins. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(1- bicyclo[1.1.1]pentanyl)-6-cyclopropyl-1-(1H-imidazol-4-ylmethyl)-2,3,4,5-tetrahydro-1,4- benzodiazepine (200 mg, crude, TFA) as a yellow solid. ESI [M+H] = 335.1

[0603] Step 6: Synthesis of 1-(1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1- yl)-6-cyclopropyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-2,2,2-trifluoroethanone (349)

[0604] Using the same procedure from Example 1.21, the title 349 (5 mg, 11.52 μmol, 16.76% yield, 99.2% purity) was made from 349-E (23 mg, 68.77 μmol, 1 eq) and TFAA (14.44 mg, 68.77 μmol, 9.56 μL, 1 eq), and purified by preparative HPLC (column: Phenomenex Luna C18100×30mm×3um;mobile phase: [H2O(0.2% FA)-ACN]; gradient:30%-70% B over 8.0 min). ESI [M+H] = 431.1

[0605] 1H NMR (400 MHz, DMSO-d6) δ = 7.93 (br d, J = 1.2 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.06 (br s, 1H), 6.74 (br d, J = 7.6 Hz, 1H), 5.45 - 4.82 (m, 1H), 4.59 - 4.38 (m, 2H), 3.57 - 3.40 (m, 3H), 2.50 - 2.17 (m, 3H), 1.82 - 1.62 (m, 4H), 1.60 - 1.45 (m, 2H), 1.01 - 0.86 (m, 2H), 0.79 - 0.38 (m, 2H). 12886058v1 Page 442 of 494Attorney Docket No.2019292-0022

[0606] Step 7: synthesis of (R)-1-(1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan- 1-yl)-6-cyclopropyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-2,2,2-trifluoroethanone and (S)-1-(1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-2,3- dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-2,2,2-trifluoroethanone

[0607] on 281 Semi- preparative HPLC system; Column: DAICEL CHIRALCEL OD(250mm×30mm,10um); Mobile phase: A for CO2 and B for EtOH(0.1% IPAm); Gradient: B%=10.00% isocratic elution mode; Flow rate: 60.00g / min; Monitor wavelength: 220&254nm; Column temperature: 40℃; System back pressure: 100 bar).

[0608] The stereochemistry is arbitrarily assigned:

[0609] Peak 1 (Rt = 3.257) 1-(1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1- yl)-6-cyclopropyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-2,2,2-trifluoroethanone (349- 1) (16.5 mg, 34.63 μmol, 7.77% yield, 100% purity, FA salt) was purified by preparative HPLC (column: Phenomenex luna C18100×40mm×3 um;mobile phase: [H2O(0.2% FA)-ACN]; gradient:20%-60% B over 8.0 min). ESI [M+H] = 431.1

[0610] 1H NMR (400 MHz, DMSO-d6) δ = 7.52 (s, 1H), 7.23 - 7.08 (m, 2H), 6.94 - 6.79 (m, 1H), 6.74 d, J = 5.4 Hz, 1H), 5.42 - 4.86 (m, 1H), 4.56 - 4.34 (m, 3H), 3.73 - 3.50 (m, 1H), 3.35 - 2.92 (m, 2H), 2.49 - 2.13 (m, 2H), 1.82 - 1.71 (m, 2H), 1.68 (br d, J = 8.4 Hz, 2H), 1.53 (br d, J = 7.2 Hz, 2H), 1.05 - 0.84 (m, 2H), 0.82 - 0.40 (m, 2H).

[0611] Peak 2 (Rt = 4.196) 1-(1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1- yl)-6-cyclopropyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-2,2,2-trifluoroethanone (349- 2) (18.1 mg, 42.05 μmol, 60.33% yield, 100.0% purity). ESI [M+H] = 431.1

[0612] 1H NMR (400 MHz, DMSO-d6) δ = 7.50 (br s, 1H), 7.25 - 7.09 (m, 2H), 6.94 - 6.65 (m, 2H), 5.38 - 4.86 (m, 1H), 4.62 - 4.28 (m, 3H), 3.78 - 3.49 (m, 1H), 3.38 - 2.78 (m, 2H), 12886058v1 Page 443 of 494Attorney Docket No.2019292-0022 2.50 - 2.15 (m, 2H), 1.80 - 1.60 (m, 4H), 1.51 (br d, J = 7.2 Hz, 2H), 1.00 - 0.82 (m, 2H), 0.79 - 0.37 (m, 2H).

[0613] Compounds in the following table were prepared according to procedures analogous to preparation of Compound 349, 349-1, and 349-2 in Example 1.34, using analogous starting materials and / or intermediates.

[0614] Difluoroacetic anhydride was used rather than 394 TFAA in the last step. O- = br z, z, br m, .2

[0615] Example 1.35: Synthesis of 1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-N-methyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-7-amine (387) and 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan- 1-yl)-N,N-dimethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin- 7-amine (388) 12886058v1 Page 444 of 494Attorney Docket No.2019292-0022 [061((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)(methyl)carbamate (387-B)

[0617] To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-7-bromo-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (100 mg, 235.15 μmol, 1 eq) and tert-butyl methylcarbamate (154.22 mg, 1.18 mmol, 5 eq) in dioxane (3 mL) was added Xphos (22.42 mg, 47.03 μmol, 0.2 eq) and Pd2(dba)3 (21.53 mg, 23.51 μmol, 0.1 eq) and Cs2CO3 (153.23 mg, 470.30 μmol, 2 eq). The mixture was stirred at 90°C for 12 hrs under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 3:1) to give tert-butyl (2-(bicyclo[1.1.1]pentan-1-yl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)(methyl)carbamate (75 mg, 157.72 μmol, 67.07% yield) as yellow solid. ESI [M+H] = 476.2

[0618] Step 2: synthesis of tert-butyl (1-((1H-imidazol-4-yl)methyl)-2- (bicyclo[1.1.1]pentan-1-yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-7-yl)(methyl)carbamate (387-C)

[0619] From intermediate 387-B (70 mg, 147.21 μmol, 1 eq) and 1H-imidazole-5- carbaldehyde (70.72 mg, 736.03 μmol, 5 eq), 387-C (70 mg, 125.99 μmol, 85.59% yield) was 12886058v1 Page 445 of 494Attorney Docket No.2019292-0022 made using the same procedure described in Example 1.1 for the reductive amination reaction. ESI [M+H] = 556.3

[0620] Step 3: synthesis of 1-((1H-imidazol-4-yl)methyl)-2-(bicyclo[1.1.1]pentan-1-yl)- N-methyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-amine (387) [0...

Claims

Attorney Docket No.2019292-0022 CLAIMS 1. A compound of formula I: or a pharmaceutically acceptable salt tL1is selected from a bond, -C(O)-, or C1-4alkylene; RaN ,, , , Rais selected from C1-4 aliphatic or a 3- to 5-membered saturated carbocyclic ring; L2is selected from a bond or a C1-4alkylene wherein one methylene unit is optionally replaced by -O- or -C(O)-; R2is selected from C1-6 aliphatic or Cy, wherein R2is substituted with 0-3 instances of Rw; Cy is selected from a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 8- to 10-membered saturated, partially unsaturated, or aryl bicyclic carbocyclic ring, a 7- to 9-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-to 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms 12886058v1 Page 483 of 494Attorney Docket No.2019292-0022 independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3is selected from ; each R4is indepen (R)2, and an optionally substituted group selected from C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10- membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5is selected from C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8- membered bridged bicyclic carbocyclic ring, phenyl, a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 7- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is substituted with 0-3 instances of Rz; each R6is independently hydrogen or C1-6aliphatic; each Rwis independently selected from halogen, cyano, oxo, -OR, -SR, -N(R)2, -C(O)R, - C(O)OR, -C(O)N(R)2, -OC(O)R, -N(R)C(O)R, and an optionally substituted group selected from C1-6aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 12886058v1 Page 484 of 494Attorney Docket No.2019292-0022 Rxis selected from hydrogen, halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a 3- to 6-membered saturated carbocyclic ring, phenyl, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: Rxand R4optionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ryis independently selected from halogen, -N(R)2, and an optionally substituted group selected from C1-4 alkyl and a 3- to 6-membered saturated carbocyclic ring; each Rzis independently selected from halogen, cyano, -OR, and optionally substituted C1-4alkyl; each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; and n is 0-2.

2. The compound according to claim 1, wherein the compound is12886058v1 Page 485 of 494Attorney Docket No.2019292-0022 or apharmaceutically acceptable salt thereof, wherein: Rxis selected from halogen, cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, phenyl, and 5- to 6-membered heteroaryl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

3. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof, wherein: 12886058v1 Page 486 of 494Attorney Docket No.2019292-0022 each R4is independently selected from cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: R4and Rxoptionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1-3.

4. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof, wherein: each R4is independently selected from cyano, -OR, -N(R)2, and an optionally substituted group selected from C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 6- 12886058v1 Page 487 of 494Attorney Docket No.2019292-0022 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: R4and Rxoptionally cyclize to form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound according to claim 1, wherein the compound is12886058v1 Page 488 of 494Attorney Docket No.2019292-0022 or a phaaceu ca y accepa e sa eeo, wee : R1is selected from12886058v1 Page 489 of 494Attorney Docket No.2019292-0022 or a phy p , L2is selected from -CH2-, -CH2O-, -CH2C(O)-, -CH2CH2CH2-, and -CH2CH2O-.

7. The compound according to claim 1, wherein the compound is selected from12886058v1 Page 490 of 494Attorney Docket No.2019292-0022or a pharmaceutically acceptable salt thereof. 12886058v1 Page 491 of 494Attorney Docket No.2019292-0022 8. The compound according to any one of claims 1-4, 6, and 7, wherein R1is selected from . o2ne of claims 1-5 and 7, wherein L is a bond.

10. The compound according to any one of claims 1-5 and 7, wherein L2is -CH2CH2-.

11. The compound according to any one of claims 1-10, wherein each R4is independently selected from halogen, cyano, -CF3, -CHF2, -OCF3, -OMe, and cyclopropyl.

12. The compound according to any one of claims 1-11, wherein Cy is selected from ,. , .

14. The compound according to claim 1, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof.

16. A method of inhibiting F-ATP hydrolase, the method comprising contacting a biological sample with a compound of formula I, or a pharmaceutically acceptable salt thereof.

17. A method of treating a disease or condition associated with F-ATP hydrolase comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof 18. The method according to claim 17, wherein the disease or condition associated with F- ATP hydrolase is selected from Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic 12886058v1 Page 492 of 494Attorney Docket No.2019292-0022 lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia.

19. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15, for use in medicine.

20. Use of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15, in inhibiting F-ATP hydrolase in a biological sample, wherein the use is in vitro.

21. Use of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15, in treating a disease or condition associated with F-ATP hydrolase.

22. Use of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15, in the manufacture of a medicament for treating a disease or condition associated with F-ATP hydrolase.

23. The use according to claim 21 or 22, wherein the disease or condition is selected from Alzheimer's disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), cancer, diabetes, stroke, and cardiac ischemia. 12886058v1 Page 493 of 494

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